Patent Application
20230338539
The invention relates to methods and systems for treating cell proliferation disorders that provide better distinction between normal, healthy cells and those cells suffering a cell proliferation disorder, disease or condition, and particularly the treatment of cell proliferation disorders within the patient that are difficult to access or difficult to treat due to their location in the patient.
Psoralens are naturally occurring compounds found in plants (furocoumarin family) with anti-cancer and immunogenic properties. Psoralens freely penetrate the phospholipid cellular bilayer membranes and intercalate into DNA between nucleic acid pyrimidines, where the psoralens are biologically inert (unless photo-activated) and ultimately excreted within 24 hours. However psoralens are photo-reactive, acquiring potent cytotoxicity after ‘activation’ by ultra-violet (UVA) light. When photo-activated, psoralens form mono-adducts and di-adducts with DNA leading to marked tumor cytotoxicity and apoptosis. Cell signaling events in response to DNA damage include up-regulation of p21waf/CiP and p53 activation, with mitochondrial induced cytochrome c release and consequent cell death. Photo-activated psoralen can also induce apoptosis by blocking oncogenic receptor tyrosine kinase signaling, and can affect immunogenicity and photochemical modification of a range of cellular proteins in treated cells.
Importantly, psoralen can promote a strong long-term clinical response, as observed in the treatment of cutaneous T Cell Lymphoma utilizing extracorporeal photopheresis (ECP). In ECP malignant CTCL cells (removed from a patient) are irradiated with ultraviolet A (UVA) light in the presence of psoralen, and then re-administered to the patient. Remarkably, complete long term responses over many decades have been observed in a sub-set of patients, even though only a small fraction of malignant cells were treated. In addition to ECP, psoralens have also found wide clinical application through PUVA treatment of proliferative skin disorders and cancer including psoriasis, vitiligo, mycosis fungoides, and melanoma. Together these results are consistent with an immunogenic role of psoralen in a number of cancers and proliferative disorders.
The cytotoxic and immunogenic effects of psoralen are often attributed to psoralen mediated photoadduct DNA damage. A principle mechanism underlying the long-term immunogenic clinical response likely derives from psoralen induced tumor cell cytotoxicity and uptake of the apoptotic cells by immature dendritic cells, in the presence of inflammatory cytokines. However, photochemical modification of proteins and other cellular components can also impact the antigenicity and potential immunogenicity of treated cells.
In one embodiment, there is provided a method for treating a human or animal body having a tumor that is difficult to access or difficult to treat due to its location within the subject. The method involves removing a sample of tumor tissue from the difficult to access/treat tumor; implanting the sample of tumor tissue to a site in the subject that is readily accessible, in such a manner that the implanted tumor tissue forms an induced metastatic tumor; infusing the induced metastatic tumor with a photoactivatable drug; and generating an activation energy in situ (i.e. in vivo) in the subject sufficient to activate the photoactivatable drug, thereby activating the photoactivatable drug to treat the induced metastatic tumor and create an autovaccine response, whereby the autovaccine response further treats the difficult to access/treat tumor site.
In one embodiment, there is provided a system (and an associated method) for treating a human or animal body. The system has a photoactivatable drug for treating a first diseased site, a first pharmaceutically acceptable carrier, optionally including one or more phosphorescent or fluorescent agents which are capable of emitting an activation energy into the body which activates the photoactivatable drug, a first device which infuses the first diseased site with a photoactivatable drug and the first pharmaceutically acceptable carrier, a source of energy generation in situ in the human or animal body sufficient to activate the photoactivatable drug, which can optionally be a first energy source which irradiates the diseased site with an initiation energy to thereby initiate emission of the activation energy into the body from the optional one or more phosphorescent or fluorescent agents, and a supplemental treatment device which administers one or both of a therapeutic drug or radiation to the body at a second diseased site or the first diseased site, to provide an immune system stimulation in the body.
In one embodiment, there is provided a method for treating a diseased sited in a human or animal body. The method includes infusing the diseased site with a photoactivatable drug, injecting in the diseased site a pharmaceutical carrier, optionally including one or more phosphorescent or fluorescent agents which are capable of emitting an activation energy in the human or animal body for activating the photoactivatable drug, generating energy in situ in the human or animal body sufficient to activate the photoactivatable drug, preferably by applying an initiation energy to the diseased site, whereby the initiation energy is absorbed by the optional one or more phosphorescent or fluorescent agents, which emit the activation energy inside the diseased site (thereby activating the photoactivatable drug), and administering a supplemental treatment to a second diseased site or the first diseased site.
It is to be understood that both the foregoing general description of the invention and the following detailed description are exemplary, but are not restrictive of the invention.
A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings, wherein:
While much of the discussion below focuses on the use of psoralen compounds as the photoactivatable drug, the present invention can use any desired photoactivatable cancer drug, including but not limited to those disclosed in the related applications noted and incorporated by reference above.
The present invention relates to a method for treating a human or animal body having a tumor that is difficult to access or difficult to treat due to its location within the subject. The method comprises removing a sample of tumor tissue from the difficult to access/treat tumor; implanting the sample of tumor tissue to a site in the subject that is readily accessible, in such a manner that the implanted tumor tissue forms an induced metastatic tumor; infusing the induced metastatic tumor with a photoactivatable drug; and generating an activation energy in situ (i.e. in vivo) in the subject sufficient to activate the photoactivatable drug, thereby activating the photoactivatable drug to treat the induced metastatic tumor and create an autovaccine response, whereby the autovaccine response further treats the difficult to access/treat tumor site.
The difficult to access/treat tumor may be a primary tumor site, or a metastatic tumor site within the subject. Within the context of the present invention, a “difficult to access/treat tumor” is a tumor that is either located in a site within the subject that makes access for treatment too difficult to accomplish safely, or that is in a region of the subject in which the infusing of the photoactivatable drug into the difficult to access/treat tumor would create an undue and/or dangerous condition within the subject, such as undue and/or dangerous pressure on a nerve, blood vessel, anatomically dangerous body element, and/or organ of the subject.
Patient-derived xenograft tumors into mice are a common practice in the generation of tumors in mice for in vivo cancer treatment studies. A key to making such transplanted tumors possible is the use of immunosuppressed mice, in order to avoid having the mouse's immune system attack the human tumor cells. In the present invention, a similar xenograft technique could be used to remove tumor cells from a tumor located in a difficult to access/treat area of a patient, and then implant into a remote area of the same patient in order to create an induced metastatic tumor in a more readily accessible location in the patient. Since the cancer cells would be getting implanted within the same subject from which they originated, there would be no need to create immunosuppression, as the subject's immune system would already be accustomed to the tumor cells (and in fact would be essentially ignoring those cells due to cancer cells' ability to “hide” from the immune system through systems such as PD-L1/PD-1 interactions and other mechanisms). However, such immunosuppression treatments can be performed in conjunction with the present invention if deemed to be medically appropriate.
Despite the positive clinical results noted above in extracorporeal applications, use of psoralen traditionally has been restricted to superficial or extra-corporeal applications because of the inability of UVA light to penetrate into tissue (maximum penetration depth <1 mm). In one embodiment of this invention, X-PACT (X-ray Psoralen Activated Cancer Therapy) is utilized to extend psoralen therapy to a wide range of solid tumors, at various depths in tissue. In X-PACT, psoralen is combined with phosphors that absorb and down-convert x-ray energy to re-radiate as UV light or other light such as visible light which can activate a photoactivatable drug at a diseased site. In one embodiment of this invention, relatively low x-ray doses (˜1 Gy) are sufficient to achieve photo-activation, greatly reducing the risks of normal tissue damage from radiation.
Accordingly, the present invention sets forth a novel method of treating cell proliferation disorders that is effective, specific, and has few side-effects. Those cells suffering from a cell proliferation disorder are referred to herein as the target cells. In one embodiment of the invention, treatment for cell proliferation disorders, including solid tumors, chemically binds cellular nucleic acids, including but not limited to, the DNA or mitochondrial DNA or RNA of the target cells. For example, a photoactivatable agent, such as a psoralen or a psoralen derivative, is exposed in situ to an energy source (e.g., x-rays) capable of activating energy modulation agents which emit light to activate photoactivatable agents such as psoralen or coumarin.
In one embodiment of the invention, X-PACT activates psoralen with UV light from non-tethered phosphors (co-incubated at the target cell with psoralen). The co-incubation process in one embodiment of the invention involves promoting the presence of psoralen (or other photoactivatable drugs) and the phosphor (energy converters) at a diseased site at the time of the x-ray exposure (or electron beam exposure). Of these two components (the psoralen component and the phosphor component), the psoralen component is more readily passed from the diseased site while the phosphor tends to be retained at the diseased site longer. Accordingly, in one embodiment of the invention, after a coinjection of a phosphor and psoralen mixture, the x-ray exposure would follow within 0.5 to 20 minutes, or 1 to 10 minutes, or 3 to 5 minutes or in general within 20 minutes. Longer times maybe used but at the potential loss in concentration of one of these components from the diseased site. In another embodiment of the invention, a separate injection of psoralen may be provided after the coinjection of the phosphor and psoralen mixture. In another embodiment of the invention, a separate injection of psoralen may be provided after an injection of phosphor alone into the diseased site. In these embodiments with separate psoralen injections, the x-ray exposure would follow within 0.5 to 20 minutes, or 1 to 10 minutes, or 3 to 5 minutes or in general within 20 minutes. Longer times maybe used but at the potential loss in concentration of one of these components from the diseased site.
As noted above, the phosphors absorb x-rays and re-radiate (e.g., phosphoresce) at UV wavelengths. Described below is the efficacy of X-PACT in both in-vitro and in-vivo settings. In-vitro studies utilized breast (4T1), glioma (CT2A) and sarcoma (KP15B8) cell lines. Cells were exposed to X-PACT treatments where the concentrations of drug (e.g., an injection of psoralen and phosphor) were varied as well as the radiation parameters (energy, dose, and dose rate). Efficacy was evaluated primarily using flow cell cytometry. A multi-variable regression on 36 independent irradiation experiments revealed neither psoralen nor phosphor alone had a strong effect on cytotoxicity (Annexin V signal). However, when combined (e.g., an injection of psoralen and phosphor) in X-PACT, a significant increase was observed (p<0.0001), with 82% cytotoxicity compared to just 31% in treated but un-irradiated controls. In-vivo work, utilized X-PACT on BALBc mice with syngeneic 4T1 tumors was conducted, including control arms for X-PACT components. The results demonstrate a pronounced tumor growth delay compared to saline controls (42% reduction at 25 days, p=0.0002).
Accordingly, in one embodiment of the invention, the dose of x-rays or electron beam to the target site of the tumor produces a cytotoxicity of greater than 20%, greater than 30%, greater than 50%, greater than 60%, greater than 70%, greater than 80%. In one embodiment of the invention, the dose of x-rays or electrons to the target site of the tumor produces a cytotoxicity between 20% and 100%, between 40% and 95%, between 60% and 90%, or between 70% and 80%. The cytotoxicity can be categorized into components involving 1) the toxicity of the phosphor itself without psoralen and 2) the apoptosis-induced cell death generated by UV activation of the psoralen. The apoptosis-induced cytotoxicity can range from greater than 20%, greater than 30%, greater than 50%, greater than 60%, greater than 70%, greater than 80%. In one embodiment of the invention, the apoptosis-induced cytotoxicity can range between 20% and 100%, between 40% and 95%, between 60% and 90%, or between 70% and 80%.
Medical applications of ionizing radiation have traditionally associated with diagnostic imaging and radiation therapy. Diagnostic imaging (planar x-rays and x-ray-CT) utilizes low energy x-rays, in order to obtain better soft-tissue—bone contrast, and lower dose exposure to the patient. In radiation therapy, higher energy MV radiation (6 MV and higher) is typically used to achieve skin sparing. The X-PACT therapeutic paradigm, in one embodiment of this invention, departs from these conventions by utilizing low energy radiation (and low doses) to initiate phosphorescence of UV light in-situ, in potentially deep seated lesions, for the purpose of activating a potent anti-tumor photo-bio-therapeutic (psoralen). In one embodiment of the invention, X-PACT produces measurable anti-tumor response.
In general, the invention described here provides for a system (and an associated method) for treating a human or animal body. The system has a photoactivatable drug (for treating a first diseased site. The photoactivatable drug can e.g., psoralen or coumarin or a derivative thereof or a photoactivatable drug selected from psoralens, pyrene cholesteryloleate, acridine, porphyrin, fluorescein, rhodamine, 16-diazorcortisone, ethidium, transition metal complexes of bleomycin, transition metal complexes of deglycobleomycin organoplatinum complexes, alloxazines, vitamin Ks, vitamin L, vitamin metabolites, vitamin precursors, naphthoquinones, naphthalenes, naphthols and derivatives thereof having planar molecular conformations, porphorinporphyrins, dyes and phenothiazine derivatives, coumarins, quinolones, quinones, and anthroquinones. The system has a first pharmaceutically acceptable carrier, which optionally includes one or more phosphorescent or fluorescent agents, such as when using an applied energy of x-rays or other high energy ionizing type radiation (gamma rays, electron beams, proton beams, etc) (e.g., sterile compositions including for example Y2O3; ZnS; ZnSe;MgS; CaS; Mn, Er ZnSe; Mn, Er MgS; Mn, Er CaS; Mn, Er ZnS; Mn,Yb ZnSe; Mn,Yb MgS; Mn, Yb CaS; Mn,Yb ZnS:Tb3+, Er3+; ZnS:Tb3+; Y2O3:Tb3+; Y2O3:Tb3+, Er3+; ZnS:Mn2+; ZnS:Mn,Er3+; CaWO4, YaTO4, YaTO4:Nb, BaSO4:Eu, La2O2S:Tb, BaSi2O5:Pb, NaI(Tl), CsI(Tl), CsI(Na), CsI(pure), CsF, KI(Tl), LiI(Eu), BaF2, CaF, CaF2(Eu), ZnS(Ag), CaWO4, CdWO4, YAG(Ce) (Y3Al5O12(Ce)), 3Ca3(PO4)2. Ca(Fl, Cl)2: Sb3+, Mn2+, BGO bismuth germanate, GSO gadolinium oxyorthosilicate, LSO lutetium oxyorthosilicate, LaCl3(Ce), LaBr3(Ce), LaPO4; Ce, Tb (doped), Zn2SiO4:Mn with Mn preferably doped between 0.05-10%, and YTaO4. The phosphorescent or fluorescent agents are capable of emitting an activation energy into the body which activates the photoactivatable drug. The system has a first device which infuses the first diseased site with a photoactivatable drug and the first pharmaceutically acceptable carrier, a source of energy generation in situ in the human or animal body sufficient to activate the photoactivatable drug, which can preferably be a first energy source which irradiates the diseased site with an initiation energy to thereby initiate emission of the activation energy into the body from the optional one or more phosphorescent or fluorescent agents to thereby activate the photoactivatable drug, and a supplemental treatment device which administers one or both of a therapeutic drug or radiation to the body at a second diseased site or the first diseased site, for example to provide an immune system stimulation in the body.
In the context of the present invention, the generating the activation energy in situ can take many forms, including, but not limited to, (i) administering one or more energy modulation agents and applying an initiation energy to the subject that is converted in vivo to produce the activation energy within the body, (ii) activating a long lived or persistent phosphor material ex vivo then administering it to the subject at the site of the implanted tumor to activate the photoactivable drug, which can be administered prior to, simultaneously or after, administration of the activated long lived or persistent phosphor material, (iii) use of a microdevice that generates the activation energy such as through LED's, which can be triggered either in the body or outside the body prior to administration, (iv) use of an upconverting gas containing capsule that can generate a light emitting plasma upon triggering, which can be triggered either within the body or outside the body prior to administration, etc. Such activation energy generation methods are described in various of the above identified related applications, the relevant portions of which are incorporated by reference.
The source of energy generation in situ in the human or animal body can be any of a variety of sources or methods of generating the necessary energy in vivo in the human or animal body, including, but not limited to, use of externally applied x-rays to generate Cherenkov UV/vis emissions within the body, use of micro or nano devices capable of generating UV light within the body, use of chemical energy sources such as chemiluminescence, phosphorescence, and bioluminescense agents, and application of external radiation (such as x-ray, gamma ray, electron beam, proton beam, infrared, microwave, etc) which interacts with one or more administered phophorescent or fluorescent agents within the body. Ultimately, any desired method can be used to generate the activation energy within the body of the subject, including but not limited to those methods above and as detailed in the various related applications mentioned and incorporated by reference at the beginning of this application.
Described below are various embodiments of the present invention.
In one embodiment of the present X-PACT therapy, psoralen is activated by light generated in-situ from phosphor particles undergoing x-ray stimulated phosphorescence. The emission profiles from the phosphor preferably overlap the absorption/activation wavelengths of psoralen. While nano-scintillating particles have been developed which were tethered to psoralen, in one embodiment of this invention, a treatment system does not necessarily (but could) use tethered phosphors. In the embodiment without tethering, the functionally of the tethering is replaced by the above-noted co-incubation of psoralen and phosphor particles at the target or diseased site, as described above. The untethered psoralen benefits from a high degree of mobility and greater intercalation with DNA. In one embodiment, phosphors of different particle size and distribution are utilized or specific absorption and emission spectra.
In one embodiment of the invention, the phosphors shown in
Both commercially available UVADEX (formulated 8-MOP psoralen) and pure 8-MOP were used as alternative formulations of psoralen agents. Prior work has shown that the number of DNA photo-adducts is a linear function of the product of 8-MOP (psoralen) concentration and light-exposure. UVADEX and 8-MOP concentrations in the range 10-60 μM were evaluated. The stability of drug in the presence of phosphors was investigated using standard UV-Vis spectroscopy and HPLC-MS.
Guava Annexin V flow cell cytometry was used to quantify cytotoxicity in 3 murine tumor cell lines (breast-4T1, glioma-CT2A, and sarcoma KP15B8). In-vitro X-PACT studies were conducted on cells prepared in the following manner. Cells were incubated in appropriate growing media and buffers before being trypsinized and plated evenly onto twelve (12) well plates for 24 hours. About 20 minutes prior to X-PACT irradiation, the wells of each plate were exposed to the following combinations of additives: (1) control-cells only with no additives, (2) UVADEX only, (3) phosphors only, (4) UVADEX+phosphors. Each plate had twelve (12) wells with three wells for each of the four treatment arms. The plates were then irradiated with x-rays by placing the plate at a known distance from the x-ray source (e.g., 50 cm). After irradiation the cells were incubated on the plate for 48 hours prior to performing flow cytometry. For compatibility with 96-well Guava Nexin® assay, the remaining cells were again trypsinized (after the 48 hour incubation) and plated onto a 96-well plate. The phosphors used in this evaluation were designated as NP 200 and GTP 4300. These phosphors have the following elemental compositions, as shown in Table 1 below:
GTP 4300=Ca, F, Cl, PO4, (96-99%)
Mn (1-3%) Sb (<1%)
Zn2SiO4:Mn with Mn doped between 0.05-10%.)
Fractional kill: Added cell kill by the combination of Psoralen and phosphor and X-Ray
In one embodiment of the invention, the phosphors are mixed in combination at a ratio of 2 parts by weight of GTP 4300 for every one part by weight of (Zn2SiO4:Mn).
X-ray stimulated emission from this combination of phosphors was taken from the following slurry using the following procedures
Acetic acid diluted in di-ionized water at a rate of 1:10 by weight or by volume was prepared. A total of 2 mL of the diluted acetic acid solution was added to 0.3 grams of the combined phosphors. The slurry hence formed was stirred using a vortex mixer for at least 60 sec. The high viscosity slurry exhibits paste-like behavior from a viscosity stand point. The test tube containing the slurry was then set inside an X-Ray chamber to be exposed to X-Ray energy radiation produced by using a 6 mA beam at a voltage of 125 kV. The test tube was placed at a distance from the X-Ray source of ˜20 cm. The fiber optic probe of a photo-spectrometer feeding to an ICCD camera was inserted inside the tube and was brought to a close proximity to the pasty slurry at a distance of 2 mm approximately. The fiber probe was then fixed in place using an adhesive tape. The X-Ray energy was turned on and the emission out of the slurry was collected.
Several emissions were collected. The slurry was found to emit both in the visible and the UV range as illustrated in
Regardless of phosphor, the following injections shown in Table 2 were illustrative of the concentration used as a function of the measured or predicted tumor volume (or the calculated volume of the diseased site). In these evaluations, vials of sterilized phosphor were mixed with UVADEX™ (100 μg/mL 8-MOP) as the sole diluent.
A range of x-ray activation protocols were investigated to determine X-PACT cytotoxic efficacy in relation to x-ray energy (kVp), total dose, and dose-rate. kVp beam energies ranging between 80 and 100 kV were investigated. kV beams were obtained from various x-ray generating equipment, including orthovoltage units, standard diagnostic radiographic, fluoroscopic, and cone-beam computed tomography (CBCT) systems. The primary kV x-ray source was a Varian on-board-imaging x-ray source commonly found on Varian medical linear accelerators. In one embodiment of the invention, the x-ray dose may be relatively low (˜1 Gy/fraction for 9 fractions). This low-dose requirement (as compared to conventional radiation therapy) provides in this embodiment safe delivery of the radiation component of X-PACT. In this embodiment, normal tissue tolerances (skin, bone) can be kept within tolerance doses. In one embodiment of the invention, the x-ray doses can specifically range from 0.2-2 Gy, with preferred doses of 0.5-1 Gy.
For x-ray irradiation, the well plates were positioned at a set distance (e.g., typically 50 cm) from the x-ray source on a solid water phantom and the position of the well plates within the x-ray beam was verified by low dose kV imaging Irradiations were typically delivered in a “radiograph” mode; where multiple pulses of a set mA (e.g., typically 200 mA) and ms (e.g., typically 800 ms) and pulses were delivered e.g., every 5-15 seconds. In one embodiment, the radiation can be delivered in a “pulsed fluoroscopy mode” (e.g., at 10 Hz) at the maximum mA setting. In one embodiment, kVp settings of 80 and 100 kVp (and ranges in between) with no added filtration in the beam (Half Value Layer=3.3 and 3.9 mm Al, respectively) are suitable for the invention. Higher kVps and lower kVps can be used.
Two primary flow cytometry metrics were used to evaluate the X-PACT treatments, both determined at 48 h after X-PACT treatment. Cells plated in 12-well plates, where individual wells in each plate may receive different experimental conditions (e.g. psoralen concentration), but the same x-ray dose (i.e. all wells in a given plate receive the same x-ray dose). The first metric is metabolically viable cell count (or cell viability) determined from the number of whole cells per well as determined using forward scattering (FSC). For each well, the cell viability was normalized to that in a control well on the same plate, which had no additives but did receive the radiation of that plate. (All wells on a given plate receive the same dose.) The second metric is Annexin V (+) signal, which is the fraction of the metabolically viable cells which expressed a positive Annexin V signal as determined by flow cell cytometry, and include any cells advancing toward early or late apoptotic cell death. The Annexin V (+) signal was corrected by subtracting the control signal from the “no-additive” well on the same plate. For both metrics, correcting for the control on the same plate, minimizes any potential inter-plate systematic bias associated with plating constancy or Annexin V gating parameters. The majority of plots in the results either use metabolically viable cell count or Annexin V(+) signal as defined by Krysko, Vanden Berghe, D'Herde, & Vandenabeele, 2008.
Metabolic cell viability was also assessed visually using Methylene blue staining and ATP-induced Luminescence imaging (Cell-Titer-Glo® Luminescence Cell Viability Assay). The luminescence imaging permitted investigation of the cytotoxicity of psoralen activated directly with a UV lamp, and in the absence of phosphors and x-ray radiation.
Several statistical analyses were evaluated, including unequal variance two-sample t-tests, Analysis of Variance (ANOVA), and multi-variable regression. The unequal variance two-sample t-test tests the null hypothesis that the means of observations (e.g. viable cells, Annexin V signal) in two different populations are equal. The p-value gives the probability that the observed difference occurred by chance. The lower the p-value, the less likely the observed difference occurred by chance. Multi-variable regression was used to test the null hypothesis that psoralen and phosphor had no effect on Annexin V (+) signal and to test if there is a first-order interaction between the two therapeutic elements. Non-parametric statistical analysis were also evaluated for each test, and showed consistent results.
The results of statistical analyses were classified in four categories: weakly significant, moderately significant, significant, and very significant. A single asterisk indicates weakly significant statistics (*), where the p-value is in the range 0.01<p<0.05. Double asterisks indicate moderately significant statistics (**), where 0.001<p<0.01. Triple asterisks indicate significant statistics (***), where 0.0001<p<0.001. Quadruple asterisks indicate very significant statistics (****), where p <0.0001. This convention will be used throughout the remaining description.
An in-vivo trial was conducted for preliminary evaluation of X-PACT administered to syngeneic 4T1-HER2 tumors grown on BALB/c mice. There were 4 arms of the trial: (1) saline only (control), (2) phosphors alone with x-ray, (3) psoralen (AMT) alone with x-ray, and (4) full X-PACT treatment including both phosphor and psoralen and x-ray irradiation. X-PACT treatments were given in 3 fractions per week, to a total of 6 fractions. In arms 2-3 a consistent x-ray irradiation technique was used (about 1.2 Gy delivered at 75 kVp by 30 mA in 3 minutes) with 100 μg of phosphor, and 5 μM psoralen (AMT) (with μM representing micromolar). 0.5 Million tumor cells were injected per mouse. There were 6-8 mice per arm, and the study was repeated a second time, yielding effective sample sizes of 12-16.
The relative effectiveness of UV activated psoralen on three (3) independent cell lines is shown in
Annexin V (+)=A+B*[8-MOP Conc]+C*[P Conc]+D*[8-MOP Conc.]*[P Conc.] Eq 1
The results from the in-vivo irradiation of syngeneic 4T1-HER2 tumors are shown in
In the 4T1 in-vitro cell viability analysis (
In the 4T1 in-vitro apoptotic analysis (
When X-PACT and components were evaluated on 3 different cell lines (
The most comprehensive in-vitro 4T1 analysis (
Another in-vitro study investigated whether changing x-ray energy affected X-PACT efficacy (
X-PACT therapy seeks to engage the anti-tumor properties of psoralens activated in-situ, in solid tumors, with the potential for engaging a long term response. The data presented in
Accordingly, in one embodiment of the invention, depending on the type of tumor being treated, the day-25 tumor volume change can range from stable (no growth), to a reduction of at least 10%, at least 20%, at least 30%, at least 40%, to complete dissolution of the tumor, or any values in between.
The above-discussed medical treatments can be implemented by the system shown in
Referring to
In preferred embodiments, the initiation energy source may be a linear accelerator equipped with image guided computer-control capability to deliver a precisely calibrated beam of radiation to a pre-selected coordinate. One example of such linear accelerators is the SmartBeam™ IMRT (intensity modulated radiation therapy) system from Varian medical systems (Varian Medical Systems, Inc., Palo Alto, Calif.). In one embodiment of the invention, the initiation energy source comprises an x-ray source configured to generate x-rays from a peak applied cathode voltage at or below 300 kVp, at or below 200 kVp, at or below 120 kVp, at or below 105 kVp, at or below 80 kVp, at or below 70 kVp, at or below 60 kVp, at or below 50 kVp, at or below 40 kVp, at or below 30 kVp, at or below 20 kVp, at or below 10 kVp, or at or below 5 kVp.
In one embodiment of the invention, besides the YTaO4, noted above, other energy modulation agents can include phosphors were obtained from the following sources. “Ruby Red” obtained from Voltarc, Masonlite & Kulka, Orange, CT, and referred to as “Neo Ruby”; “Flamingo Red” obtained from EGL Lighting, Berkeley Heights, NJ and referred to as “Flamingo”; “Green” obtained from EGL Lighting, Berkeley Heights, NJ and referred to as “Tropic Green”; “Orange” obtained from Voltarc, Masonlite & Kulka, Orange, CT, and referred to as “Majestic Orange”; “Yellow” obtained from Voltarc, Masonlite & Kulka, Orange, CT, and referred to as “Clear Bright Yellow.” The “BP” phosphors are shown in detail below:
The “BP” phosphors are available from PhosphorTech Corporation of Kennesaw, Ga, from BASF Corporation, or from Phosphor Technology Ltd, Norton Park, Norton Road Stevenage, Herts, SG1 2BB, England.
Other useful energy modulation agents include semiconductor materials including for example TiO2, ZnO, and Fe2O3 which are biocompatible, and CdTe and CdSe which would preferably be encapsulated because of their expected toxicity. Other useful energy modulation agents include ZnS, CaS, BaS, SrS and Y2O3 which are less toxic. Other suitable energy modulation agents which would seem the most biocompatible are zinc sulfide, ZnS:Mn2+, ferric oxide, titanium oxide, zinc oxide, zinc oxide containing small amounts of Al2O3 and AgI nanoclusters encapsulated in zeolite. For non-medical applications, where toxicity may not be as critical a concern, the following materials (as well as those listed elsewhere) are considered suitable: lanthanum and gadolinium oxyhalides activated with thulium; Er3+ doped BaTiO3 nanoparticles, Yb+ doped CsMnCl3 and RbMnCl3, BaFBr:Eu2+ nanoparticles, cesium iodide, bismuth germanate, cadmium tungstate, and CsBr doped with divalent Eu. Table 4 below provides a list of various useful energy modulation agents
In various embodiments of the invention, the following luminescent polymers are also suitable as energy modulation agents: poly(phenylene ethynylene), poly(phenylene vinylene), poly(p-phenylene), poly(thiophene), poly(pyridyl vinylene), poly(pyrrole), poly(acetylene), poly(vinyl carbazole), poly(fluorenes), and the like, as well as copolymers and/or derivatives thereof.
As a non-limiting list, the following are suitable energy modulation agents: Y2O3; ZnS; ZnSe; MgS; CaS; Mn, Er ZnSe; Mn, Er MgS; Mn, Er CaS; Mn, Er ZnS; Mn,Yb ZnSe; Mn,Yb MgS; Mn, Yb CaS; Mn,Yb ZnS:Tb3+, Er3+; ZnS:Tb3+; Y2O3:Tb3+; Y2O3:Tb3+, Er3+; ZnS:Mn2+; ZnS:Mn,Er3+; CaWO4, YaTO4, YaTO4:Nb, BaSO4:Eu, La2O2S:Tb, BaSi2O5:Pb, NaI(Tl), CsI(Tl), CsI(Na), CsI(pure), CsF, KI(Tl), LiI(Eu), BaF2, CaF, CaF2(Eu), ZnS(Ag), CaWO4, CdWO4, YAG(Ce) (Y3Al5O12(Ce)), BGO bismuth germanate, GSO gadolinium oxyorthosilicate, LSO lutetium oxyorthosilicate, LaCl3(Ce), LaBr3(Ce), LaPO4; Ce, Tb (doped), Zn2SiO4:Mn with Mn doped between 0.05-10%, and YTaO4.
O4
2O5:Pb2+
:Eu2+
2O7:Pb2+
:Eu2+
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:Tb3+
:Ce3+
1.8Y0.2SiO5:Ce
:Ag
3+
2O2
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O12 (Ce)
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indicates data missing or illegible when filed
In one embodiment, phosphors used in the invention as energy modulation agents can include phosphor particles, ionic doped phosphor particles, single crystal or poly-crystalline powders, single crystal or poly-crystalline monoliths, scintillator particles, a metallic shell encapsulating at least a fraction of a surface of the phosphors, a semiconductor shell encapsulating at least a fraction of a surface of the phosphors, and an insulator shell encapsulating at least a fraction of a surface of the phosphors; and phosphors of a distributed particle size.
In further embodiments, dose calculation and robotic manipulation devices may also be included in the system.
In yet another embodiment, there is also provided a computer implemented system for designing and selecting suitable combinations of initiation energy source (listed in the initiation energy source database), energy modulation agent (listed in the energy transfer database), and activatable pharmaceutical agent (listed in the activatable agent database).
Referring to
In one embodiment, a photoactivatable drug is selected from psoralens, pyrene cholesteryloleate, acridine, porphyrin, fluorescein, rhodamine, 16-diazorcortisone, ethidium, transition metal complexes of bleomycin, transition metal complexes of deglycobleomycin organoplatinum complexes, alloxazines, vitamin Ks, vitamin L, vitamin metabolites, vitamin precursors, naphthoquinones, naphthalenes, naphthols and derivatives thereof having planar molecular conformations, porphorinporphyrins, dyes and phenothiazine derivatives, coumarins, quinolones, quinones, and anthroquinones.
A patient's immune system is a complex network of cells, tissues, organs, and the substances that help the body fight infections and other diseases. White blood cells, or leukocytes, play the main role in immune responses. These cells carry out the many tasks required to protect the body against disease-causing microbes and abnormal cells. Some types of leukocytes patrol the circulatory system, seeking foreign invaders and diseased, damaged, or dead cells. These white blood cells provide a general—or nonspecific—level of immune protection. Other types of leukocytes, known as lymphocytes, provide targeted protection against specific threats, whether from a specific microbe or a diseased or abnormal cell. The most important groups of lymphocytes responsible for carrying out immune responses against such threats are B cells and T cells. B cells make antibodies, which are large secreted proteins that bind to, inactivate, and help destroy foreign invaders or abnormal cells. Cytotoxic T cells, which are also known as killer T cells, kill infected or abnormal cells by releasing toxic chemicals or by prompting the cells to self-destruct (in a process known as apoptosis).
Other types of lymphocytes and leukocytes play supporting roles to ensure that B cells and killer T cells do their jobs effectively. These supporting cells include helper T cells and dendritic cells, which help activate both B cells and killer T cells and enable them to respond to specific threats.
Antigens are substances that have the potential to cause the body to mount an immune response against them. Antigens help the immune system determine whether something is foreign, or “non-self.” Normal cells in the body have antigens that identify them as “self” Self antigens tell the immune system that normal cells are not a threat and should be ignored. In contrast, microbes are recognized by the immune system as a potential threat that should be destroyed because they carry foreign, or non-self, antigens.
Cancer cells can carry both self antigens as well as what are referred to as cancer-associated antigens. Cancer-associated antigens mark cancer cells as abnormal or foreign and can cause killer T cells to mount an attack against them. Cancer-associated antigens may be: self antigens that are made in much larger amounts by cancer cells than normal cells and, thus, are viewed as foreign by the immune system, self antigens that are not normally made by the tissue in which the cancer developed (for example, antigens that are normally made only by embryonic tissue but are expressed in an adult cancer) and, thus, are viewed as foreign by the immune system, and/or newly formed antigens, or neoantigens, that result from gene mutations in cancer cells and have not been seen previously by the immune system.
In general, vaccines are medicines that boost the immune system's natural ability to protect the body against “foreign invaders,” mainly infectious agents, that may cause disease. When an infectious microbe invades the body, the immune system recognizes it as foreign, destroys it, and “remembers” it to prevent another infection should the microbe invade the body again in the future. Vaccines take advantage of this defensive memory response.
In one embodiment of the invention, there is provided a system for treating a human or animal body. This system includes a first pharmaceutically acceptable carrier, optionally and preferably including one or more phosphorescent or fluorescent agents which are capable of emitting light (preferably ultraviolet or visible light) into the body, a photoactivatable drug for treating a first diseased site, a first device which infuses the first diseased site with the photoactivatable drug and the first pharmaceutically acceptable carrier, and a source for generating energy in situ in the human or animal body sufficient to activate the photoactivatable drug, which is optionally and preferably a first energy source, preferably an x-ray or high energy source, which irradiates the diseased site with an initiation energy (preferably at least one of x-rays, gamma rays, or electrons) to thereby initiate emission of the light (preferably ultraviolet or visible light) into the body from the preferred one or more phosphorescent or fluorescent agents, thus activating the photoactivatable drug. This part of this system provides the treatment to the first diseased site.
This system can include a supplemental treatment device which administers a therapeutic drug or radiation or both for treating a second diseased site or the first diseased site. The supplemental treatment device can be at least one of 1) a second device which infuses a second diseased site with an immune system stimulant or chemotherapeutic drug or a targeted cancer growth suppressant, and 3) a second energy source (preferably an x-ray or high energy source) which irradiates a second diseased site, preferably with at least one of x-rays, gamma rays, or electrons. Alternatively, this system can use the initial energy source in a further irradiation of the first diseased site, preferably with x-rays, gamma rays, or electrons.
Accordingly, when a supplemental treatment of the human or animal body is prescribed, the second device infuses a second diseased site with an immune system stimulant. Alternatively or additionally, when a supplemental treatment of the human or animal body is prescribed, the second x-ray or high energy source irradiates a second diseased site with at least one of x-rays, gamma rays, or electrons.
The first and second energy (initiation energy) sources can be the same or different energy sources or the same or different x-ray or high energy electron sources. The first and second devices can be the same or different drug-infusion devices which infuse a diseased site with the photoactivatable drug or the immune system stimulant.
In one embodiment of the invention, one or more “booster” treatments are used as an immune system stimulant. These one or more “booster” treatments can be performed after the initial treatment (considered a “priming treatment”), or when the initial treatment is performed as a series of treatments, the “booster” treatment(s) can be performed between sequential priming treatments, alternating with priming treatments, or even simultaneously with the priming treatments. A “booster treatment” in one embodiment could involve re-injecting the tumor with psoralen (or other photoactivatable drug) and radiating the tumor site again. A “booster treatment” in another embodiment could involve re-injecting the tumor with psoralen (or other photoactivatable drug) and an energy modulation agent and radiating the tumor site again. A “booster treatment” in another embodiment could involve radiating the tumor site again, but at a radiation level considered to be at either a palliative or therapeutic level. The purpose of any of these “booster” treatments is to activate/stimulate/boost the immune response initially or originally generated within the patient during the initial treatments.
In one embodiment of the booster treatment as an immune system stimulant, the phosphor concentration is increased to 20 mg/mL, the amount of UVADEX is increased 2-4 times, and the treatment frequency is increased to five (5) treatments in five (5) consecutive days. Furthermore, the timing between the prime (initial treatment sessions such as the nine treatments described above) and the booster treatment is set to allow for an initial humoral or cellular immune response, followed by a period of homeostasis, most typically weeks or months after the initial priming treatment.
In another embodiment, particularly for more aggressive cancers, an intervening treatment between the prime and boost stages can be provided to stunt the growth of the tumor while the immune system develops a response. The intervening treatment can take the form of palliative radiation, or other treatments known to those skilled in the art. A “booster treatment” in a further embodiment can involve irradiating a different tumor site within the patient (such as a metastasis site), at a radiation level considered to be at either a palliative or therapeutic level or at a radiation induced cell kill level. Since the goal of the “booster treatments” is to activate/stimulate/boost the patient's immune system, any of the “booster treatments” can be performed after completion of all of the primer treatments, between primer treatments during a series of the primer treatments, or prior to the primer treatments (although this may seem odd to perform the primer treatment after the booster treatment, the booster treatment can activate/stimulate/boost the immune system, thus providing a boost or supplement to the primer treatment once performed).
While not limited to the following theory, the basic prime—boost strategy involves priming the immune system to a target antigen, or a plurality of antigens created by the drug and/or radiation induced cell kill and then selectively stimulating/boosting this immunity by re-exposing the antigen or plurality of antigens in the boost treatment. One aspect of this strategy is that greater levels of immunity are established by heterologous prime—boost than can be attained by a single vaccine administration or homologous boost strategies. For example, the initial priming events elicited by a first exposure to an antigen or a plurality of antigens appear to be imprinted on the immune system. This phenomenon is particularly strong in T cells and is exploited in prime—boost strategies to selectively increase the numbers of memory T cells specific for a shared antigen in the prime and boost vaccines. As described in the literature, these increased numbers of T cells ‘push’ the cellular immune response over certain thresholds that are required to fight specific pathogens or cells containing tumor specific antigens. Furthermore, the general avidity of the boosted T-cell response is enhanced, which presumably increases the efficacy of the treatment.
Here, in this invention and without limitation as to the details but rather for the purpose of explanation, the initial treatment protocol develops antibodies or cellular immune responses to the psoralen-modified or X-ray modified cancer cells. These “initial” responses can then be stimulated/boosted by the occurrence of a large number of newly created psoralen-modified or X-ray modified cancer cells. As such, the patient's immune system would mount a more robust response against the cancer than would be realized in a single treatment series.
In one embodiment of the invention, cancer cells can be removed from a diseased site in the patient, and then treated ex-vivo with psoralen and ultraviolet light to induce cell kill. The “killed” cancer cells are then as part of an initial treatment or a booster treatment injected into the disease region of the patient. In one embodiment of the invention, the removed cancer cells are cultured to provide a larger number of cells to be exposed to psoralen and ultraviolet light, and therefore to produce a larger number of “killed” cells to inject. The body in response to these “killed” cells (in a manner similar to how the psoralen-modified or X-ray modified cancer cells would be received) would trigger the patient's immune system to thereby activate/stimulate/boost the patient's immune system as an immune system stimulant.
In one embodiment of the invention, prior to the initial treatment or prior to booster treatments, the immune system of the subject could be further activated/stimulated/boosted by injection of a more conventional vaccine such as for example a tetanus vaccine. Prior work has shown the efficacy of a tetanus booster to bolster the immune system's attack on the tumor by helping cancer vaccines present in the subject migrate to the lymph nodes, activating an immune response. Here, in this invention, the autovaccines generated internally from the treatments described above could also benefit from this effect.
As noted above, a booster treatment is one way to activate/stimulate/boost the immune system.
Cancer vaccines belong to a class of substances known as biological response modifiers. Biological response modifiers work by stimulating or restoring the immune system's ability to fight infections and disease. Treatment (or therapeutic) vaccines treat an existing cancer by strengthening the body's natural immune response against the cancer as an immune system stimulant. More specifically, cancer treatment vaccines are used to treat cancers that have already developed. Cancer treatment vaccines are intended to delay or stop cancer cell growth; to cause tumor shrinkage; to prevent cancer from coming back; or to eliminate cancer cells that have not been killed by other forms of treatment.
Cancer treatment vaccines are designed to work by activating cytotoxic T cells and directing the cytotoxic T cells to recognize and act against specific types of cancer or by inducing the production of antibodies that bind to molecules on the surface of cancer cells. To do so, treatment vaccines introduce one or more antigens into the body, usually by injection, where they cause an immune response that results in T cell activation or antibody production. Antibodies recognize and bind to antigens on the surface of cancer cells, whereas T cells can also detect cancer antigens inside cancer cells. One cancer treatment vaccine which can be used with XPACT treatment includes sipuleucel-T (Provenge®), approved for use in some men with metastatic prostate cancer. It is designed to stimulate an immune response to prostatic acid phosphatase (PAP), an antigen that is found on most prostate cancer cells.
One cancer treatment vaccine which can be used with XPACT treatment includes talimogene laherparepvec (T-VEC, or Imlygic®) for the treatment of some patients with metastatic melanoma that cannot be surgically removed. In addition to infecting and lysing cancer cells when injected directly into melanoma tumors, T-VEC induces responses in non-injected lesions, suggesting that it triggers an antitumor immune response similar to those of other anticancer vaccines.
Other types of cancer treatment vaccines that can be used as the supplemental treatment include those made using molecules of DNA or RNA that contain the genetic instructions for cancer-associated antigens. The DNA or RNA can be injected alone into a patient as a “naked nucleic acid” vaccine, or packaged into a harmless virus. After the naked nucleic acid or virus is injected into the body, the DNA or RNA is taken up by cells, which begin to manufacture the tumor-associated antigens. In theory, the cells will make enough of the tumor-associated antigens to stimulate a strong immune response.
Accordingly, in one embodiment of the invention, cancer treatment vaccines are provided as the above-noted supplemental treatment providing an immune system stimulant. In this embodiment, a cancer vaccine would supplement the XPACT treatment by delaying or stopping cancer cell growth or by causing tumor shrinkage while the XPACT autoimmune response develops. The cancer treatment vaccines could be injected at the same or a different site (different organ) from the XPACT treated area.
In one embodiment of the invention, hormone injections are used to promote white and red blood cell counts. In one embodiment of the invention, interleukin-2 (IL-2) injections are used to promote functions of the patient's immune system.
Other ways to activate/stimulate/boost the immune system include immunotherapy, also called biologic therapy, which is designed to boost the body's natural defenses to fight the cancer. Immunotherapy uses materials made either by the body or in a laboratory to improve, target, or restore immune system function. One particular focus in such immunotherapy approaches relates to immune checkpoints and their inhibition Immune checkpoints are molecules in the immune system that either turn up a signal (co-stimulatory molecules) or turn down a signal (inhibitor molecules). Many cancers protect themselves from the immune system by inhibiting the T cell signal or other aspects of the immune system. Since around 2010, immune checkpoint inhibitors have been increasingly considered as new targets for cancer immunotherapies. For example, the PD-1 pathway may be critical in the immune system's ability to control cancer growth. PD-1, short for Programmed Death 1 (PD-1) receptor, has two ligands, PD-L1 and PD-L2. An advantage of targeting PD-1 is that it can restore immune function in the tumor microenvironment. Blocking this pathway with PD-L1 and/or PD-L2 antibodies has stopped or slowed the growth of lung cancer for some patients. In addition to PD-1, other immune checkpoint inhibitors include:
More recently, immunotherapy drugs are also being used to treat genetic cancers, including mismatch repair deficient cancers such as Lynch Syndrome, in which one or more of a set of mismatch repair genes are found to be defective, thus allowing the buildup of errors in DNA of those affected as cells divide. These mismatch repair deficiencies have been found to be the cause of cancer syndromes such as Lynch Syndrome, in which one or more of the MLH1, MSH2, MSH6, PMS2, or EPCAM genes are mutated to lose their ability to repair gene mismatches caused by cell division. Immunotherapy has shown to be effective in treating such genetic cancers, with Pembrolizumab (Keytruda) being recently approved for such use. Another immunotherapy drug is Nivolumab (Opdivo).
In general, cancer immunotherapy stimulates a patient's immune system to destroy tumors. A variety of strategies are possible. In one approach, G-CSF lymphocytes are extracted from the blood of a patient and expanded in vitro against a tumor antigen before reinjecting the cells with appropriate stimulatory cytokines. The cells then destroy the tumor cells that express the antigen.
In an embodiment of the present invention, the present treatment method can be combined with administration of conventional immunotherapy drugs, such as Pembrolizumab (Keytruda) or Nivolumab (Opdivo), as a way to stimulate the immune system of the patient through two pathways, the auto-vaccine effect of the present treatment, and the immune stimulation provided by the immunotherapy drug.
In another related approach, substances known as adjuvants are often added to vaccines or separately injected to induce potent anticancer immune responses. Adjuvants used for cancer vaccines come from many different sources. Bacillus Calmette-Guérin (BCG) immunotherapy which has been used for early stage (non-invasive) bladder cancer. BCG immunotherapy instills attenuated live bacteria into the bladder and is effective in preventing recurrence in up to two thirds of cases. More particularly, a live attenuated strain of Mycobacterium bovis, has been approved by the US Food and Drug Administration for this approach.
Additionally, substances produced by bacteria, such as Detox B (an oil droplet emulsion of monophosphoryl lipid A and mycobacterial cell wall skeleton), are also frequently used as adjuvants. Biological products derived from nonmicrobial organisms can also be used as adjuvants. One example is keyhole limpet hemocyanin (KLH), which is a large protein produced by a marine mollusk. Attaching antigens to KLH has been shown to increase their ability to stimulate immune responses. Even some nonbiological substances, such as an emulsified oil known as montanide ISA-51, can be used as adjuvants.
Natural or synthetic cytokines can also be used as adjuvants. Cytokines are substances that are naturally produced by white blood cells to regulate and fine-tune immune responses. Some cytokines increase the activity of B cells and killer T cells, whereas other cytokines suppress the activities of these cells. Cytokines frequently used in cancer treatment vaccines or given together with them include interleukin 2 (IL2, also known as aldesleukin), interferon alpha, and granulocyte-macrophage colony-stimulating factor (GM—CSF, also known as sargramostim).
Accordingly, in one embodiment of the invention, the above-noted adjuvants can be used as the supplemental treatment noted above used with the XPACT treatment as an immune system stimulant.
In another approach, topical immunotherapy utilizes an immune enhancement cream (imiquimod) which produces interferon, causing the recipient's killer T cells to destroy warts, actinic keratoses, basal cell cancer, vaginal intraepithelial neoplasia, squamous cell cancer, cutaneous lymphoma, and superficial malignant melanoma.
In another approach, injection immunotherapy (“intralesional” or “intratumoral”) uses mumps, candida, the HPV vaccine or trichophytin antigen injections to treat warts (HPV induced tumors).
In another approach, adoptive cell transfer (ACT) can be used. In ACT, T cells are transferred into a patient. The transferred cells may have originated from the patient or from another individual. In cancer immunotherapy, T cells are extracted from the patient, genetically modified and cultured in vitro and returned to the same patient. As an example, T cells, referred to as tumor-infiltrating lymphocytes (TIL), are multiplied using high concentrations of Interleukin-2, anti-CD3 and allo-reactive feeder cells. These T cells are then transferred back into the patient along with administration of Interleukin-2 (IL-2) to further boost their anti-cancer activity. Before reinfusion, lymphodepletion of the recipient is used to eliminate regulatory T cells as well as unmodified, endogenous lymphocytes that compete with the transferred cells for homeostatic cytokines. Lymphodepletion can be achieved by total body irradiation. Transferred cells multiplied in vivo and persisted in peripheral blood in many people, sometimes representing levels of 75% of all CD8+ T cells at 6-12 months after infusion.
In another approach, dendritic cell-based pump-priming can be used. Dendritic cells can be stimulated to activate a cytotoxic response towards an antigen. Dendritic cells, a type of antigen presenting cell, are harvested from the patient. These cells are then either pulsed with an antigen or tumor lysate or transfected with a viral vector, causing them to display the antigen. Upon transfusion into the person, these activated cells present the antigen to the effector lymphocytes (CD4+ helper T cells, cytotoxic CD8+ T cells and B cells). This initiates a cytotoxic response against tumor cells expressing the antigen (against which the adaptive response has now been primed). The cancer vaccine Sipuleucel-T is one example of this approach.
In another approach, an autologous immune enhancement therapy uses a person's own peripheral blood-derived natural killer cells. In this approach, cytotoxic T lymphocytes and other relevant immune cells are expanded in vitro and then reinfused.
In another approach, genetically engineered T cells are created by harvesting T cells and then infecting the T cells with a retrovirus that contains a copy of a T cell receptor (TCR) gene that is specialized to recognize tumor antigens. The virus integrates the receptor into the T cells' genome. The cells are expanded non-specifically and/or stimulated. The cells are then reinfused and produce an immune response against the tumor cells. The technique has been tested on refractory stage IV metastatic melanomas and advanced skin cancer.
Any or all of these treatments above can be used with the XPACT treatment as an immune system stimulant.
In one embodiment of the invention, the supplemental treatment can include any number of conventional and developing cancer treatments such as for example radiation therapy, chemotherapy, targeted therapy to kill or block cancer cell growth, for example those noted above and others.
In one embodiment of the invention, the supplemental treatment provided includes radiation therapy, which is the use of high energy x-rays or other particles to destroy cancer cells. The most common type of radiation treatment is called external-beam radiation therapy, which is radiation given from a machine outside the body. Radiation destroys cancer cells directly in the path of the radiation beam. It also damages the healthy cells in its path; for this reason, it preferably not used to treat large areas of the body. However, in one embodiment of the invention, in conjunction with the XPACT treatment, a widespread radiation exposure could be used. With radiation therapy, a radiation therapy regimen (schedule) usually consists of a specific number of treatments given over a set period of time. The treatment can vary from just a few days of treatment to several weeks. In one embodiment of the invention, the status of the treatment site is monitored for an indication that the XPACT treatment of the patient has started to develop its autoimmune response to the cancer in the patient's body. Once tumor growth has stopped or is in regression, the radiation therapy can be stopped.
With radiation therapy, CT scans (imaging scans) can be used to plan out exactly where to direct the radiation to lower the risk of damaging healthy parts of the body. The CT scans can be part of the XPACT treatment when a supplemental treatment is directed to the same diseased site and the XPACT treatment. With radiation therapy, intensity modulated radiation therapy (IMRT) or stereotactic body radiation therapy (SBRT) can be used for the supplemental treatment of the same diseased site XPACT treated or a different diseased site.
In one embodiment of the invention, the supplemental treatment provided includes chemotherapy which is the use of drugs to destroy cancer cells, usually by stopping the cancer cells' ability to grow and divide. Chemotherapy has been shown to improve both the length and quality of life for people with cancer. Systemic chemotherapy gets into the bloodstream to reach cancer cells throughout the body. Common ways to give chemotherapy include an intravenous (IV) tube placed into a vein using a needle or in a pill or capsule that is swallowed (orally). Most chemotherapy used for lung cancer is given by IV injection. As known, chemotherapy may also damage healthy cells in the body, including blood cells, skin cells, and nerve cells. Accordingly, chemotherapy in the present invention as a supplemental treatment is used with restrictive amounts of the drug in an effort to slow the cancer progression until the XPACT autoimmune response develops.
Drugs of possible use in the present invention for chemotherapy include carboplatin (Paraplatin) or cisplatin (Platinol), docetaxel (Docefrez, Taxotere), Gemcitabine (Gemzar), Nab-paclitaxel (Abraxane), Paclitaxel (Taxol), Pemetrexed (Alimta), and Vinorelbine (Navelbine).
In one embodiment of the invention, the supplemental treatment provided the above noted chemotherapy drugs to supplement the XPACT treatment.
In one embodiment of the invention, the supplemental treatment provided includes targeted therapy which is a treatment that targets the cancer's specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. This type of treatment blocks the growth and spread of cancer cells while limiting damage to healthy cells.
Not all tumors have the same targets. Of the targeted therapies, anti-angiogenesis therapy is focused on stopping angiogenesis, which is the process of making new blood vessels. Because a tumor needs the nutrients delivered by blood vessels to grow and spread, the goal of anti-angiogenesis therapies is to “starve” the tumor. The following and other anti-angiogenic drugs may be used at the XPACT treated site or a different site: Bevacizumab (Avastin), Ramucirumab (Cyramza), Epidermal growth factor receptor (EGFR) inhibitors, Erlotinib (Tarceva), Gefitinib (Iressa), Afatinib (Gilotrif), Osimertinib (Tagrisso), Necitumumab (Portrazza), anaplastic lymphoma kinase (ALK) inhibitors, Crizotinib (Xalkori), Ceritinib (Zykadia), and Alectinib (Alecensa).
In another embodiment, Avastin can be administered to reduce swelling in the treated tumors. Avastin is a monoclonal antibody, a synthetic version of antibodies that occur in our bodies and which fight foreign substances. Avastin typically binds to a molecule called vascular endothelial growth factor or VEGF. VEGF is a key player in the growth of new blood vessels. Avastin turns VEGF off. Blocking VEGF may prevent the growth of new blood vessels, including normal blood vessels and blood vessels that feed tumors. Avastin is FDA approved for 6 cancer types: metastatic colorectal cancer (MCRC), metastatic non-squamous non-small cell lung cancer (NSCLC), metastatic renal cell carcinoma (mRCC), recurrent glioblastoma (rGBM), persistent, recurrent, or metastatic cervical cancer (CC), and platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (prOC).
Any or all of these treatments noted above can be used with the XPACT treatment as a treatment to kill or block cancer cell growth.
In a further embodiment, methods in accordance with the present invention may further include adding an additive to alleviate treatment side-effects. Exemplary additives may include, but are not limited to, antioxidants, adjuvant, or combinations thereof. In one exemplary embodiment, psoralen is used as the activatable pharmaceutical agent, UV-A is used as the activating energy, and antioxidants are added to reduce the unwanted side-effects of irradiation.
The activatable pharmaceutical agent and derivatives thereof as well as the energy modulation agent, can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the activatable pharmaceutical agent and a pharmaceutically acceptable carrier. The pharmaceutical composition also comprises at least one additive having a complementary therapeutic or diagnostic effect, wherein the additive is one selected from an antioxidant, an adjuvant, or a combination thereof.
As used herein, “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions. Modifications can be made to the compound of the present invention to affect solubility or clearance of the compound. These molecules may also be synthesized with D-amino acids to increase resistance to enzymatic degradation. If necessary, the activatable pharmaceutical agent can be co-administered with a solubilizing agent, such as cyclodextran.
A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, rectal administration, and direct injection into the affected area, such as direct injection into a tumor. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfate; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Oral compositions generally include an inert diluent or an edible carrier. The oral compositions can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery. In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.
It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
It will also be understood that the order of administering the different agents is not particularly limited. Thus in some embodiments the activatable pharmaceutical agent may be administered before the energy modulation agent, while in other embodiments the energy modulation agent may be administered prior to the activatable pharmaceutical agent. It will be appreciated that different combinations of ordering may be advantageously employed depending on factors such as the absorption rate of the agents, the localization and molecular trafficking properties of the agents, and other pharmacokinetics or pharmacodynamics considerations.
In one embodiment of the invention, the reagents and chemicals useful for methods and systems of the present invention may be packaged in kits to facilitate application of the present invention. In one exemplary embodiment, a kit including a psoralen, and fractionating containers for easy fractionation and isolation of autovaccines is contemplated. A further embodiment of kit would comprise at least one activatable pharmaceutical agent capable of causing a predetermined cellular change, at least one energy modulation agent capable of activating the at least one activatable agent when energized, and containers suitable for storing the agents in stable form, and preferably further comprising instructions for administering the at least one activatable pharmaceutical agent and at least one energy modulation agent to a subject, and for applying an initiation energy from an initiation energy source to activate the activatable pharmaceutical agent. The instructions could be in any desired form, including but not limited to, printed on a kit insert, printed on one or more containers, as well as electronically stored instructions provided on an electronic storage medium, such as a computer readable storage medium. Also optionally included is a software package on a computer readable storage medium that permits the user to integrate the information and calculate a control dose, to calculate and control intensity of the irradiation source.
The following enumerated Embodiments describe generalized aspects of the invention and are not provided to limit the invention beyond that which is expressly provided in the appended claims.
Embodiment 1. A method for treating a difficult to access/treat tumor in a subject, comprising:
Embodiment 2. The method of Embodiment 1, wherein the difficult to access/treat tumor site is a primary tumor.
Embodiment 3. The method of Embodiment 1, wherein the difficult to access/treat tumor site is a metastatic tumor.
Embodiment 4. The method of any one of Embodiments 1-3, wherein generating the activation energy in situ in the subject comprises injecting in the induced metastatic tumor a pharmaceutical carrier including one or more phosphorescent or fluorescent agents which are capable of emitting an activation energy in the subject for activating the photoactivatable drug; and
Embodiment 5. The method of Embodiment 4, wherein applying an initiation energy comprises providing a controlled radiation dose of x-ray or high energy electrons to the induced metastatic tumor.
Embodiment 6. The method of any one of Embodiments 1-3, further comprising providing a booster treatment to the induced metastatic tumor, before, during and/or after an initial treatment of the induced metastatic tumor.
Embodiment 7. The method of Embodiment 6, wherein said booster treatment is performed before an initial treatment of the induced metastatic tumor.
Embodiment 8. The method of Embodiment 6, wherein said booster treatment is performed during an initial treatment of the induced metastatic tumor.
Embodiment 9. The method of Embodiment 6, wherein said booster treatment is performed after an initial treatment of the growing metastatic tumor.
Embodiment 10. The method of Embodiment 9, wherein said booster treatment is repeated on a periodic basis after an initial treatment of the induced metastatic tumor.
Embodiment 11. The method of Embodiment 6, wherein, in the booster treatment, at least one of phosphor concentration, photoactivatable drug concentration, and the radiation dose is increased by a factor of at least two times initial values.
Embodiment 12. The method of Embodiment 6, wherein the booster treatment produces psoralen-modified cancer cells or X-ray modified cancer cells.
Embodiment 13. The method of Embodiment 6, wherein the booster treatment produces radiation damaged cancer cells.
Embodiment 14. The method of Embodiment 6, further comprising delaying a period between booster treatments according to a tolerance level of the subject for radiation-modified cells generated during the booster treatment.
Embodiment 15. The method of Embodiment 6, wherein the booster treatment provides radiating the subject at either a palliative level or a therapeutic level.
Embodiment 16. The method of Embodiment 15, wherein the radiating the subject at either a palliative or therapeutic level comprises radiating the subject at the induced metastatic tumor, or at a remote site on the subject relative to the induced metastatic tumor, before, during, and/or after an initial treatment with said phosphors, said photoactivatable drug, and said applying an initiation energy to the induced metastatic tumor.
Embodiment 17. The method of Embodiment 4, further comprising radiating the subject with a first energy source or as part of a supplemental treatment at at least one of a palliative level, a therapeutic level, or a radiation induced cell kill level.
Embodiment 18. The method of Embodiment 17, wherein said radiating the subject comprises radiating at said palliative level.
Embodiment 19. The method of Embodiment 17, wherein said radiating the subject comprises radiating at said radiation induced cell kill level.
Embodiment 20. The method of Embodiment 17, wherein said radiating the subject comprises radiating at said palliative level as an intervening treatment after an initial treatment with said phosphors, said photoactivatable drug, and said applying initiation energy to the induced metastatic tumor and prior to a subsequent booster treatment with said phosphors, said photoactivatable drug, and said applying initiation energy to the induced metastatic tumor.
Embodiment 21. The method of Embodiment 4, wherein the method further comprises, before, during, and/or after an initial treatment with said phosphors, said photoactivatable drug, and said applying initiation energy to the induced metastatic tumor, radiating the human or animal body at a region different from the induced metastatic tumor.
Embodiment 22. The method of Embodiment 4, wherein the method further comprises, before, during, and/or after an initial treatment with said phosphors, said photoactivatable drug, and said applying initiation energy to the induced metastatic tumor, radiating the subject with a palliative level of radiation at a region different from the induced metastatic tumor.
Embodiment 23. The method of Embodiment 4, wherein the method further comprises, before, during and/or after an initial treatment with said phosphors, said photoactivatable drug, and said applying initiation energy to the induced metastatic tumor, radiating the subject with a radiation induced cell kill level of radiation at a region different from the induced metastatic tumor.
Embodiment 24. The method of any one of Embodiments 1-3, further comprising stunting growth of the difficult to access/treat tumor in the subject until the activated photoactivatable drug causes said auto-vaccine effect in the subject.
Embodiment 25. The method of any one of Embodiments 1-3, further comprising actively stimulating said auto-vaccine response in the subject by performance of a booster treatment.
Embodiment 26. The method of Embodiment 25, wherein the booster treatment for stimulating said auto-vaccine response comprises injecting a vaccine into the subject.
Embodiment 27. The method of Embodiment 26, wherein stimulating said auto-vaccine effect comprises injecting a tetanus vaccine into the subject.
Embodiment 28. The method of Embodiment 25, further comprising radiating the subject with a palliative level of radiation.
Embodiment 29. The method of any one of Embodiments 1-3, further comprising directing radiation to at least one of the difficult to access tumor, induced metastatic tumor, or elsewhere in the body.
Embodiment 30. The method of any one of Embodiments 1-3, further comprising providing a therapeutic drug as an immune system stimulant.
Embodiment 31. The method of Embodiment 30, wherein the therapeutic drug comprises a vaccine.
Embodiment 32. The method of any one of Embodiments 1-3, wherein generating the activation energy comprises applying an initiation energy selected from x-rays, gamma rays, electron beams and proton beams, whereby the initiation energy is converted into the activation energy in situ within the subject in the absence of an added energy modulation agent, or in the presence of one or more co-administered energy modulation agents.
Embodiment 33. The method of Embodiment 32, wherein the initiation energy is converted into the activation energy in the subject in the absence of an added energy modulation agent.
Embodiment 34. The method of any one of Embodiments 1-3, wherein generating the activation energy in the subject comprises administering a light emitting device to the subject and causing the light emitting device to emit the activation energy.
Embodiment 35. The method of Embodiment 4, wherein the pharmaceutical carrier including the one or more phosphorescent or fluorescent agents also comprises the photoactivatable drug, such that the photoactivatable drug and the one or more phosphorescent or fluorescent agents are co-infused to the induced metastatic tumor.
Embodiment 36. The method of Embodiment 4, wherein the pharmaceutical carrier including the one or more phosphorescent or fluorescent agents is sequentially administered into the induced metastatic tumor before or after infusing the induced metastatic tumor with the photoactivatable drug.
Embodiment 38. The method of Embodiment 2, wherein the pharmaceutical carrier including the one or more phosphorescent or fluorescent agents is simultaneously administered into the induced metastatic tumor while infusing the induced metastatic tumor with the photoactivatable drug.
Embodiment 39. The method of any one of Embodiments 1-3, wherein generating the activation energy in the subject comprises modifying cells of the sample of tumor tissue to be fluorescent upon receiving an initiation energy, and, after implanting to form the induced metastatic tumor, applying the initiation energy to the induced metastatic tumor to cause fluorescence from the cells of the induced metastatic tumor.
Embodiment 40. The method of any one of Embodiments 1-3, wherein the difficult to access/treat tumor is a brain tumor.
Embodiment 41. The method of any one of Embodiments 1-3, wherein the difficult to access/treat tumor is a tumor in close proximity to a major artery.
Embodiment 42. The method of any one of Embodiments 1-3, wherein the difficult to access/treat tumor is a tumor in close proximity to the subject's spinal cord.
Embodiment 43. The method of any one of Embodiments 1-3, wherein the difficult to access/treat tumor is in a region of the subject in which the infusing into the difficult to access/treat tumor would create undue and/or dangerous pressure on a nerve, blood vessel, anatomically dangerous body element, and/or organ of the subject.
Numerous modifications and variations of the invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein. All of the publications, references, patents, patent applications, and other documents identified above are incorporated by reference herein in their entirety.
This application is related to U.S. provisional Ser. No. 62/243,465 filed Oct. 19, 2015, the entire content of which is incorporated herein by reference. This application is related to U.S. provisional Ser. No. 61/982,585, filed Apr. 22, 2014, entitled “INTERIOR ENERGY-ACTIVATION OF PHOTO-REACTIVE SPECIES INSIDE A MEDIUM OR BODY USING AN X-RAY SOURCE EMITTING LOW ENERGY X-RAYS AS INITIATION ENERGY SOURCE”, the entire contents of which are hereby incorporated by references. This application is related to provisional Ser. No. 62/096,773, filed: Dec. 24, 2014, entitled “ INTERIOR ENERGY-ACTIVATION OF PHOTO-REACTIVE SPECIES INSIDE A MEDIUM OR BODY USING AN X-RAY SOURCE EMITTING LOW ENERGY X-RAYS AS INITIATION ENERGY SOURCE,” the entire contents of each of which is incorporated herein by reference. This application is related to U.S. provisional Ser. No. 62/132,270, filed Mar. 12, 2015, entitled “TUMOR IMAGING WITH X-RAYS AND OTHER HIGH ENERGY SOURCES USING AS CONTRAST AGENTS PHOTON-EMITTING PHOSPHORS HAVING THERAPEUTIC PROPERTIES”, the entire contents of which are hereby incorporated by references. This application is related to U.S. provisional Ser. No. 62/147,390, filed Apr. 14, 2015, entitled “TUMOR IMAGING WITH X-RAYS AND OTHER HIGH ENERGY SOURCES USING AS CONTRAST AGENTS PHOTON-EMITTING PHOSPHORS HAVING THERAPEUTIC PROPERTIES”, the entire contents of which are hereby incorporated by references. This application is related to provisional application U.S. Ser. No. 62/955,533, filed Dec. 31, 2019, entitled ENERGY AUGMENTATION STRUCTURE; ENERGY COLLECTOR CONTAINING THE SAME; AND EMISSION ENHANCEMENTS UTILIZING AT LEAST ONE ENERGY AUGMENTATION STRUCTURE, the entire disclosure of which is incorporated herein by reference. This application is related to provisional application U.S. Ser. No. 62/946,648, filed Dec. 11, 2019, entitled ENERGY AUGMENTATION STRUCTURE; ENERGY COLLECTOR CONTAINING THE SAME; AND EMISSION ENHANCEMENTS UTILIZING AT LEAST ONE ENERGY AUGMENTATION STRUCTURE, the entire disclosure of which is incorporated herein by reference. This application is related to provisional application U.S. Ser. No. 62/897,677, filed Sep. 9, 2019, entitled ENERGY AUGMENTATION STRUCTURE; ENERGY COLLECTOR CONTAINING THE SAME; AND EMISSION ENHANCEMENTS UTILIZING AT LEAST ONE ENERGY AUGMENTATION STRUCTURE, the entire disclosure of which is incorporated herein by reference. This application is related to provisional application U.S. Ser. No. 62/855,508, filed May 31, 2019, entitled ENERGY AUGMENTATION STRUCTURE; ENERGY COLLECTOR CONTAINING THE SAME; AND COLOR ENHANCEMENT UTILIZING AT LEAST ONE ENERGY AUGMENTATION STRUCTURE, the entire disclosure of which is hereby incorporated by reference. This application is related to provisional application U.S. Ser. No. 62/813,390, filed Mar. 4, 2019, entitled COLOR ENHANCEMENT UTILIZING AT LEAST ONE ENERGY AUGMENTATION STRUCTURE, the entire disclosure of which is hereby incorporated by reference. This application is related to U.S. application Ser. No. 16/599,732, filed Oct. 11, 2019, pending, which claims priority to provisional application U.S. Ser. No. 62/745,057, filed Oct. 12, 2018, the entire contents of each of which are hereby incorporated by reference. This application is related to U.S. Ser. No. 13/204,355 filed Aug. 5, 2011, the entire disclosures of which are hereby incorporated by reference. This application is related to U.S. provisional patent application 61/371,549, filed Aug. 6, 2010. This application is related to U.S. provisional patent application 61/161,328, filed Mar. 18, 2009 and to U.S. provisional patent application 61/259,940, filed Nov. 10, 2009, the entire disclosures of which are hereby incorporated by reference. This application is related to U.S. Ser. No. 12/725,108, the entire disclosures of which are hereby incorporated by reference. This application is related to Provisional Applications Ser. Nos. 60/954,263, filed Aug. 6, 2007, and 61/030,437, filed Feb. 21, 2008, and U.S. application Ser. No. 12/059,484, filed Mar. 31, 2008, the contents of which are hereby incorporated herein by reference. This application is also related to U.S. application Ser. No. 11/935,655, filed Nov. 6, 2007; and Provisional Applications Ser. Nos. 61/042,561, filed Apr. 4, 2008; 61/035,559, filed Mar. 11, 2008, and 61/080,140, filed Jul. 11, 2008, the entire contents of which are hereby incorporated herein by reference. This application is related to U.S. patent application Ser. No. 12/401,478 filed Mar. 10, 2009, the entire contents of which are hereby incorporated herein by reference. This application is related to U.S. patent application Ser. No. 11/935,655, filed Nov. 6, 2007, and Ser. No. 12/059,484, filed Mar. 31, 2008; U.S. patent application Ser. No. 12/389,946, filed Feb. 20, 2009; U.S. patent application Ser. No. 12/417,779, filed Apr. 3,2009, the entire disclosures of which are hereby incorporated by reference. This application is related to provisional U.S. Ser. No. 12/401,478 (now U.S. Pat. No. 8,376,013) entitled “PLASMONIC ASSISTED SYSTEMS AND METHODS FOR INTERIOR ENERGY-ACTIVATION FROM AN EXTERIOR SOURCE, filed Mar. 10, 2009, the entire contents of which are incorporated herein by reference. This application is related to U.S. Ser. No. 13/102,277 entitled “ADHESIVE BONDING COMPOSITION AND METHOD OF USE,” filed May 6, 2011, the entire contents of which are incorporated herein by reference. This application is related to provisional Ser. No. 61/035,559, filed Mar. 11, 2008, entitled “SYSTEMS AND METHODS FOR INTERIOR ENERGY-ACTIVATION FROM AN EXTERIOR SOURCE,” the entire contents of which are hereby incorporated herein by reference. This application is related to provisional Ser. No. 61/030,437, filed Feb. 21, 2008, entitled “METHODS AND SYSTEMS FOR TREATING CELL PROLIFERATION DISORDERS USING PLASMONICS ENHANCED PHOTOSPECTRAL THERAPY (PEPST) AND EXCITON-PLASMON ENHANCED PHOTOTHERAPY (EPEP),” the entire contents of which are hereby incorporated herein by reference. This application is related to non-provisional Ser. No. 12/389,946, filed Feb. 20, 2009, entitled “METHODS AND SYSTEMS FOR TREATING CELL PROLIFERATION DISORDERS USING PLASMONICS ENHANCED PHOTOSPECTRAL THERAPY (PEPST) AND EXCITON-PLASMON ENHANCED PHOTOTHERAPY (EPEP),” the entire contents of which are hereby incorporated herein by reference. This application is related to non-provisional Ser. No. 11/935,655, filed Nov. 6, 2007, entitled “METHODS AND SYSTEMS FOR TREATING CELL PROLIFERATION RELATED DISORDERS,” and to provisional Ser. No. 60/910,663, filed Apr. 8, 2007, entitled “METHOD OF TREATING CELL PROLIFERATION DISORDERS,” the contents of each of which are hereby incorporated by reference in their entireties. This application is related to provisional Ser. No. 61/035,559, filed Mar. 11, 2008, entitled “SYSTEMS AND METHODS FOR INTERIOR ENERGY-ACTIVATION FROM AN EXTERIOR SOURCE,” the entire contents of which are hereby incorporated herein by reference. This application is also related to provisional Ser. No. 61/792,125, filed Mar. 15, 2013, entitled “INTERIOR ENERGY-ACTIVATION OF PHOTO-REACTIVE SPECIES INSIDE A MEDIUM OR BODY,” the entire contents of which are hereby incorporated herein by reference. This application is further related to provisional Ser. No. 61/505,849 filed Jul. 8, 2011, and U.S. application Ser. No. 14/131,564, filed Jan. 8, 2014, each entitled “PHOSPHORS AND SCINTILLATORS FOR LIGHT STIMULATION WITHIN A MEDIUM,” the entire contents of each of which is incorporated herein by reference. This application is related to and U.S. application Ser. No. 14/206,337, filed Mar. 12, 2014, entitled “INTERIOR ENERGY-ACTIVATION OF PHOTO-REACTIVE SPECIES INSIDE A MEDIUM OR BODY,” the entire contents of which are hereby incorporated herein by reference. This application is related to national stage PCT/US2015/027058 filed Apr. 22, 2015, entitled “TUMOR IMAGING WITH X-RAYS AND OTHER HIGH ENERGY SOURCES USING AS CONTRAST AGENTS PHOTON-EMITTING PHOSPHORUS HAVING THERAPEUTIC PROPERTIES,” the entire contents of which are hereby incorporated herein by reference. This application is related to U.S. Ser. No. 12/943,787, filed Nov. 10, 2010, now U.S. Pat. No. 9,232,618, the entire contents of which are hereby incorporated by reference. This application is also related to U.S. Ser. No. 16/096,174, filed Oct. 24, 2018, pending, the entire contents of which are hereby incorporated by reference. This application is related to PCT/US2016/057685, filed Oct. 19, 2016, entitled “X-RAY PSORALEN ACTIVATED CANCER THERAPY (X-PACT),” the entire contents of which are hereby incorporated herein by reference. This application is related to U.S. Ser. No. 15/434,871, filed Feb. 16, 2017, entitled “X-RAY PSORALEN ACTIVATED CANCER THERAPY (X-PACT),” the entire contents of which are hereby incorporated herein by reference. This application is related to U.S. Ser. No. 62/512,974, filed May 31, 2017, entitled “X-RAY PSORALEN ACTIVATED CANCER THERAPY (X-PACT) WITH ASSOCIATED TREATMENTS,” the entire contents of which are hereby incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2021/036218 | 6/7/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63039826 | Jun 2020 | US |
