Patent Application
20210196337
None.
The present invention relates to systems and methods for treating cancer with cold atmospheric plasma.
Cancer is a disease that results from abnormal cells growing without control. Normal cells are pre-controlled by genes that promote the process of cell division. Life is dependent on the function of cells to reproduce or make exact copies of each other. Cell division is a process that one cell divides into two cells. This process is called mitosis. The cells go through a cell cycle, a process of growing, breaking down and repair about 50 times before death. When the normal cell cannot be repaired, it goes through a pre-programmed cell death or apoptosis. Cancer cells avoid repair and apoptosis pathway and continue grow rapidly, uncontrolled that results in tumor formation. In summary cancer is a disease of mitosis. The normal regulatory pathways for mitosis are ignored or bypass by cancer cells. Cancer starts when a single cell is transformed or converted from normal cell to a cancer cell. This process is a result from change in function of genes that control growth or suppress tumor formation.
Cancer is among leading causes of death worldwide. In descending order breast cancer, lung and bronchus cancer, prostate cancer, colon and rectum, anal, melanoma of the skin, bladder cancer, non-Hodgkin Lymphoma, kidney and renal and pelvis cancer, endometrial cancer, leukemia, pancreatic cancer, thyroid cancer and liver are the most common new cancer cases in 2018.
Breast cancer is the most common cancer diagnosed among US women and is the second leading cause of death among women after lung cancer. The estimated cases and deaths in 2017 related to breast cancer are 252,710 new cases of invasive breast cancer and 63,410 cases of in situ breast cancer and 40,000 deaths. Cody and Van Zee3 reported that 180,000 women underwent breast—conserving surgery. The other breast cancer epidemic reported by Cody and Van Zee that the re-excision rate for microscopic positive margins at the surgical site range from 10% to 50%.
Tumor spreading within the abdominal cavity is defined as peritoneal carcinomatosis (PC). Tumor arises primarily from peritoneal surface or visceral organs. Uncontrolled expansion of the primary tumor leads to spreading that allows the tumor cells to peel off and circulate within the peritoneal fluid, permitting an increase progression of disease given the decrease growth inhibition in the implanted peritoneal metastases. The end result of this diffuse tumor cell implantation of vital organs is malnutrition, bowel obstruction and death.
Surgical resection has not been accepted as a standard option for PC from GI cancers. Median survival is 6 to 12 months with systemic chemotherapy. In the 1990's Dr. Paul Sugarbaker and others published cytoreductive surgery (CRS), peritonectomy combined with hyperthermic intraperitoneal chemotherapy (HIPEC) to treat peritoneal surface malignancy. Several authors have reported that CRS plus HIPEC have increased survival in selected patients with colorectal, appendiceal and primary peritoneal cases. The application of CRS and HIPEC is an aggressive local regional approach for the treatment PC. The purpose of CRS is to leave little or no residual disease within the abdomen. After surgery HIPEC is used to wash the abdominal cavity with a heated high concentrated chemo-therapeutic drug. The pharmokinetic benefits of the intraperitoneal route of chemotherapy are increased drug concentrations, locally dose intensive therapy and the synergistic effect of hyperthermia. Hyperthermia alone has a cytotoxic effect on malignant cells and facilitate greater tissue penetration of the antineoplastic agents. The combination of CRS and HIPEC is believed to achieve macroscopic and microscopic disease clearance and possible improved survival. Despite the promise of improved survival in patients with PC, HIPEC is associated with significant morbidity and mortality.
Lympho-proliferative cancers (leukemia, lymphoma) most patients diagnosed with solid cancerous tumors (i.e., colon, ovarian, cervical, lung, liver, bile duct, brain, bone, small intestine, melanoma, sarcoma) require surgical treatment as a single modality therapy or as a major component in a multi-modality therapy. The main limitations of surgery are the inability of the surgeon to identify occult disease and unable to completely resect tumors adjacent to vital organs. As a result, the tumor returns in the form of loco-regional or metachronous distant metastasis. Application of chemotherapy or radiation therapy before, during- or after surgery may decrease disease recurrence.
Cold atmospheric plasma (CAP) has been extensively studied in various biomedical fields. It is a novel approach to targeted cancer treatment and has demonstrated its anti-cancer effects in vitro. See, Rowe, W., X. Cheng, L. Ly, et al., The Canady Helios cold plasma scalpel significantly decreases viability in malignant solid tumor cells in a dose-dependent manner. Plasma, 2018. 1(1): p. 177-188; Barekzi, N. and M. Laroussi, Effects of low temperature plasmas on cancer cells. Plasma Processes and Polymers, 2013. 10(12): p. 1039-1050; Barekzi, N. und M. Laroussi, Dose-dependent killing or leukemia cells by low temperature plasma. Journal of Physics D: Applied Physics, 2012.45(42); and Keidar, M., R. Walk, A. Shashurin; et al., Cold plasma selectivity and the possibility of a paradigm shift in cancer therapy. Br J Cancer, 2011. 105(9): p. 1295-301. The detailed mechanism has not been fully elucidated; however, studies have established that CAP selectively induces apoptosis and DNA damage in tumor cells. Arndt, S., M. Landthaler, J. L. Zimmermann, et al., Effects of cold atmospheric plasma (cap) on ss-defensins, inflammatory cytokines, and apoptosis-related molecules in keratinocytes in vitro and in vivo. PLoS One, 2015. 10(3): p. e0120041; Bauer, G., D. Sersenova, D. B. Graves, et al., Cold atmospheric plasma and plasma activated medium trigger rans-based tumor cell apoptosis. Sci Rep, 2019. 9(1): p. 14210; Cheng, X., W. Rowe, L. Ly, et al., Treatment of triple-negative breast cancer cells with the Canady cold plasma conversion system: Preliminary results. Plasma, 2018. 1 (1): p. 218-228. Further research indicates low doses of CAP does not damage normal tissue. See, e.g., Lee, J. II., J. Y. Om, Y. H. Kim, et al., Selective killing effects of cold atmospheric pressure plasma with no induced dysfunction of epidermal growth factor receptor in oral squamous cell carcinoma. PLoS One, 2016. 11(2): p. e0150279. Recently, indirect CAP treatment was effective for the treatment of CCA in vitro, selectively killing CCA cells over normal hepatocytes. Vaquero, J., F. Judee, M. Vallette, et al., Cold-atmospheric plasma induces tumor cell death in preclinical in vivo and in vitro models of human cholangiocarcinoma. Cancers, 2020. 12(5). Research on CAP in combination with other therapies has shown some potential synergism with anti-neoplastic agents in melanoma cells (Sagwal, S. K., G. Pasqual-Melo, Y. Bodnar, et al., Combination of chemotherapy and physical plasma elicits melanoma cell death via upregulation of slc22al 6. Cell Death Dis, 2018. 9(12): p. 1179), drug loaded nanoparticles in breast cancer cells (Zhu, W., S. J. Lee, N.J. Castro, et al., Synergistic effect of cold atmospheric plasma and drug loaded core-shell nanoparticles on inhibiting breast cancer cell growth. Sci Rep, 2016.6: p. 21974), and gemcitabine in murine pancreatic cancer cells (Masur, K., M. van Behr, S. Bekeschus, et al., Synergistic inhibition of tumor cell proliferation by cold plasma and gemcitabine. Plasma Processes and Polymers, 2015.12(12): p. 1377-1382).
Delivery of cold atmospheric plasma at the surgical margins immediately after tumor resection has shown potential as an anti-cancer therapy. A Canady Cold Plasma Conversion System is an electrosurgical system that produces CAP for the treatment of surgical margins upon tumor resection (U.S. Pat. No. 9,999,462). One of the advantages of cold atmospheric plasma systems is that the CAP temperature remains between 26-30° C. during the duration of the treatment (Cheng, X., et al., Treatment of Triple-Negative Breast Cancer Cells with the Canady Cold Plasma Conversion System: Preliminary Results. Plasma, 2018. 1(1): p. 218-228) and does not cause any thermal or physical damage to normal tissue (Ly, L., et al., A New Cold Plasma Jet: Performance Evaluation of Cold Plasma, Hybrid Plasma and Argon Plasma Coagulation. Plasma, 2018. 1(1): p. 189-200).
In a preferred embodiment, the present invention is a method for treatment of solid cancer tumors. The method comprises pre-operatively treating a patient having a solid cancer tumor with at least one of chemotherapy and radiation therapy, surgically removing the solid cancer tumor, and applying cold atmospheric plasma to the surgical margins surrounding the area in the patient from which the solid cancer tumor was removed. The step of pre-operatively treating a patient may comprise treating the patient pre-operatively with both chemotherapy and radiation therapy. The method may further comprise post-operatively treating the patient having a solid cancer tumor with at least one of chemotherapy and radiation therapy. The step of applying cold atmospheric plasma to the surgical margins comprises applying cold atmospheric plasma to the surgical margins for no more than 5 minutes, no more than 3 minutes or no more than one minute. Further, the step of applying cold atmospheric plasma to the surgical margins may comprise applying cold atmospheric plasma to the surgical margins at 120p with a helium flow rate of 3 l/min. Still further, the method may comprise intra-operatively treating a patient having a solid cancer tumor with at least one of chemotherapy and radiation therapy. The method further may comprise performing at least one of cytoreductive surgery and peritonectomy combined with hyperthermic intraperitoneal chemotherapy on the patient.
Still other aspects, features, and advantages of the present invention are readily apparent from the following detailed description, simply by illustrating a preferable embodiments and implementations. The present invention is also capable of other and different embodiments and its several details can be modified in various obvious respects, all without departing from the spirit and scope of the present invention. Accordingly, the drawings and descriptions are to be regarded as illustrative in nature, and not as restrictive. Additional objects and advantages of the invention will be set forth in part in the description which follows and in part will be obvious from the description or may be learned by practice of the invention.
For a more complete understanding of the present invention and the advantages thereof, reference is now made to the following description and the accompanying drawings, in which:
Cholangiocarcinomas are rare with a low five-year survival rate. Cold atmospheric plasma (CAP) is a promising technology as a selective cancer treatment due to its anticancer properties. In pancreatic and liver cancers, FOLFIRINOX has emerged as an effective combination cancer drug treatment. It has been reported that FOLFIRINOX increased overall patient survival over gemcitabine treatment in patients with metastatic pancreatic cancer but is limited due to toxicity. See, T. Conroy et al., N. Engl. J. Med., 364, pp. 1817-1825 (2011) and T. Conroy et al., N. Engl. J. Med., 379, pp. 2395-2406 (2018).
The present invention is a method for treating cancer with a combination of cold atmospheric plasma (CAP) in combination with other therapies. CAP has been shown to produce no thermal damage to healthy tissues after the margins of resected tumor tissues. Rossi F, De Mitri R, Bobin S, et al. Plasma sterilisation: mechanisms overview and influence of discharge parameters. In: D'Agostino R, Favia P, Oehr C, et al., editors. (eds) Plasma processes and polymers. Germany: Wiley-VCH Verlag GmbH & Co. KGaA, 2005, pp. 319-331. CAP also has been shown to have an effect on cancer tissues and cells located at a remote site form the treated lesion. C, Berganza C, Zhang J. Cold atmospheric plasma: methods of production and application in dentistry and oncology. Med Gas Res 2013; 3: 21.
The present invention uses CAP in patients undergoing surgical treatment of solid tumors in combination with systemic chemotherapy, hyperthermic intraoperative chemotherapy, intraoperative or external beam radiation therapy or cytoreductive surgery for the treatment of solid tumors. The method is to apply CAP treatment for ablation of cancerous cells at the surgical margin and macroscopic tumor sites in combination with systemic chemotherapy, cytoreductive surgery, HIPEC, external beam or intraoperative radiation therapy for solid tumors.
Cold atmospheric plasma (CAP) provides a unique, rich environment of reactive oxygen species (ROS), reactive nitrogen species (RNS), charged particles, photons, and electric field. This unique combination of chemical and physical properties of CAP technology has enabled recent biomedical applications including cancer therapy. Some chemical components of the CAP are highly selective, such as ROS, which might promote a “plasma killing effect,” while others such as RNS could produce a “plasma healing” effect. Combining these species in various controlled blends provides an unprecedented potential to activate specific signaling pathways in cells. Combining RON species in various controlled blends provides an unprecedented potential to activate specific signaling pathways in cells.
What makes plasma absolutely unique is its ability to self-organize and form coherent structures. These coherent structures modulate plasma chemistry and composition, including reactive species, the electric field and charged particles. These coherent structures tend to modulate plasma chemistry and composition, including reactive species, the electric field and charged particles. Formation of coherent plasma structures allows the plasma to adapt to external boundary conditions, such as different cells types and their contextual tissues. As result, plasma interaction with cells is altered leading to differential effect of plasma on different cells, i.e., selective killing of cancer cells in comparison with normal cells.
The mechanism by which CAP affects the cancer is based on the production and efficient delivery of reactive oxygen and nitrogen species (RONS) analogous to those produced naturally by cells. The CAP-originated reactive species will cause a noticeable rise of intracellular ROS, which weakens the intracellular antioxidant system and further causes serious DNA double-strand break. As a result, cell cycle arrest and apoptosis based on mitochondrion-pathway or tumor necrosis factor receptor-pathway occur.
CAP is capable of gentle non-thermal modification of the radical balance in cells leading to apoptosis rather than necrosis. In contrast, conventional lasers in medical devices are based on the thermal interaction with tissues, which lead to necrosis and permanent tissue damage. Tuning the gas pressure (helium), gas composition (helium/oxygen) and energy can control the chemical responses of the tissue to a CAP jet. Various chemical components of the CAP jet (e.g., RONS) are highly selective, such as oxygen, which might promote a “plasma killing effect”, while nitric oxide could produce a “plasma healing” effect. Conceptually, it is the introduction/delivery of these potentially selective toxic ion-species into the tumors through diffusion processes and the electric field produced by plasma that will form this foundation of new cancer therapy. Recently our group and other groups world-wide reported that the CAP jet; a) selectively kills cancer cells in vitro with a significantly lesser effect on normal cells; and b) significantly reduces tumor size in vivo. We established the following mechanism to describe the plasma effect: the synergistic effect of selective diffusion of RONS into tumor cells (via activation of the aquiporins (AQP)) and the high basic RONS level in tumor cells would make a dramatic difference in the response of normal and tumor cells to CAP, thereby crossing a survival threshold for tumor cells and leading to cell death through DNA damage, apoptosis or cell cycle arrest.
In addition, the RONS metabolism and oxidative stress-responsive genes are deregulated following CAP application, and the differential effects of CAP on various cancer cells results in G2/M arrest. Fewer normal cells were in S-phase (˜10%) compared to the two cancer cell lines (transformed cells are highly proliferative): ˜50% for 308 cells and ˜45% for PAM212 cells. No increase in the fraction of cells in the S-phase after CAP treatment was observed for the three cell types: their number either remained the same or decreased. However, the present inventors observed an increase in the ranging of standard deviation value of CAP treated cells in S-phase of around ˜20% for all three cell types suggesting that not all cells within the population of cells responded the same to CAP treatment. While there is no significant difference in the numbers of cells in the S-phase of the cell cycle, one can see that the number of cells in the G2/M fraction increased by ˜25% for normal cells and two- to threefold for transformed cells. The increase in the fraction of cells at the G2/M-phase of the cell cycle is accompanied a decrease in the number of cells in the G0/G1 fraction. The general trend in the distribution of cells within the cell cycle indicates that timing of the cell cycle is different for chosen cells. Overall analysis of CAP effect on carcinoma, papilloma and glioblastoma cells suggested that the CAP treatment causes significant arrest in the G2/M phase. As such, the present inventors have found that CAP treatment can be combined with chemotherapy and radiation therapy targeting cancer cells in specific phase of the cell cycle.
For example, GBM is a highly malignant very aggressive neoplasm of the central nervous system characterized by rapid growth, extensive angiogenesis, and resistance to all current therapies. Thereby, GBM is associated with poor survival and high mortality where approximately 7,500 patients die from GBM each year. Treatments of GBM tumors remain largely palliative despite recent advances with the integration of multi-modal therapies. The standard of care for newly diagnosed GBM is maximal surgical resection followed by six cycles of concurrent radiation and chemotherapy (i.e., Temozolamide, TMZ), which has been shown to only improve median survival up to 14.6 months and a continued dismal five-year survival at less than 10%. The major limitations of tumor treatment and eventual tumor recurrence are: (a) the tumor cells are very resistant to conventional therapies; (b) the brain is susceptible to damage with conventional therapies; (c) the brain has a very limited capacity to repair itself, and (d) many drugs cannot cross the blood-brain barrier to act on the brain tumor. Thus, it is necessary to develop novel tools that can provide selective targeting of proliferating tumor cells and also enhance existing therapies.
To evaluate effect of CAP on brain tumor, a micro-CAP device was developed and directly applied to glioblastoma tumors in the brain of living mice via an implanted endoscopic tube. See U.S. Published Patent Application No. 2018/0271579. Using in vivo bioluminescence imaging, the tumor volume in a control animal (helium only) increased nearly 600% over the course of two days, whereas micro-CAP-treated tumor volume decreased approximately 50% compared with baseline levels. In the control animals, there is a clear increase in tumor volume over the 2-day period. In contrast, micro-CAP-treated animals fell below baseline values. These striking findings demonstrate the potential of CAP to inhibit glioblastoma tumor growth in vivo. Given these findings, it can be suggested that cold plasma represents a promising new adjunct for cancer therapy, offering the ability to directly target and selectively kill neoplastic tissue. Notably, CAP device provides a method for practical administration of this cancer therapy. Plasma therapy could potentially target internal malignancies via an endoscopic delivery system, thus enabling this technology to serve as either a standalone treatment option or, more realistically, an adjuvant to existing therapies.
A method for treating solid tumors with a combination of CAP and other therapies in accordance with a preferred embodiment of the present invention is shown in
A preferred embodiment of a CAP enabled generator is described with reference to the drawings. A gas-enhanced electrosurgical generator 200 in accordance with a preferred embodiment of the present invention is shown in
A generator housing front panel 210 is connected to the housing 202. On the face front panel 210 there is a touchscreen display 212 and there may be one or a plurality of connectors 214 for connecting various accessories to the generator 200. For a cold atmospheric plasma generator such as is shown in
As shown in
As shown in
Another embodiment, shown in
In the above-disclosed embodiment, a cold atmospheric plasma below 35° C. is produced. When applied to the tissue surrounding the surgical area, the cold atmospheric plasma induces metabolic suppression in only the tumor cells and enhances the response to the drugs that are injected into the patient.
The cold plasma applicator 500 may be in a form such as is disclosed in U.S. Pat. No. 10,405,913 and shown in
As summarized in
The patients' vital sign statuses were monitored during the surgery and CAP administration. Graphs of the intraoperative data of O2 saturation, body temperature and pulse for the fifteen subjects treated with combination therapy are shown in
Additionally, subject tumor samples were treated ex vivo with CAP at the time of surgery and dissociated and cultured in the lab. Images of cells were taken for both treated and untreated samples.
From the culture images shown in
Translational molecular processing also was performed on resected cancer tissue and blood from the subject patients.
The foregoing description of the preferred embodiment of the invention has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed, and modifications and variations are possible in light of the above teachings or may be acquired from practice of the invention. The embodiment was chosen and described in order to explain the principles of the invention and its practical application to enable one skilled in the art to utilize the invention in various embodiments as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims appended hereto, and their equivalents. The entirety of each of the aforementioned documents is incorporated by reference herein.
The present application claims the benefit of the filing date of U.S. Provisional Patent Application Ser. No. 62/983,636 filed by the present inventors on Feb. 29, 2020. The present application further is a continuation-in-part of U.S. Non-provisional patent application Ser. No. 17/135,866, filed on Dec. 28, 2020, which claims the benefit of the filing of U.S. Provisional Patent Application Ser. No. 62/953,783 filed by the present inventors on Dec. 26, 2019. The aforementioned patent applications are hereby incorporated by reference in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| 62983636 | Feb 2020 | US | |
| 62953783 | Dec 2019 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 17135866 | Dec 2020 | US |
| Child | 17189185 | US |
