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The Technology Corner: Disruptive Technology for Prostate Cancer

In this special series we present emerging technologies which hold the promise to significantly improve the prognosis of patients diagnosed with prostate cancer, and cancer in general.  The goal of this series is to deeply investigate the unique technology that may soon change the mainstream approach to prostate cancer. ************************* The prostate is a component of the male exocrine gland system that is essential for normal reproductive function. Secretory fluid produced by the prostate physiologically supports male gamete cells to successfully achieve conception. In medicine, prostate cancer is the most common cancer found in the male population, afflicting one in six men. It is the second leading cause of cancer-based deaths amongst men in the US . Malignancy of the prostate has profound health consequences, including urinary dysfunction, pelvic pain, and erectile dysfunction 4-6. The disease rarely presents under the age of 40, making age the most significant risk factor – the longer life expectancy of men and the high morbidity/mortality observed makes prostate-cancer a high need condition. Although there are several treatment options available for patients diagnosed with progressive prostate cancer, the currently used modalities of treatment have important limitations 7,8. Surgical intervention – such as prostatectomy – comes with the normal risks associated with surgery, as well as the possibility of resultant erectile and urinary dysfunction. Radiotherapy such as XRT (external radiation therapy) and brachytherapy provide localized radiation to the prostate that can salvage surrounding healthy tissue, but is often associated with urinary urgency and frequency, painful urination, and rectal inflammation. Androgen deprivation hormone therapy, which includes the newly approved drug Abiraterone, provides a pivotal treatment regimen to inhibit the progression of advanced prostate cancer, but results in serious side effects that include cardiovascular disease, osteoporosis, cognitive deficits, and insulin resistance. Chemotherapy, which includes the newly approved drug cabazetaxel, is important for treating refractory prostate cancer, but does not salvage healthy tissue and includes significant side effects, such as blood cell suppression and peripheral neuropathy. Therefore, there remains a high-need for a broad-based therapeutic regimen to treat prostate cancer with minimal side effects. ************************ Advaxis Inc. is a biotechnology company that has developed a novel immune system stimulating technology; a bioengineered form of the bacterium Listeria monocytogenes indicated for the treatment of cancer and infectious diseases. The company has modified this bacterium to lack the virulence capabilities it requires to cause an active infection, but has preserved its potent immune adjuvant properties that elicit a maximum immune system response. Capitalizing on the retained immune-stimulating capabilities, the company has fused disease-specific protein elements, or antigens, to the bacteria’s immune adjuvant proteins, causing the mounted immune response to be an attack against the disease. The ability to modify the antigen elements as needed enables Advaxis to utilize its platform to treat a broad-scope of conditions, such as infectious diseases and cancer. Currently, Advaxis has developed its technology for the treatment of over 6 different types of cancers, including breast cancer, head and neck cancer, cervical cancer, and prostate cancer. In pre-clinical and clinical studies Advaxis has been able to show that its therapies not only produces a strong systemic response against the cancer, but unlike current medications it is also able to change the microenvironment of tumors to make them susceptible to an immune system attack, leading to a therapeutic response that has shown unprecedented complete tumor regression in the pre-clinical studies. The company’s therapy for prostate cancer is currently in pre-clinical studies and incorporates the hallmark PSA antigen of prostate cancer. Apovax Inc. is a biotechnology company that has developed a powerful therapeutic-protein platform that modulates the patient’s immune system in order to treat diseases. Depending on the goal of these therapies, the company’s products can either up-regulate or down-regulate the immune system to obtain the desired therapeutic outcome. In the latter case, the therapeutic protein is able to mount an immune response against an infectious disease or particular cancer that the patient is suffering from. At the core of Apovax’s immunological-stimulating technology is a chimeric protein with dual characteristic properties; a streptavidin protein segment that enables aggregation of these proteins into tetramers and an immuno-regulatory protein segment that can bind to immune cells and activate them. This design not only enables these therapeutic proteins (self termed Apovax) to bind the immune cells, but also to aggregate into a complex upon binding, which is required for obtaining a maximal immune response. Conventionally used protein methodologies that bind to immune cells to activate them lack the capabilities of aggregating into complexes and therefore only achieve a weak stimulation of the immune system. These Apovax proteins are then combined with a disease-specific marker, or antigen, to comprise the complete therapy that produces a strong immune system response against the specified disease. Apovax is currently developing its platform to treat cervical cancer, colon cancer and prostate cancer. Pre-clinical studies have shown that Apovax is far more effective and less toxic than counter part vaccine technologies currently in clinical trials, including agonistic antibodies. Furthermore, studies have shown that while Apovax generates a potent immune response, it also suppresses a specific component of the immune system known as T-regulatory cells that confer tumors with the ability to evade the immune system. T-regulatory cells shut down normal immune defense in the tumor microenvironment making them an immune privileged, and Apovax’s capability to suppress this action give it a considerable advantage as a therapeutic cancer treatment. The company is utilizing its Apovax technology in conjunction with the hallmark PSA prostate cancer antigen indicated for the treatment of prostate cancer. Inovio Pharmaceuticals is an emerging leader in the development of powerful therapeutic DNA vaccines that serve to actively induce a potent immune system response against and for the treatment of infectious diseases and cancer. DNA vaccines function by expressing the genetic material for a specific disease-marker, or antigen, in conjunction with a known immune adjuvant within the cells of the patient. Expression of the antigen/adjuvant by the patient’s cells mounts an acute immune response against the disease that serves to treat the condition by decimating the afflicted cells. DNA vaccines are the next generation of vaccine technology providing significant improvement over the attenuated pathogen protein-based vaccines conventionally used. Unlike their older counterparts DNA vaccines provide scalable production capabilities, increased shelf life stability, increased safety profile with no risk of causing the disease, and most importantly, mounts an immune response that provides the protective immunity seen with today’s vaccines, as well as therapeutic treatment of the ongoing disease. Although DNA vaccines hold the potential to serve as breakthrough therapies for high-need unmet medical conditions, their clinical development has been hampered by significant obstacles. Two principle challenges have been the efficient transfer of the DNA vaccine into the cell of the patient and the development of vaccines that can mount an immune response against the different strains of an individual virus. To this end, Inovio has developed breakthrough, proprietary DNA vaccine design and DNA delivery platforms. The companies SynCon-DNA vaccine design technology utilizes bioinformatics, extensive genetic data, sophisticated mathematical algorithms and ultra-powerful computing to develop vaccines that are competent to mount an immune response against different viral sub-types of a given virus family. In pre-clinical studies Inovio has shown that its SynCon DNA vaccine design is able to elicit an immune response against multiple sub-types of HIV, HCV, HPV or influenza virus. To deliver its DNA vaccines, Inovio employs its Electroporation DNA delivery platform. This technology works by applying controlled, millisecond electrical pulses across the injection site where the DNA vaccine is being administered. The electrical pulses create a huge increase in the permeability of the cells at the injection site enabling a dramatic uptake of the DNA vaccine that was previously not possible. Furthermore, the electorporation itself serves as an immune adjuvant that enhances the response by the immune system. In pre-clinical and clinical studies Inovio has shown that in comparison to injection alone, electroporation increases expression of the vaccine by over 100-fold and develops an immune response that is approximately 100-fold stronger. Electroporation has been shown to be tolerable without anesthetic, cost effective in manufacturing processes, and does not elicit unwanted side effects thereby enabling repeated use for administration. Taken together, Inovio’s proprietary DNA vaccine design and delivery platform poises the company at the forefront of clinically actualizing this therapeutic modality. Inovio’s DNA vaccine indicated for the treatment of prostate cancer is currently in Phase I clinical trials.   References   1. Rhoades R, Pflanzer R. Human Physiology. 4 ed: Brooks/Cole; 2002. 2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010 Sep-      Oct;60(5):277-300. 3. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating     socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011     Jul-Aug;61(4):212-36. 4. Hoffman RM. Clinical practice. Screening for prostate cancer. N Engl J Med. 2011 Nov     24;365(21):2013-9. 5. Dunn MW, Kazer MW. Prostate cancer overview. Semin Oncol Nurs. 2011 Nov;27(4):241-     50. 6. Wei JT, Dunn RL, Sandler HM, et al. Comprehensive comparison of health-related quality      of life after contemporary therapies for localized prostate cancer. J Clin Oncol. 2002 Jan      15;20(2):557-66. 7. Higano CS, Crawford ED. New and emerging agents for the treatment of castration-     resistant prostate cancer. Urol Oncol. 2011 Nov-Dec;29(6 Suppl):S1-8. 8. Osanto S, Van Poppel H. Emerging novel therapies for advanced prostate cancer. Ther Adv     Urol. 2012 Feb;4(1):3-12.   Mario with television series ‘the doctors’

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