May 31, 2013

$PVCT's PV-10: Resistance is Futile

GSK gets 2 cancer pills approved, but a deeper question is left unanswered, by Marc Iskowitz at Medical Marketing & Media (italicized quotes below, without attribution, are from the above article).

Before we excessively hail the arrival of GlaxoSmithKline's Tafinlar (dabrafenib) and Mekinist (trametinib), let's be thoughtful about their approval tells us (or, frankly, does not).

"Two targeted cancer pills that received the FDA's nod yesterday offer physicians another set of weapons to fight the disease. They also highlight a difficulty that has plagued recent advances—the body's resistance to personalized drugs."

"The approvals add to the excitement going into the American Society of Clinical Oncology (ASCO) annual meeting, which gets under way tomorrow in Chicago. However, they also underscore a difficulty. As drug makers advance in identifying targeted therapies for particular biomarker segments, in many cases where they've developed such a treatment, the cancer comes back months later."

A tumor's core is an anaerobic necrotic area where more dangerous cancer cells reside, compared to the outer layers and exterior of the tumor where cancerous cells are less abnormal and virulent. Standard chemotherapy or radiation kills the "easy" cancerous targets on the periphery of the tumor. The "hard" targets in the anaerobic core are difficult for drugs and radiation to destroy. A very Darwinian natural selection process occurs. The more hardy and vicious variants in the core survive, feeding off of and expanding into the room provided by the destruction of the easier-to-kill cancer cells at the periphery. Tumors re-occur and the next generation of them is drug- and radiation-resistant, having selected for the more virulent population. If you miss with the first round, everything is made worse for the patient.

"Scientists are realizing that “targeted therapies do not lead to long-term tumor control,” said Richard Wagner, PhD, a VP at Kantar Health. “This is a problem that shadows progress.” One example is Zelboraf, the drug approved in 2011 which targets the roughly 50% of melanoma patients whose tumors carry the BRAF gene mutation. In virtually all of these patients, the tumor starts to progress again in about five months."

The historic and current work on cancer vaccines faces the challenge of not being strong enough to generate an adequate immune response. Like with failed chemotherapy or radiation, where the treatment miss makes everything worse for the patient, vaccines are inducing tolerance by repeated exposure to antigens, convincing the immune not to react to tumor-associated antigens.

"But trying to find ways to prevent the development of resistance with targeted therapies has become another front in the war on cancer. It's also among the reasons why there is so much excitement about the immuno-oncology agents from BMS (nivolumab), Merck (MK-3475) and Roche (MPDL3280) that offer a third approach to treating the disease, beyond targeted therapies and conventional chemotherapy."

So, the industry is getting there. Slowly. Recall Craig et al.'s conclusion at SITC:

PV-10 in situ vaccination. Let the the antigen presenting cells (APCs) pick the antigen, rather than the other way around (as others are doing) and kill the tumor in situ. Let the APCs do their job and present antigens to T cells.

To Moffitt, PV-10 is the pathway to a more potent (i.e., generates a much stronger immune response), more effective (i.e., it heals, it cures), more broad (i.e., multi-indication) cancer vaccine.

Moffitt, however, through their focus on adoptive T cell immunotherapy, believes PV-10 induces better T cells, and thus T cell activation for very specific tumor targeting. Moffitt's AACR poster concluded PV-10 induced a systemic anti-tumor immune response in murine models of melanoma and breast cancer. Moffitt has concluded the same, through its murine work, in lung cancer, colorectal cancer, pancreatic cancer and liver cancer.

(Source withheld, 2009) There have been well documented but exceedingly rare cases of spontaneous or post-infection remissions in melanoma that appear to be immunologically mediated. There is a correlation between treatment-associated autoimmune depigmentation, or vitiligo, and favorable melanoma outcomes. Regression of uninjected melanoma modules after intralesional BCG therapy had been demonstrated.

Results with conventional therapy for metastatic melanoma up to that point remained poor. Melanoma patients at high risk of recurrence are readily identifiable. Tumor-induced immunosuppression increases with tumor burden. Immunotherapy should be more effective the earlier it is applied. 

But there are major obstacles to overcome: patient heterogeneity (variable outcomes for patients within similar stages, HLA haplotype differences), tumor antigenic heterogeneity (not all tumors express the same antigens), antigen loss (most immunogenic proteins are not essential to survival), tumor-induced immunosuppression, and the length of time needed for an immune response.

A weak or partial immune response to the tumor selects for more virulent tumor cells to survive, akin to antibiotic resistance in microbial infections. Vaccines are inducing “tolerance” by repeated exposure to antigen, convincing the immune system not to react to tumor-associated antigens and/or stimulating the generation of “suppressor” cells.

Tumor heterogeneity is a critical problem. In any given cell there are, say, 15,000 unique mRNAs at any given second. A few seconds later, illustratively, 15,000 new ones. There are, for example, at least 15,000 to 20,000 unique proteins on a membrane surface at any one time. These change continuously. Does picking one of them to form the basis of a cancer vaccine make sense? Does targeting a specific antigen as a holistic solution make sense?

Heterogeneity is so wide, trying to target a specific antigen might be tough if not hopeless task. A needle in a haystack? Maybe a needle in an entire whole galaxy.

Treating as many tumors as you can with PV-10 intratumorally achieves two significant positive outcomes. First, you lower the patient's overall tumor burden so as to allow the immune system to work better. Second, you allow more of the heterogeneous antigens (from the injected heterogeneous tumor) to be seen by the immune system. The more tumors treated by PV-10 the better.

"Speaking as part of a panel assembled by Kantar Health, King said that what he thinks is compelling about the experimental agents is the "ability to get treated for a year and walk away for three to five years.""

PV-10 is displaying impressive durable response in patients. Recall, via Provectus News, management informed shareholders and others about a Practical Dermatology article on PV-10 that included comments from principal investigator Dr. Sanjiv Agarwala, MD: "Since those data were first reported, “There are now data for longer follow-up periods that show those initial results are holding up,” says Sanjiv S. Agarwala, MD, Professor of Medicine at Temple University School of Medicine in Philadelphia and Chief, Oncology & Hematology at St. Luke’s Cancer Center in Bethlehem, PA."

As a monotherapy, clinicians want to use PV-10 before surgery when the immune system is not, moderately or less severely compromised, by itself after surgery too, and in very late stage disease patients with other agents when the immune system is overwhelmed and severely compromised.

PV-10 has a very good answer for this deeper question that other agents, including CTLA-4, PD-1, PDL-1 and OXO-40, have yet to answer as well.

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