March 2, 2013

Late-night $PVCT...

“A further impetus toward teasing out the precise mechanism of how PV-10 can exert a systemic 
immune response in patients,” said Dr. Sarnaik in an interview, “is to allow us to rationally combine PV-10 treatment with some of the exciting emerging immunotherapies for metastatic melanoma.” The focus at Moffitt, Dr. Sarnaik continued, is on discerning the presence of immune cell infiltrate in untreated tumors after PV-10 injections into other lesions. “We are really interested in harnessing immune cell infiltrate as a form of treatment,” he said, noting also that while creating cancer vaccines has been thought of traditionally as one of the Holy Grails of cancer research, cancer vaccines have turned out to be not strong enough to generate an adequate immune response. CANCER WATCH, VOL. 22, FEBRUARY 2013

I kept coming back to this portion of the article for two reasons. First, was Sarnaik's quote rationally combining PV-10 with other exciting emerging immunotherapies. What, PV-10 isn't exciting? Second, was his quote about harnessing immune cell infiltrate as a form of treatment. A better cancer vaccine because of PV-10?

The crux of the matter is that PV-10, as a local agent, needs to show systemic potential for life science investors, Big Pharma and the FDA to view the drug as clinically relevant. This is the local agent "burden of proof." There must be systemic potential to be relevant for treating cancer after surgery, where cancer is viewed by definition as a systemic disease. PV-10 is an drug with tremendous local efficacy and before unseen systemic benefit (even more so than systemic agents).

But PV-10 still is a local agent.

The mindset of the industry -- medical oncologists and hematologist-oncologists, but not surgeons -- is that a local agent has to be combined with a systemic agent to be relevant.  The industry does not yet realize how much of an impact PV-10 will be just as a local agent. All it can currently understand is that PV-10 works, and harnesses the immune system in novel manner. It is obvious to industry PV-10 will get even better systemic results when combined with other agents, or, other agents will get better results when combined with PV-10.

I am getting hung up about trying to understanding PV-10's potential as a monotherapy, but that's not where the industry's mindset currently resides (i.e., as I wrote above, it's in combination for now). That should come, however, and probably quickly.

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.

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.

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.

Moffitt, however, through their focus on adoptive T cell immunotherapy, believes PV-10 induces better T cells. T cell activation to very specific tumor targets. The ability to transfer immunity. Notice Moffitt's AACR abstract about PV-10 inducing a systemic anti-tumor immune response in murine models of melanoma and, now, breast cancer. More cancer indications validated by Moffitt on the way?

Moffitt, it seems to me, thinks 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.

I admit this post is a work in progress. The much greater point is understanding what PV-10 does to the immune system. PV-10: The Holy Grail? The cure for cancer? Perhaps...

No comments:

Post a Comment