February 26, 2013

$PVCT: #Tumor Heterogeneity

I’ve tried to understand the issue, problem and challenge of tumor heterogeneity, and why and how PV-10 works so well. I’ve previously written that to understand PV-10 is to understand the relationship between chemoablation and immune-mediated signaling. It's what Craig means when he says the immune system responds in direct proportion to the degree of insult. Think of PV-10 chemoablation as the proxy for the degree of insult, which is rapid, complete and durable in the case of PV-10. But when Craig describes his approach in this way, what is he really getting at? How did he approach tackling or solving tumor heterogeneity?

(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.

PV-10: 1. Lower tumor burden. 2. Cover the antigenic spectrum as broad as one can.

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