December 21, 2012

$PVCT: What Could An Autopsy of Failed Drug $ONTY Tell Us About $PVCT

I found Martin Shkreli's article on about Oncothyreon's Stimuvax failure a few days ago interesting. Shkreli wrote an earlier article too on the same topic in July 2011. It's the second article and the section on Mechanism of Action that I want to focus on (bold is my emphasis).
Stimuvax is often referred to as a MUC1 “cancer vaccine”. The problem with this terminology is Stimuvax is not a vaccine in any way, shape or form.­­ Vaccines typically stimulate an immune response against an introduced antigen. This allows the immune system to fight off this antigen in the future. 
MUC1 is widely expressed in humans. Stimuvax is liposomal MUC1, so Stimuvax can’t be a MUC1 vaccine because the immune system won’t know that MUC1 is an antigen to fight off. 
Without some leukopheresis/immune-training process, a-la Dendreon or a specialized adjuvant, it is difficult to generate a vaccine to an endogenously found peptide. A MUC1 antibody or small molecule antagonist would make a lot more sense. Indeed, several companies are attempting to improve the immune response for prospective MUC1 vaccines as well as attempting targeted payload strategies for MUC1. MUC1 is certainly a good marker for cancer, but it still isn’t useful. MUC1 tests are no longer used. MUC16, which you may know better as CEA125, is widely used to determine ovarian cancer staging and status. Antibodies, armed antibodies and vaccines to CEA125 went nowhere.
According to the NIH’s protein database, mucin 1 (MUC1) is a 1255 amino acid protein. Stimuvax is the common repeat found in mucin 1. I wonder if the inventors assumed this will serve as an antigen to the immune system and T cells will destroy any cell with mucin 1 expression. It doesn’t take a cell biologist to appreciate this is not a good idea given the widespread expression of MUC1. 
Furthermore, without legitimate immune response data and with no side effects, my supposition that Stimuvax is inert is likely correct. The tandem repeat found in Stimuvax is no different from native MUC1. While the glycosylation patterns may be different, it’s hard to see MUC1 inducing a potent immune response. Indeed, the failure of the similar MUC16 to generate a viable anticancer candidate bodes poorly for MUC1 and Stimuvax.
Getting back to the question of whether Stimuvax is an effective vaccine, we noticed that only 21% of Stimuvax patients in the Phase IIB study had an immune response to Stimuvax. Because the only way Stimuvax could have any anti-cancer effect would be through immune recognition of the MUC1 tandem repeat, and a subsequent immune response strong enough to destroy MUC1 expressing cells (a long shot), a 21% immune response (forget evidence of a CR/PR) is not promising. 
Most good vaccines have to have 100% immune responses or close to it. The immune response data is uncontrolled and hazy at best. For a drug billed as a vaccine, Stimuvax doesn’t do a great job of proving it is a vaccine. Even in a small n=22 trial that tested a new formulation of Stimuvax, immune response results were not disclosed.
Oncothyreon tried the Dendreon approach of cherry picking antigens to generate immune responses. Immunotherapuetic advancements need to harness much more comprehensive immune-mediated response than limiting selection criteria.

I think Moffitt will have a lot more to say about vaccine-like PV-10.

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