Getting a grasp on GVAX

A study of immune responses from patients in a Phase II study of GVAX for prostate cancer by Cell Genesys was presented at AACR yesterday (abstract 4139). The analytical methodology used was quite nice: an expression library of cDNAs from the two allogeneic (meaning coming from other people) prostate cancer cells used as immunizing agents was constructed, and screened for immunoreactivity with sera from patients receiving immunotherapy, and counterscreened with pretreatment sera. The researchers eventually settled on 20 proteins that were frequently targetted in the immune responses to profile immune responses, and found patients receiving GVAX raised antibodies to different subsets of these proteins. Proteins included HLA-A24, filamin B, and NSFL1C.

The companies interpretation in a press release from yesterday, annotated with what I think are remaining important questions:
"Evaluation of antibody responses in patients with advanced prostate cancer from these studies shows that the GVAX cell-based immunotherapy induces antibody responses to a broad array of prostate cancer- associated antigens, including some not previously known to be associated with prostate cancer [1]. In addition, the antibody responses to this non patient- specific product were predominantly patient-specific and unique from patient to patient, indicating the potential advantage of a cell-based multi-antigen product such as GVAX to generate the broadest and most relevant immune response [2]. Serological analysis of gene expression (SEREX) technology was also used to identify target antigens involved in response to the immunotherapy. More than 148 proteins to which antibody responses were induced were identified and many of these proteins had not been identified previously as prostate cancer-associated antigens [1]. These findings were presented today by Dr. Thomas Harding and colleagues from Cell Genesys at the annual meeting of the American Association for Clinical Research being held in Los Angeles, CA."

[1] As far as I can tell, it is still not known if the newly identified antigens are specifically associated with prostate cancer. Certainly HLA-A24, filamin B, and NSFL1C are broadly expressed, based on cDNA sources (www.ncbi.nlm.nih.gov/UniGene/clust.cgi?ORG=Hs&CID=181244, www.ncbi.nlm.nih.gov/UniGene/clust.cgi?ORG=Hs&CID=476448, www.ncbi.nlm.nih.gov/UniGene/clust.cgi?ORG=Hs&CID=12865). So how specific are these or other newly identified antigens for prostate cells or cancerous cells?
[2] It should be noted that at the moment the authors can only hypothesize that the multitargetted immune response is the "most relevant" or that it is the "broadest". (And I assume they mean broadest relevant, as opposed to the theoretical broadest, which would be every antigen in the immunogen, which is decidedly not desirable, so "broadest and most relevant immune response" is a bit of sloppy language. "The broadest relevant immune response" would be better.) How can the authors test the relevance of each component of the immune response to clinical benefit, and prove that the different mixtures of responses seen in different patients are on the whole better than consistent responses across all patients to a small set of targets?

Hopefully some answers will be forthcoming (especially to question 1, which should be straightforward), in either upcoming publications or future research. That said, it's not necessary to know the answers for patients to benefit and the drug to be a great thing. Indeed, GVAX patients are living longer than historical controls, with no severe autoimmune cases reported so far. The worst case scenario is that this has happened by chance or by an artifact of the patient selection process or open label treatment protocol in the past Phase II trials and that autoimmunity crops up later. The best case is that the effect is real, and the body's immune response somehow is able to target a set of antigens that mediates anti-tumor activity without overt autoimmune sequalae. Natural systems have a way of surprising us with their robustness and adaptability.

Two Phase III trials, one comparing GVAX to docetaxel and prednisone, and the other comparing GVAX plus docetaxel and prednisone to docetaxel and prednisone alone, are ongoing. These trials are randomized, but not blinded or placebo controlled. That already introduces the possibility of bias as everybody roots for the new drug to work and may subconsciously pay a little more attention to what they can do to help the experimental subjects along. Hopefully there will be a benefit in survival, and it will be large enough to be convincing.

Very nice discussion here: www.extendmed.com/capvaccine/p7info.html