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
Wednesday, April 18, 2007
Tuesday, April 17, 2007
The immune system - master snooper
Vaccines are not limited to recognizing antigens on the surface of cells. In all cells, intracellular proteins are processed into peptides and translocated to the surface in Class I MHC molecules which are then recognized by antigen-specific receptors on T cells. If provided with the right stimulation at the same time that they are recognizing an antigen in the Class I MHC complex, these cells can go on to become cytotoxic T lymphocytes (CTLs) that go around killing cells expressing the antigen. In this way the immune system is always checking up on the identity of your body's cells and taking lethal action when appropriate. Creepy, isn't it?
This becomes important for efforts to develop vaccines to intracellular proteins such as p53. A study at AACR The particular study by Chikamatsu et al. claims that the presentation of wild-type (nonmutated) p53 peptides is enhanced in some tumors, providing a rationale for making vaccines against wild-type p53. The authors found several peptides from p53 that could elicit CTL activation in vitro when presented by dendritic cells, and these CTLs showed cytolytic activity toward squamous cell carcinoma of the head and neck cells in vitro. It remains to be seen how well this would work in the in vivo background of lots of cells expressing p53. Previous studies had proposed generating immune responses to particular mutant sequences of p53 commonly occurring in cancers.
This becomes important for efforts to develop vaccines to intracellular proteins such as p53. A study at AACR The particular study by Chikamatsu et al. claims that the presentation of wild-type (nonmutated) p53 peptides is enhanced in some tumors, providing a rationale for making vaccines against wild-type p53. The authors found several peptides from p53 that could elicit CTL activation in vitro when presented by dendritic cells, and these CTLs showed cytolytic activity toward squamous cell carcinoma of the head and neck cells in vitro. It remains to be seen how well this would work in the in vivo background of lots of cells expressing p53. Previous studies had proposed generating immune responses to particular mutant sequences of p53 commonly occurring in cancers.
Cancer vaccines - Different approaches
It has been asked what the risk of creating autoimmune disorders would be from a cancer vaccine. Good question and its certainly a theoretical concern if you are training the immune system to target antigens that are also expressed on normal cells. It's unlikely to be a concern with Provenge, because prostate cells are the only ones expressing PAP, and the patient would have had the prostate already removed. It's more a concern with approaches such as Cell Genesys' GVAX or Antigenics' Oncophage which use cell lysates, i.e. mixtures of all antigens in the cell, most of which will be universal, rather than just one.
That said, it may be possible to create an immune response against a widely expressed antigen and still have it result in a therapeutic index > 1 if the antigen is more highly expressed in cancerous tissue and if the immune response is not too strong. This is what already seems to be occuring in passive immunotherapy, e.g. administration of anti-HER2 antibodies for breast cancer aka Herceptin aka Genentech's hot-selling drug. HER2 is by no means confined to breast cancer cells; its just more highly expressed in them. Given these complexities, I think it's safer to use the single antigen approach like Dendreon is doing because it allows testing of the therapeutic ratio of immune responses to a single trigger, rather than the throw everything at the wall and see what sticks approach of Cell Genesys or Antigenics. The latter could still work, but it is less predictable, I think.
Where else could a single-antigen approach work? Spontaneous immune-mediated remissions has often been seen with melanomas, which seem to be naturally antigenic, likely because melanocytes express several antigens that are not found in any other tissue and because the skin is full of dendritic cells that are ready to sound the alarm to the immune system if they smell something fishy. Anybody who has undergone allergy testing or has allergic dermatitis or eczema can attest to this. The fact that one can live without melanocytes makes melanoma like prostate cancer a good target for immunotherapy, and in fact there are many cancer vaccines under development for melanoma.
That said, it may be possible to create an immune response against a widely expressed antigen and still have it result in a therapeutic index > 1 if the antigen is more highly expressed in cancerous tissue and if the immune response is not too strong. This is what already seems to be occuring in passive immunotherapy, e.g. administration of anti-HER2 antibodies for breast cancer aka Herceptin aka Genentech's hot-selling drug. HER2 is by no means confined to breast cancer cells; its just more highly expressed in them. Given these complexities, I think it's safer to use the single antigen approach like Dendreon is doing because it allows testing of the therapeutic ratio of immune responses to a single trigger, rather than the throw everything at the wall and see what sticks approach of Cell Genesys or Antigenics. The latter could still work, but it is less predictable, I think.
Where else could a single-antigen approach work? Spontaneous immune-mediated remissions has often been seen with melanomas, which seem to be naturally antigenic, likely because melanocytes express several antigens that are not found in any other tissue and because the skin is full of dendritic cells that are ready to sound the alarm to the immune system if they smell something fishy. Anybody who has undergone allergy testing or has allergic dermatitis or eczema can attest to this. The fact that one can live without melanocytes makes melanoma like prostate cancer a good target for immunotherapy, and in fact there are many cancer vaccines under development for melanoma.
AACR in the news
Cancer vaccines are getting some news from the ongoing AACR meeting in Los Angeles. Most of the news in the media is about the HPV vaccine to prevent cervical cancer. However, the cervical cancer vaccines are really only vaccines against the virus that causes cervical cancer, and so are more like other microbio vaccines, e.g. flu vaccines. To call them cancer vaccines is a bit of a misnomer, and also trivializes the much more difficult issue of making true cancer vaccines, i.e. vaccines that can effectively discriminate cancerous from noncancerous cells and can overcome self tolerance.
The most interesting developments in cancer vaccines are in Dendreon's Provenge for prostate cancer. This is a vaccine against prostatic acid phosphatase, and is basically designed for the immune system to mop up any residual prostate cells after prostatectomy. Provenge is awaiting final clearance from the FDA for marketing in advanced prostate cancer (hormone-refractory prostate cancer, HRPC); it got a very favorable advisory panel review in late March. Provenge is the most important cancer vaccine to discuss because it is the first to show efficacy in Phase III trials, will most likely be the first to be approved, and also is designed to target the most common cancer in men.
The way Provenge works is of general geeky interest and explains its relative effectiveness sans side effects versus other vaccine approaches. First, a patient's blood is drawn and the dendritic cells (the primary antigen-presenting cells of the immune system) are purified. These are then stimulated by a fusion protein of GM-CSF (a potent dendritic cell activator) and a prostatic acid phosphatase peptide. The cells are then reinfused back into the patient, where they will present the PAP epitope and costimulatory molecules to lymphocytes, inducing a specific immune response to PAP and overcoming the previously established tolerance to self antigens.
Provenge (aka Sipuleucel-T) is also being presented at AACR, with data showing the immune response to PAP can be boosted by repeated treatments in earlier stage prostate cancer (hormone-dependent prostate cancer, or HRPC). About 1 in 6 men will get some form of prostate cancer if they live to age 80. If it weren't for smoking, prostate cancer would be the number one cause of cancer deaths among men. (A similar situation exists for breast cancer in women.)
The most interesting developments in cancer vaccines are in Dendreon's Provenge for prostate cancer. This is a vaccine against prostatic acid phosphatase, and is basically designed for the immune system to mop up any residual prostate cells after prostatectomy. Provenge is awaiting final clearance from the FDA for marketing in advanced prostate cancer (hormone-refractory prostate cancer, HRPC); it got a very favorable advisory panel review in late March. Provenge is the most important cancer vaccine to discuss because it is the first to show efficacy in Phase III trials, will most likely be the first to be approved, and also is designed to target the most common cancer in men.
The way Provenge works is of general geeky interest and explains its relative effectiveness sans side effects versus other vaccine approaches. First, a patient's blood is drawn and the dendritic cells (the primary antigen-presenting cells of the immune system) are purified. These are then stimulated by a fusion protein of GM-CSF (a potent dendritic cell activator) and a prostatic acid phosphatase peptide. The cells are then reinfused back into the patient, where they will present the PAP epitope and costimulatory molecules to lymphocytes, inducing a specific immune response to PAP and overcoming the previously established tolerance to self antigens.
Provenge (aka Sipuleucel-T) is also being presented at AACR, with data showing the immune response to PAP can be boosted by repeated treatments in earlier stage prostate cancer (hormone-dependent prostate cancer, or HRPC). About 1 in 6 men will get some form of prostate cancer if they live to age 80. If it weren't for smoking, prostate cancer would be the number one cause of cancer deaths among men. (A similar situation exists for breast cancer in women.)
Subscribe to:
Posts (Atom)