Therapeutic cancer vaccines: Optimism for the future at BIO 2012
There has been a lot of talk about vaccines for cancer, and the move to market has seemed a little slow, with only one on the market so far--Dendreon's Provenge, for prostate cancer. However, the field is still very active, and Glenn Dranoff of the Cancer Vaccine Center at Dana-Farber Cancer Institute, opened "Therapeutic Cancer Vaccines: Renewed Optimism for the Product Pipeline" at BIO2012 with a positive note: "It's an exciting time for immunotherapy."
One of the issues facing developers of cancer vaccines, according to Dranoff, is that tumors send mixed messages. They can trigger the innate arm of the immune system, but they can also defeat the immune system because they can "hide," as they retain features of "self," and they can also have immunosuppressive effects. This means that the key objectives of a cancer vaccine are two-fold--not only to trigger an immune reaction, but also to block the tumor's tendency to immunosuppression.
One approach to this is to block CTLA4, a protein that regulates the immune system, and Dranoff showed some examples of the combination of BioSante Pharmaceuticals' ($BPAX) GVAX vaccines and Bristol-Myers Squibb's ($BMY) Yervoy (ipilimumab), an anti-CTLA4 monoclonal antibody improving survival, with patients still alive even at 8 or 9 years after treatment.
John Bell, CSO at Jennerex, introduced the concept of oncolytic viruses--viruses that selectively attack tumors. A genetically-engineered version of the smallpox (vaccinia) vaccine, these are administered intravenously or straight into the tumor and replicate and spread beyond their original site of administration. As well as acting as a vaccine and triggering an immune response, they also attack the tumor and its blood vessels, making the most of the fact that the processes that the tumor uses to hide from the immune system make it more vulnerable to infection. In Phase I trials in metastatic melanoma, injecting JX-594 into some of the cancer sites also reduced cancer in non-injected sites, and in liver cancer, there were signs of improvements in survival. As a smallpox vaccine, the vaccinia virus has been used safely throughout the world for many years, and the virus is stable in the bloodstream and is large enough to carry a genetic message for a "payload" (JX-594 codes for GM-CSF, which improves its immune response). This ability differentiates it from other virus-based vaccines in development--reoviruses can be given intravenously but can't carry a payload, and herpes viruses, such as OncoVex (picked up from BioVex by Amgen in January 2011 and now known as talimogene laherparepvec; in phase III for melanoma) can only be given directly into the tumor.
James Trager, senior director of researcher at Dendreon, reviewed data for Provenge (sipleucel-T, its autologous cancer vaccine for prostate cancer, and looked to the future. The immune responses to Provenge seem to correlate with better outcomes for survival, which could lead to the development of markers that could guide physicians to select which patients should be the best responders and which should get other therapies. He noted that the pattern of cytokine responses differed between patients, stating: "If we can learn what successful patients look like, this will help us to develop new vaccines."
With a different approach, Marc Mansour, CSO, Immunovaccine, looked at vaccines as maintenance therapy, based on the idea of a life with well-controlled cancer, rather than cure. Vaccines have a lot to do to have an impact on an established tumor, so Immunovaccine's approach is to use the vaccine as maintenance therapy in patients with minimal residual disease after chemotherapy and radiotherapy. The company's target of choice is survivin, a target that is expressed on many cancer cells.
Immunovaccine's DPX-Survivac uses the DepoVax depot formulation for slow release, providing a controlled and prolonged exposure to the vaccine, and the company combines this with low-dose cyclophosphamide, which supports the vaccine's anticancer effect. The vaccine is currently in Phase I/II trials in Canada in advanced ovarian cancer.
Mansour's conclusion was that, to beat cancer, we need to target multiple pathways with a range of approaches. This includes triggering an immune response to the cancer along with attacking the tumor's blood supply and returning the lymphatic system to normal, by combining vaccines, chemotherapy, radiotherapy and surgery. -- Suzanne Elvidge (email)