Challenges for cancer vaccine development in the academic and commercial sectors.

CS03-03

Preventive cancer vaccines hold the promise of exquisitely targeted specificity with long-term effects lasting well past the time of vaccination. More than sixty companies and an untold number of academic laboratories are developing cancer vaccines. Cancer vaccines have proven capable of inducing regression of advanced stage cancer, albeit in small numbers of patients. It's axiomatic that cancer therapies work best against small amounts of disease. Accordingly, vaccines with some efficacy against advanced cancer are currently being tested in large-scale trials for prevention of recurrence of cancer in remission, i.e., minimal residual disease. Despite considerable efforts and great optimism, no commercial cancer vaccines have been approved in the United States and few cancer vaccines have been approved worldwide. This presentation will review the basis for optimism from the perspective of companies and academic labs as well as some of the biologic, regulatory and commercial issues that are limiting the development effective vaccines. One biologic issue is that effective cancer vaccines and vaccine regimens require multiple components. Antigens injected alone often do not elicit substantial immune responses. Induction of a substantial immune response requires the concurrent injection of adjuvant with antigen. Adjuvants most often are bacterial components or other compounds that stimulate the innate immune system. Prophylactic infectious disease vaccines, including those that can prevent the cancer cause viruses HPV and HBV, can be formulated with a foreign protein alone or with employment of a "weak" non-toxic adjuvant. Vaccines targeting cancer cells, as opposed to cancer causing viruses, normally target some form of "self" antigen(s). There is a high degree of natural immune tolerance to self-antigens. Overcoming or circumventing immune tolerance requires "strong" adjuvants or combinations of adjuvants or combinations of adjuvants with other immunotherapeutic agents. Moreover, whereas an antibody response can prevent infection with HPV and HBV, a T cell response is considered important for destruction of cancer cells. Accordingly, effective cancer vaccines are more complex to formulate and can be more toxic or reactogenic than prophylactic infectious disease vaccines. The substantial degree of toxicity that is acceptable for therapeutic cancer vaccine regimens would be less acceptable for preventive cancer vaccines designated for large populations of otherwise normal individuals, many of who might not be destined to develop cancer. Thus, the clearest path to approval would be to develop vaccines to prevent recurrence of minimal residual disease, prior to applying the vaccines to a purely preventive role. In addition to adjuvants, there are many new drugs in development that, if incorporated into cancer vaccine regimens, could considerably augment the vaccine induced immune responses including agents that target suppressive molecules, regulatory cells and immune check points. Combinations of new immunotherapeutic agents have proven to have substantial power in combination with cancer vaccines in preclinical models, but the hurdles of developing such complex regimens in humans are daunting. The necessity for multiple component vaccines increases the biologic, commercial and regulatory risks of development for industry. The lack of broad availability of essential components makes development of optimal vaccines in academia virtually impossible. The majority of components needed for effective vaccines and vaccine regimens are not commercially available, making is exceedingly difficult, if not impossible to develop multi-component vaccines with the highest potential for success in academic centers. Commercial barriers similarly prevent testing of the potentially most effective vaccine regimens by industry. The majority of oncology drug development in takes place post FDA approval. Combination drug therapies are typically developed by combining drugs that have already been approved for other purposes, or in combination with an already approved drug. There is very little concurrent development multiple experimental agents. Many of the ongoing vaccine regimens being developed in academia employ one of the few drugs that have been approved for other purposes including GM-CSF, imiquimod, IL-2, BCG and denileukin diftitox. As the best example, many academic cancer vaccines employ GM-CSF as an adjuvant because it is commercially available, even though GM-CSF might not be the best adjuvant for the intended purpose. GM-CSF was approved to stimulate granulocyte recovery in neutropenic patients, not as an adjuvant. By FDA policy, adjuvants are now approved only as components of vaccines. If GM-CSF had activity only as an adjuvant, it might not now be available for testing in cancer vaccines. The "Catch 22" of cancer vaccine adjuvants is that adjuvants approved for non-vaccine purposes are broadly available, whereas adjuvants that function only as adjuvants are not broadly available, regardless of potency. The most economically viable and regulatory simple pathway for commercial immunotherapeutic drug approval, including potential vaccine adjuvants, is to develop them as stand alone immunotherapeutic drugs. If the immunotherapeutic drugs or adjuvants fail as stand-alone anticancer drugs, and most will, development is commonly abandoned. The issue of lack of availability of immunotherapy agents for testing in cancer therapy is a pervasive problem. There are many agents with proven efficacy in patients for augmenting immune responses that have been "left on the shelf" by industry. Examples are Flt3 ligand, IL12 and IL-4. Each was tested in patients as mono-therapy. Each proved to be immunologically or physiologically effective with potential in cancer vaccine regimens, but failed as mono-therapy. There presumably was no perceived reasonable commercial or regulatory path left open for development. There is an ongoing explosion of knowledge in the immunological sciences with the discovery of many agents with the potential to serve as immunotherapeutic drugs for augmenting the efficacy of cancer vaccines. Many of the agents with known immunologic or physiologic effectiveness in animal models are not broadly available for testing in humans for a variety of reasons including commercial, regulatory and funding priority issues. If the limiting issues are appropriately identified and resolved, cancer vaccines offer great hope as highly targeted preventive agents.