The notion that the immune system can prevent the emergence and growth of cancer is a century old. Despite considerable evidence in animal models that "cancer vaccines" induce effective immunological responses against tumors, the development of efficacious vaccines to treat cancer in humans has been much slower and far less promising. In the past decade, however, several vaccine strategies have made considerable clinical advancement, renewing the interest and confidence that a human cancer vaccine will be successfully launched. This article highlights several vaccines that have advanced to later stages of clinical and commercial development. Emphasis is on the development of vaccines using the cancer patient's own autologous antigen-presenting cells (APCs). Mature APCs play a pivotal role in initiating an immune response, especially T-cell mediated immunity, which is critical for the effective killing of tumor cells. Employing APCs in a vaccine to present tumor-associated antigens and stimulate cytotoxic T-cells will enhance the clinical efficacy of the cancer vaccine. As personalized therapeutic products, autologous APC vaccines pose interesting clinical development, regulatory approval, and commercial manufacturing and distribution challenges. Strategies to address some of these challenges are discussed.
It is impossible to cover all of the recent developments in cancer vaccines in this brief review. Therefore, the objective is to present a broad overview of the field by providing examples of a few cancer vaccines currently in commercial development. Emphasis is on the challenges of developing these vaccines.
Immunological Basis for Cancer Vaccines
The immune system can protect against cancer, as well as allow tumors to escape immune destruction.1 Antibodies and various effector cells, e.g., cytotoxic T-cells (CTLs) and natural killer cells, can recognize and kill tumor cells. Figure 1 depicts the basic mechanisms of the tumor immune response. Most cancer cells express tumor associated antigens (TAAs) that distinguish them as "foreign" tissue to the immune system. Some examples of TAAs targeted by cancer vaccines include: MART-1, MAGE-3, NY-ESO-1, prostate specific antigen (PSA), and prostatic acid phosphatase (PAP). Soluble and membrane-bound TAAs are captured and processed by antigen-presenting cells (APCs) which carry them to lymph nodes that drain the tumor site. Immunogenic fragments (epitopes) of processed TAAs are associated with the major histocompatability complex (MHC) molecules on the surface of the APCs. In concert with various cyotokines, the TAA-loaded APCs present the antigens to T-cells (thymus derived lymphocytes) and/or B-cells (bone marrow derived lymphocytes), which activates the T and B cells to proliferate and differentiate into immune effector cells. B-cells differentiate into plasmacytes that secrete soluble, antigen-specific antibodies that mediate killing of cancer cells by binding to the membrane-bound tumor antigens to activate the compliment cascade, or attracting antibody-dependent cytotoxic cells to the tumor. T-cells can differentiate into TAA-specific CTLs that migrate from the lymph nodes to the site of the tumor, where they kill the tumor through the release of cytotoxic enzymes such as perforin and granzyme B. Other cells that participate in a tumor immune response include helper T-cells that release cytokines to activate CTLs and B-cells, and regulatory T-cells that can allow tumor immune escape by inhibiting an effective tumor immune response. Cancer vaccines are intended to introduce TAAs to the patient in a way that stimulates a potent tumor immune response.
Figure 1. The tumor immune response