In theory at least, for immunotherapy, a therapeutic cancer vaccine has the potential to stimulate specific immunity against tumors while sparing normal tissues, leading not only to tumor lysis but also to the induction of a long lasting, systemic immunological memory that protects against recurrent disease and metastasis. Three major vaccine strategies emerged:
Peptide/Protein vaccines in cancer immunotherapy
(1) Defined tumor antigen vaccines are based on specific gene products, and can come in the form of peptides, full-length proteins, or genetically encoded vectors. NY-ESO-1, MAGE-A3, gp100, MART-1, Muc1 and some other antigens have been developped as vaccines. The data in the past research highlight several major challenges for cancer vaccines based on peptides and proteins regardless of design and tumor type: (a) antigen/epitope selection for optimal binding to MHC molecules; (b) suitable adjuvant for each vaccine based on antigen property and desired immunological outcome; (c) presence of regulatory cells that suppress immune activation; and (d) effector cell exhaustion.
Whole tumor cell vaccines in cancer immunotherapy
(2) Whole-cell cancer vaccines employ the entire tumor cell and, in the cases of autologous tumors, the associated tumor stroma and vasculature, to potentiate immune activation. For whole cell cancer vaccines, retroviral or adenoviral transduction of tumor cells to express molecules relevant for immune activation has been explored as another strategy to improve tumor immunogenicity. Of many immunostimulatory mediators evaluated in the context of gene-modified tumor cell vaccines, GM-CSF emerged as the most potent in generating protective antitumor immunity.
Ex vivo dendritic cell vaccines in cancer immunotherapy
(3) A third approach involves the direct loading of whole tumor material or defined antigen to autologous DCs ex vivo followed by inoculation into patients. Mature DCs mediate three critical functions central for the clinical success of a cancer vaccine: (a) the capture of extracellular tumor-derived peptides or full-length proteins and subsequent processing to produce MHC-peptide complexes; (b) migration into lymph node for presentation of peptide–MHC complexes to T cells; (c) expression of costimulatory molecules, such as CD80, CD86, and CD40L, and production of cytokines such as IL-12 that are required for effector T cell activation and differentiation. In patients with late stage disease, who are typically enrolled in various vaccine studies, systemic immunosuppression is common and could further hinder immune activation. Based on these observations, a therapeutic vaccination strategy in which autologous DCs are expanded and activated with cytokine combinations and then loaded with antigens was developed. Sipuleucel T, an autologous vaccine consisting of peripheral blood mononuclear cells pulsed with a fusion protein composed of full-length prostatic acid phosphatase and GM-CSF (to enhance antigen-presenting cell function) was approved by the FDA in 2010 as the first cell-based cancer immunotherapy, based on an overall survival benefit of 4 months in metastatic prostate cancer patients.
Many approaches to therapeutic cancer vaccines have been explored, with varying levels of success. However, with the exception of Sipuleucel T, no therapeutic cancer vaccine has yet shown clinical efficacy in phase 3 randomized trials. Though disappointing, lessons learned from these studies have suggested new strategies to improve cancer vaccines.
Wong K K, et al. Advances in Therapeutic Cancer Vaccines[J]. Advances in Immunology, 2016.
Kaufman, H. L et al. Phase II randomized study of vaccine treatment of advanced prostate cancer (E7897): A trial of the Eastern Cooperative Oncology Group. Journal of Clinical Oncology, 22, 2122.