Table 5 Potential avenues for improving therapeutic value of cancer vaccines
From: Progress and controversies in developing cancer vaccines
Obstacle | Potential solution | Status |
|---|---|---|
Heterogeneity of antigen expression | Multi-antigen vaccines | 12 peptide vaccine induces T cell responses in 100% of patients. Peptide competition for MHC binding does not inhibit immunogenicity [ref 43] |
MHC downregulation on tumor cells | Targeting peptides associated with multiple MHC molecules | Being investigated in many centers |
Failure of T cells induced in the periphery with vaccines to expand in the tumor microenvironment (inadequate memory) | Addition of melanoma (or other cancer) associated helper peptides in vaccines [refs 24, 44] | Early data inadequate to address the question refs [45–47]. Data in the HIV setting supports this approach [ref 48.] ECOG 1602 trial will address the questions with a cocktail of 6 melanoma helper peptides. |
Increased regulatory T cells in patients with advanced cancer, and in tumor microenvironment | Inhibition of T reg function (anti-CTLA4 antibody); specific depletion of CD25+ regulatory T cells (Ontak); depletion of regulatory cells with chemotherapy (eg: cytoxan) | Clinical trials with all of these agents are underway. |
Limited expansion of antigen-specific T cells after vaccination | Pre-vaccine lymphodepletion to allow vaccination in the setting of naturally induced cytokines supporting homeostatic proliferation (eg IL7 and IL15) | Studies are being designed to address this approach |
T cells induced by vaccination may not be activated effector cells | Increase adjuvant function, perhaps by use of Toll-like receptor agonists | CpGs and other TLR agonists being investigated as adjuvants [29]. Randomized phase II trials with immunologic endpoints needed. |