Table 5.

Potential avenues for improving therapeutic value of 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.