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Currently, much attention is focused on the development of tumor vaccines that incorporate defined tumor-associated antigen (TAA) peptides. Following the first report of the successful molecular cloning of a gene encoding a cytotoxic T lymphocyte-defined (CTL-defined) TAA (1), critical questions have surfaced — not only with respect to the optimal composition of such vaccines (including the choice of TAA, adjuvant, and delivery mode), but also how its effectiveness should be best measured in terms of laboratory and clinical parameters. There is much controversy surrounding these issues, ranging from whether a particular peptide sequence is truly a tumor rejection antigen to whether a dendritic cell, rather than some particular cytokine or nonspecific agent, would serve as the most efficient adjuvant. In a recent issue of the JCI, Knutson and colleagues describe the immunologic monitoring results of a pilot clinical trial of a multipeptide vaccine admixed with GM-CSF in patients with breast cancer (2). Surprisingly, the authors found that MHC class I–restricted epitope sequences nested inside MHC class II sequences were capable of eliciting CTL immunity.  This work, which incorporated a number of correlative studies measuring immune responses, was aimed in part to test the hypothesis that the direct addition of GM-CSF can boost the generation of local antigen-presenting cells, an idea that has been demonstrated in mice using GM-CSF–transfected cell vaccines (3). Clinically, in small pilot studies conducted by Jager (4) and Jaffee (5) and their colleagues, the addition of GM-CSF appeared to augment antigen-specific CTL responses to peptide- or whole-cell vaccines. In contrast, recently presented preliminary data suggest that GM-CSF does not add to the immunogenicity of a peptide vaccine prepared with incomplete Freund’s Adjuvant (6). Otherwise, no randomized trials testing the clinical or immunologic utility of GM-CSF as an adjuvant in cancer patients have yet been reported. The current study (2) was also intended to test the idea that MHC class II–restricted helper peptides could generate detectable and durable CD4+ T-cell immunity in cancer patients, which would result in augmented MHC class I–restricted CD8+ CTL responses. The authors got an unexpected bonus, since they not only detected helper peptide–specific responses, but they also found that certain MHC class I epitopes that acted on CD8+ CTLs correspond to sequences nested within longer helper peptides that act on CD4+ cells. The authors’ previous small pilot trials (7, 8) demonstrated that breast cancer patients immunized with HER-2/neu helper peptides develop both HER-2/neu peptide–specific T-cell responses and also HER-2/neu protein–specific responses, a consequence of epitope spreading. Immune T cells elicited by vaccination generated delayed-type hypersensitivity (DTH) responses, which indicated the potential ability to traffic distally from the vaccine site.

How much help does a vaccine-induced T-cell response need?