Cancer vaccines: moving beyond current paradigms

Abstract

The field of cancer vaccines is currently in an active state of preclinical and clinical investigations. Although no therapeutic cancer vaccine has to date been approved by the Food and Drug Administration, several new paradigms are emerging from recent clinical findings both in the use of combination therapy approaches and, perhaps more importantly, in clinical trial design and end point analyses. This article will review recent clinical trials involving several different cancer vaccines from which data are emerging contrasting classic "tumor response" (Response Evaluation Criteria in Solid Tumors) criteria with "patient response" in the manifestation of increased patient survival post-vaccine therapy. Also described are several strategies in which cancer vaccines can be exploited in combination with other agents and therapeutic modalities that are quite unique when compared with "conventional" combination therapies. This is most likely due to the phenomena that (a) cancer vaccines initiate a dynamic immune process that can be exploited in subsequent therapies and (b) both radiation and certain chemotherapeutic agents have been shown to alter the phenotype of tumor cells as to render them more susceptible to T-cell--mediated killing. Consequently, evidence is emerging from several studies in which patient cohorts who first receive a cancer vaccine (as contrasted with control cohorts) benefit clinically from subsequent therapies.

Fig. 1

Randomized, placebo controlled, Phase III trial of Sipuleucel-T vaccine (antigen-presenting cells with PAP-GM-CSF fusion protein) vs. placebo in patients with metastatic asymptomatic hormone refractory prostate cancer. (A) Time to progression, i.e., percent without progression. (B) Overall survival. Ref. (19).

Fig. 2

Survival of patients with metastatic asymptomatic hormone refractory prostate cancer receiving low-, mid-, or high-dose GVAX whole tumor cell vaccine. Ref. (20, 21).

Fig. 3

Randomized Phase II study in patients with metastatic androgen-independent asymptomatic prostate cancer receiving PSA-TRICOM vaccines (n = 84) versus control fowlpox vector (n = 41). Ref. (29).

Fig. 4

Enhanced survival to docetaxel in patients having received prior vaccine. Overall survival in a randomized trial of patients with metastatic asymptomatic hormone refractory prostate cancer receiving Sipuleucel-T vaccine or placebo. At progression, patients went on to receive docetaxel. There was a statistically significant increase in survival (p=0.023, HR 1.9) when patients received prior vaccine. Ref. (45).

Fig. 5

Overall survival in a randomized trial of patients with hormone refractory prostate cancer receiving vaccine (rV-PSA + rV-B7.1 prime, rF-PSA boosts, n = 21) vs. nilutamide therapy (n = 21) with patients “crossing over” to receive both therapies at progression. Ref. (46,47).