Paradigm shifts in cancer vaccine therapy

Abstract

Cancer vaccines constitute a unique therapeutic modality in that they initiate a dynamic process involving the host's immune response. Consequently, (a) repeated doses (vaccinations) over months may be required before patient clinical benefit is observed and (b) there most likely will be a "dynamic balance" between the induction and maintenance of host immune response elements to the vaccinations vs. host/tumor factors that have the potential to diminish those responses. Thus "patient response" in the form of disease stabilization and prolonged survival may be more appropriate to monitor than strictly adhering to "tumor response" in the form of Response Criteria In Solid Tumors (RECIST) criteria. This can be manifested in the form of enhanced patient benefit to subsequent therapies following vaccine therapy. This article will review these phenomena unique to cancer vaccines with emphasis on prostate cancer vaccines as a prototype for vaccine therapy. The unique features of this modality require the consideration of paradigm shifts both in the way cancer vaccine clinical trials are designed and in the way patient benefit is evaluated.

Figure 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. 22). (C) Enhanced survival to docetaxel in patients having received prior vaccine. At progression, patients went on to receive docetaxel. There was a statistically significant increase in survival (P ¼ 0.023, HR ¼ 1.9) when patients received prior vaccine (Ref. 59).

Figure 2.

A randomized ECOG Phase II study using PSA-vaccine in DO prostate cancer patients. Taken from Refs. and . TTP is time to progression.

Figure 3.

(A) Phase II study in patients with metastatic asymptomatic CRPC receiving PSA-TRICOM vaccines (n = 84) or control fowlpox vector (n =41) (Ref. 34). (B) 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 (Refs. 60, 61).