Therapeutic cancer vaccines: current status and moving forward

Abstract

Concurrent with U.S. Food and Drug Administration (FDA) approval of the first therapeutic cancer vaccine, a wide spectrum of other cancer vaccine platforms that target a diverse range of tumor-associated antigens is currently being evaluated in randomized phase II and phase III trials. The profound influence of the tumor microenvironment and other immunosuppressive entities, however, can limit the effectiveness of these vaccines. Numerous strategies are currently being evaluated both preclinically and clinically to counteract these immunosuppressive entities, including the combined use of vaccines with immune checkpoint inhibitors, certain chemotherapeutics, small-molecule targeted therapies, and radiation. The potential influence of the appropriate patient population and clinical trial endpoint in vaccine therapy studies is discussed, as well as the potential importance of biomarkers in future directions of this field.

Figure 1

Overall survival (OS) in patients with metastatic castrate-resistant prostate cancer using cancer vaccines. A) Results of the primary efficacy analysis of treatment with Spiluleucel-T as compared with placebo control. Sipuleucel-T did improve patients’ OS (hazard ratio for death = 0.78; 95% confidence interval = 0.61 to 0.98; P = .03) [adapted with permission from reference (41)]. The placebo control consisted of cultured antigen-presenting cells (APCs) from leukapheresis, without prostatic acid phosphatase–granulocyte macrophage colony-stimulating factor (PAP–GM-CSF) antigen. Per the trial protocol, the control group could receive cryopreserved APCs with antigen upon disease progression. B) OS of a randomized, placebo-controlled 43-center trial of PROSTVAC vaccine consisting of recombinant vaccinia and fowlpox vectors containing transgenes for prostate-specific antigen, B7.1, intercellular adhesion molecule 1, and lymphocyte function-associated antigen-3 (PSA-TRICOM) in patients with metastatic castrate-resistant prostate cancer; the trial compared PROSTVAC vaccine vs empty vector. There was an OS advantage of 8.5 months (OS = 25.1 vs 16.6 months; P = .006) and a 44% reduction in death in the vaccine arm [adapted with permission from reference (24)].

Figure 2

Tumor growth rates following chemotherapy vs vaccine therapy [adapted from data in references (–88)]. A) Average tumor growth rates and time to death in patients with metastatic prostate cancer, from five clinical trials [four with chemotherapy and one with PROSTVAC vaccine (also known as PSA-TRICOM)]. Growth rate of tumor if no therapy is initiated (line a). With the use of chemotherapy, there was an initial tumor reduction, but the growth rate of tumors at relapse was similar to the initial tumor growth rate before therapy (line b). With PROSTVAC, there was a reduction in tumor growth rate following vaccine therapy (line c). Thus, for patients who received vaccine therapy with little if any tumor reduction (among whom there was virtually no increase in time to progression), an increase in overall survival was observed. Dagger denotes time to death. B) This phenomenon could potentially be enhanced if vaccine therapy is initiated earlier in disease progression or in patients with low tumor burden metastatic disease (line d) but would have minimal effect in patients with large tumor burden (line e). C) Predictions of enhanced overall survival if patients are treated with both vaccination and chemotherapy.