Exploring Essential Issues for Improving Therapeutic Cancer Vaccine Trial Design

Abstract

Therapeutic cancer vaccines have been at the forefront of cancer immunotherapy for more than 20 years, with promising results in phase I and-in some cases-phase II clinical trials, but with failures in large phase III studies. After dozens of clinical studies, only Dendreon's dendritic cell vaccine Sipuleucel-T has succeeded in receiving US FDA approval for the treatment of metastatic castrate-resistant prostate cancer. Although scientists working on cancer immunotherapy feel that this is an essential breakthrough for the field, they still expect that new vaccine regimens will yield better clinical benefits compared to the four months prolonged median overall survival (OS) Sipuleucel-T demonstrated in the IMPACT phase III clinical trial. Clinical development of cancer vaccines has been unsuccessful due to failures either in randomized phase II or-even worse-phase III trials. Thus, rigorous re-evaluation of these trials is urgently required in order to redefine aspects and optimize the benefits offered by therapeutic cancer vaccines. The scope of this review is to provide to the reader our thoughts on the key challenges in maximizing the therapeutic potentials of cancer vaccines, with a special focus on issues that touch upon clinical trial design.

Keywords: AE37 vaccine; Cancer vaccines; biomarkers; clinical design; delayed clinical effect; vaccine formulation.

Figure 1

There are two major pillars that determine the potency of therapeutic cancer vaccines. The first pillar deals with issues aimed at increasing vaccine efficacy by optimizing vaccine formulation. The second pillar addresses issues of the proper design of clinical trials that ultimately lead to the selection of the appropriate patient group to vaccinate. The successful use of these two pillars will result in robust antitumor immunity that will translate to antitumor reactivity and meaningful clinical efficacy.

Figure 2

Clinical cancer trials utilizing cancer vaccines report vaccine-induced immunity in the context of different clinical outcomes. Based on our knowledge of why therapeutic cancer vaccines have produced negative results, we propose six key issues that should be critically examined in order to make vaccines work better. These include: (a) the vaccine formulation; (b) the delayed therapeutic effects during vaccinations that should be considered while planning a vaccine trial; (c) the discovery of reliable biomarkers to guide the selection of patients most likely to benefit clinically; (d) the duration of a clinical trial to allow the detection of vaccine-mediated substantial clinical efficacy considering the standard-of-care of the vaccinated patients; (e) adequate statistical models; and (f) the role of regulatory agencies to better assist the clinical development of cancer vaccines.