Exploring Essential Issues for Improving Therapeutic Cancer Vaccine Trial Design

Simple Summary Therapeutic cancer vaccines have failed to demonstrate clinical improvements in phase III clinical trials over the past two decades. This has led to a rather discouraging view regarding their role in the field of cancer immunotherapy. Herein, we critically examine important issues for improving cancer vaccination strategies in an attempt to rekindle interest for this type of immunotherapy. We highlight the importance of proper clinical design in terms of selected groups of patients, taking into consideration (a) changes in initially established standard-of-care treatments; (b) the appropriate follow-up period necessary to achieve meaningful results; (c) statistical considerations for the delay of treatment effects (i.e., time for development of an effective immune response), thus excluding irrelevant early events; and (d) appropriate biomarkers that could guide vaccinations with clinical benefits to patients. Tackling the aforementioned challenges, therapeutic vaccines could take their rightful place in the immunotherapy hall of fame. 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.