Cross-sectional and longitudinal analysis of cancer vaccination trials registered on the US Clinical Trials Database demonstrates paucity of immunological trial endpoints and decline in registration since 2008

INTRODUCTION: Cancer vaccination has been researched as a means of treating and preventing cancer, but successful translational efforts yielding clinical therapeutics have been limited. Numerous reasons have been offered in explanation, pertaining both to the vaccine formulation, and the clinical trial methodology used. This study aims to characterize the tumor vaccine clinical trial landscape quantitatively, and explore the possible validity of the offered explanations including the translational obstacles posed by the current common endpoints. METHODS: We performed a detailed cross-sectional and longitudinal analysis of tumor vaccine trials (n=955) registered in the US Clinical Trials database. RESULTS: The number of tumor vaccine trials initiated per annum has declined 30% since a peak in 2008. In terms of vaccine formulation, 25% of trials use tumor cell/lysate preparations; whereas, 73% of trials vaccinate subjects against defined protein/peptide antigens. Also, 68% of trials do not use vectors for antigen delivery. Both these characteristics of tumor vaccines have remained unchanged since 1996. The top five types of cancer studied are: melanoma (22.6%); cervical cancer (13.0%); breast cancer (11.3%); lung cancer (9.5%); and prostate cancer (9.4%). In addition, 86% of the trials are performed where there is established disease rather than prophylactically, of which 67% are performed exclusively in the adjuvant setting. Also, 42% of Phase II trials do not measure any survival-related endpoint, and only 23% of Phase III trials assess the immune response to vaccination. CONCLUSION: The clinical trial effort in tumor vaccination is declining, necessitating a greater urgency in identifying and removing the obstacles to clinical translation. These obstacles may include: 1) vaccination against a small range of antigens; 2) naked delivery of antigen; 3) investigation of less immunogenic cancer types; and 4) investigation in the setting of established disease. In addition, the prevalence of late phase failure may be due to inadequate assessment of survival-related endpoints in Phase II trials. The clinical trial development of tumor vaccines should include mechanism-based translational endpoints, as well as the discovery of immune biomarkers with which to stratify, monitor, and prognosticate patients.