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

Abstract

IntroductionCancer 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.MethodsWe performed a detailed cross-sectional and longitudinal analysis of tumor vaccine trials (n=955) registered in the US Clinical Trials database.ResultsThe 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.ConclusionThe 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.

The Therapeutic Potential of Tackling Tumor-Induced Dendritic Cell Dysfunction in Colorectal Cancer

“…This highly specific approach, combined with a relatively low risk of toxicity, makes DC vaccines particularly promising (10,205). However, despite initial encouraging results including increased T cell responses and a good safety profile, DC vaccines have not shown strong therapeutic benefit in CRC patients (206)(207)(208)(209)(210)(211)(212)(213)(214)(215)(216). This is hypothesized to be linked to the strongly suppressive TME, particularly a TGF-b rich TME (10,217,218) and, consequently, defective and immunosuppressive DC populations.…”

Previously unidentified duplicate registrations of clinical trials: an exploratory analysis of registry data worldwide

“…The ICTRP should play a central role in the international registry system, but given the current state of affairs, it is sometimes ignored. Instead, major studies using registry data have focussed their efforts on using ClinicalTrials.gov [ 7 – 9 , 24 – 27 ], even though its coverage of trials conducted worldwide is not as comprehensive as that of the ICTRP portal.…”

Nanotechnology as a Promising Method in the Treatment of Skin Cancer

“…In addition, the liposomes may have applications in the development of vaccines for the treatment and prevention of melanoma. Subsequent studies indicate their potential role in immunotherapy against melanomas [101][102][103][104][105].…”