Endpoints, patient selection, and biomarkers in the design of clinical trials for cancer vaccines

Abstract

Therapeutic cancer vaccines are an emerging and potentially effective treatment modality. Cancer vaccines are usually very well tolerated, with minimal toxicity compared with chemotherapy. Unlike conventional cytotoxic therapies, immunotherapy does not result in immediate tumor shrinkage, but may alter growth rate and thus prolong survival. Multiple randomized controlled trials of various immunotherapeutic agents have shown a delayed separation in Kaplan-Meier survival curves, with no evidence of clinical benefit within the first 6 to 12 months of vaccine treatment. Overall survival benefit is seen in patients with lower disease burden who are not expected to die within those initial 6 to 12 months. The concept of improved overall survival without marked initial tumor reduction represents a significant shift from the current paradigms established by standard cytotoxic therapies. Future clinical studies of therapeutic vaccines should enroll patients with lower tumor burden, more indolent disease, or both, and must seek to identify early markers of clinical benefit that may correlate with survival. Until then, improved overall survival is the only clear, discriminatory endpoint for therapeutic vaccines as monotherapies.

Therapeutic vaccines

“…Thus, the kinetics of a clinical response following treatment with a therapeutic vaccine are predictably different from the kinetics of a cytotoxic agent. [1][2][3][4] Indeed, because of their very different mechanisms of action, therapeutic vaccines initiate an ongoing, dynamic response that may result initially in subtle changes to the tumor growth rate; over time, however, if these changes are maintained or expanded, improvements in outcome may be substantial. In other words, the immune response may start slowly, but over time it may grow deeper, broader, and more clinically active, and may persist long after initial administration of the vaccine.…”

Therapeutic cancer vaccines: a long and winding road to success

“…Thus, cytotoxic therapy may affect tumor load effectively during administration but its effect is short-lived and disappears after the drug is discontinued. In contrast, immune responses often take time to develop and can potentially be enhanced by booster vaccinations inducing tumorspecific immunological memory [72]. Thus, an effective vaccineinduced antitumor immune response should include a memory response through which a cumulative slowing pressure on tumor growth rates will continue beyond the end of vaccinations.…”

“…This implies that therapeutic vaccines should be applied at earlier disease stages. In addition, there are studies to show that patients in the adjuvant setting or in the metastatic setting, but with indolent disease, have better chances of benefitting upon therapeutic vaccination [38,72]. A striking example of a currently available vaccine that may be benefited from early application, includes a breast cancer vaccine consisting of a HER-2/neu peptide (E75) mixed with GM-CSF, that has been successful in preventing disease recurrence in nodepositive patients with minimal disease burden.…”

Predictive biomarkers and effectiveness of MUC1-targeted dendritic-cell-based vaccine in patients with refractory non-small cell lung cancer

“…In terms of the time to onset of antitumor effects, cancer vaccines, such as peptide-based and DC-based vaccines, behave quite distinctively from other kinds of cancer immunotherapies and chemotherapies [Bilusic and Gulley, 2012]. This is because anticancer vaccines need to activate an antitumor immune response prior to the cancer cells being attacked, which causes a delay in antitumor effects [Schlom et al 2007].…”