MUC1 Vaccine for Individuals with Advanced Adenoma of the Colon: A Cancer Immunoprevention Feasibility Study

Abstract

Cancer vaccines based on human tumor associated antigens (TAA) have been tested in patients with advanced or recurrent cancer, in combination with or following standard therapy. Their immunogenicity and therapeutic efficacy has been difficult to properly evaluate in that setting characterized by multiple highly suppressive effects of the tumor and the standard therapy on the patient’s immune system. In animal models of human cancer, vaccines administered in the prophylactic setting are most immunogenic and effectively prevent cancer development and progression. We report results of a clinical study that show that in patients without cancer but with a history of premalignant lesions (advanced colonic adenomas, precursors to colon cancer), a vaccine based on the TAA MUC1 was highly immunogenic in 17/39 (43.6%) of vaccinated individuals, eliciting high levels of anti-MUC1 IgG and long-lasting immune memory. Lack of response in 22/39 individuals was correlated with high levels of circulating myeloid derived suppressor cells pre-vaccination. Vaccine-elicited MUC1-specific immune response and immune memory were not associated with any toxicity. Our study shows that vaccines based on human tumor associated antigens are immunogenic and safe and capable of eliciting long term memory that is important for cancer prevention. We also show that in the premalignant setting, immunosuppressive environment (e.g. high levels of MDSC) might already exist in some individuals, suggesting an even earlier premalignant stage or preselection of non-immunosuppressed patients for prophylactic vaccination.

Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected

“…Similar results were found in patients treated with high-dose IL-2 (103). In a cancer-preventative setting, the presence of MDSCs in patients with advanced colonic adenomas was inversely correlated with responsiveness to a vaccination against the tumor antigen mucin 1 (MUC1) (104). These studies highlight MDSCs as a valuable biomarker and suggest that targeting MDSCs may be an attractive strategy for improving the efficacy of concurrent therapies.…”

Tapping CD4 T Cells for Cancer Immunotherapy: The Choice of Personalized Genomics

“…These frequently overexpressed proteins could lend themselves to inclusion in vaccines designed to exploit Th-Th cooperation (139)(140)(141)(142)(143). Presentation of unmutated peptides by the APC, along with a suitably selected nonself CD4 T cell determinant, may prove sufficient for immunological and clinical effects.…”

Functio Laesa: Cancer Inflammation and Therapeutic Resistance

“…[42][43][44][45] These findings form the basis for early-phase clinical trials evaluating immune checkpoint inhibitors in combination with strategies designed to inhibit the recruitment of myeloid cells (eg, inhibitors of FAK, CCR2, and CXCR2) or deplete myeloid cells (eg, CSF1R antagonists; Table 2). Combining multiple immune modulatory agents, though, poses challenges in determining the contribution of each therapeutic intervention to observed clinical responses.…”