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 of 39 (43.6%) of vaccinated individuals, eliciting high levels of anti-MUC1 immunoglobulin G (IgG) and long-lasting immune memory. Lack of response in 22 of 39 individuals was correlated with high levels of circulating myeloid-derived suppressor cells (MDSC) prevaccination. Vaccine-elicited MUC1-specific immune response and immune memory were not associated with significant toxicity. Our study shows that vaccines based on human TAAs 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 nonimmunosuppressed patients for prophylactic vaccination.

Fig. 1

Vaccine elicited anti-MUC1 IgG responses. A. Ratio of week 12/week 0 anti MUC1 IgG in ascending order. Subjects with ratio >2 were considered responders (black bars) and those with ratio <2 were non-responders (white bar). Data are presented as OD 405 values for 1:40 dilution of plasma. Dashed line represents ratio of 2. B. Time and kinetics of anti MUC1 IgG development in responders. Vaccine was administered at Week 0, 2, 10 and 52 (arrows).

Fig. 2

PBMC of non-responders contain increased levels of myeloid derived suppressor cells (MDSC). A. Representative PBMC flow cytometry profile of a responder (left) and a non-responder (right) showing a difference in the CD33 +/low, CD11b+ and HLA-DR- cell populations (MDSC). B. MDSC percentage in PBMC of healthy donors (N=19) compared to pre-vaccination PBMC of vaccine responders (N=12) and vaccine non-responders (N=19). 9 patients were not evaluated due to insufficient number of PBMC. * <0.01, **<0.05

Fig. 3

Depletion of MDSC improves T cell response. A. Representative flow cytometry result showing that depletion of CD15+ cells from PBMC removes the CD33^+/low, CD11b⁺ HLA-DR^low MDSC population. B. IFNγ production by T cells stimulated with anti-CD3/anti-CD28 antibody before and after MDSC depletion from PBMC of one responder and two non-responders. MDSC depletion does not affect IFNγ production in responder but increases response in non-responders (* <0.01).

Fig. 4

Regulatory T cells (Treg) are not increased in vaccine non-responders. Percentage of Foxp3⁺ CD4 T cells analyzed by flow cytometry in healthy donors (N=10), vaccine responders (N=7) and vaccine non-responders (N=11).