Using a CMV-epitope-expressing transplanted tumor in transgenic immune tolerant mice that express CMV epitopes in pancreatic islet cells, Sultan et al. show that a highly effective CMV-based vaccine can overcome tolerance and induce potent anti-tumor activity but also induce severe diabetogenic symptoms. Boosting immunization with a agonist-CD40 antibody generated T cells sensitive to negative signaling via the PD-1 axis, which was not observed when immunization was boosted with long-lived IL-2.
Immunotherapy has shown a tremendous success in treating cancer. Unfortunately, this success is frequently associated with severe autoimmune pathology. In this study, we used the transgenic RIP-gp mouse model to assess the antitumor therapeutic benefit of peptide vaccination while evaluating the possible associated autoimmune pathology. We report that palmitoylated gp33-41 peptide and poly-IC adjuvant vaccine (BiVax) generated approximately 5-10 % of antigen specific T cell responses in wild type and supposedly immune tolerant RIP-gp mice. Boosting with BiVax in combination with alphaCD40 antibody (TriVax) or BiVax in combination with IL-2/alphaIL-2 antibody complexes (IL2Cx) significantly increased the immune responses ( approximately 30-50%). Interestingly, although both boosts were equally effective in generating vast T cell responses, BiVax/IL2Cx showed better control of tumor growth than TriVax. However, this effect was associated with high incidence of diabetes in an antigen and CD8 dependent fashion. T cell responses generated by BiVax/IL2Cx, but not those generated by TriVax were highly resistant to PD-1/PD-L1 inhibitory signals. Nevertheless, PD-1 blockade enhanced the ability of TriVax to control tumor growth but increased the incidence of diabetes. Finally, we show that severe autoimmunity by BiVax/IL2Cx was prevented while preserving outstanding antitumor responses by utilizing a tumor antigen not expressed in the pancreas. Our data provides a clear evidence that peptide based vaccines can expand vast endogenous T cell responses which effectively control tumor growth but with high potential of autoimmune pathology.
Author Info: (1) Cancer Immunology, Immunotherapy and Tolerance Program, Georgia Cancer Center, Augusta University, Augusta, GA, USA. Biochemistry and Cancer Biology Department, Georgia Cancer
Author Info: (1) Cancer Immunology, Immunotherapy and Tolerance Program, Georgia Cancer Center, Augusta University, Augusta, GA, USA. Biochemistry and Cancer Biology Department, Georgia Cancer Center, Augusta University, Augusta, GA, USA. (2) Cancer Immunology, Immunotherapy and Tolerance Program, Georgia Cancer Center, Augusta University, Augusta, GA, USA. (3) Cancer Immunology, Immunotherapy and Tolerance Program, Georgia Cancer Center, Augusta University, Augusta, GA, USA. (4) Cancer Immunology, Immunotherapy and Tolerance Program, Georgia Cancer Center, Augusta University, Augusta, GA, USA. Biochemistry and Cancer Biology Department, Georgia Cancer Center, Augusta University, Augusta, GA, USA.
