Vaccines Targeting MHC Class II Epitopes Promote Tumor Clearance

Tumor-specific mutations represent potential immunotherapy targets, as they are absent in normal cells and have been suggested to promote a T-cell response when detected as neo-antigens. The unique mutational landscape of an individual tumor, however, poses a challenge to the systematic design of vaccines targeting these mutations. To better understand the immunogenic potential of cancer mutations, Kreiter, Vormehr, van de Roemer, and colleagues evaluated the T-cell response against tumor-specific neo-epitopes in several murine tumor models and showed that a substantial percentage of nonsynonymous cancer mutations, including MHC class II–restricted epitopes, was immunogenic and primarily recognized by CD4⁺ T-cells. Vaccination of a murine melanoma model with RNA encoding a single immunogenic MHC class II–restricted neo-epitope resulted in CD4⁺ T-cell–dependent antitumor and antimetastatic activity in vivo. In support of the notion that targeting multiple mutations may be advantageous to bypass tumor heterogeneity and achieve maximum antitumorigenic effects, mice vaccinated with RNA pentatopes consisting of a combination of MHC class I and II neo-epitopes showed increased T-cell infiltration in tumor lesions, reduced tumor load, and prolonged survival. Due to the high correlation between MHC class II binding and immunogenic potential, polytope RNA vaccines were designed using an algorithm that combined epitopes with a good MHC class II binding score and high expression of the mRNA encoding the epitope. Vaccination of animals with established lung tumors using algorithm-designed RNA pentatopes led to a significant reduction in tumor burden and rejection of lung metastases due to strong T-cell responses and epitope spreading. In addition, various human cancers were found to harbor an abundance of nonsynonymous mutations predicted to bind MHC class II molecules. Together, these data suggest that immunogenic MHC class II–restricted neo-epitopes are prominent in cancer and raise the possibility that they may be successfully targeted using individually tailored polytope RNA vaccines that reshape the tumor microenvironment and inhibit tumor growth.

Kreiter S, Vormehr M, van de Roemer N, Diken M, Löwer M, Diekmann J, et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 2015;520:692–6.