Augmentation of PD-1 immune checkpoint blockade through the combined administration of a HER2 viral vaccine to direct T-cell and B-cell responses against a credentialed oncogenic driver gene
Crosby EJ1, Lei GJ1, Wei JP1, Yang XY1, Wang T1, Liu CX1, Lyerly HK1, Hartman ZC1*
1Department of Surgery, Duke University, Durham NC
The use of PD-1 and PD-L1 immune checkpoint blockade (ICB) antibodies (mAbs) has led to striking responses in certain types of more 'immunogenic' tumors, characterized by effector T-cells at the site of the tumor (tumor infiltrating lymphocytes- TILs), perhaps recruited due to a high number of somatic mutations encoding for peptide neoepitopes. This suggests that the mechanistic pathway determining ICB responsiveness is a tumor antigen (Ag) specific T cell response. To enhance ICB responsiveness, we tested the concept of “precision immunotherapy”, in which we direct both T and B cell immunity against an oncogenic driver using targeted vaccination in combination with ICBs. Rather than passively relying on the presence of somatic mutations to elicit T cell responses, this strategy actively induces oncogene specific adaptive immune responses using potent viral vaccines to elicit robust T and B cell responses, which can be augmented by the sequential administration of ICBs.
To test this hypothesis, we developed adenoviral vaccines targeting the HER2 oncogene and utilized them in combination with PD-1 ICB mAbs in endogenous model of HER2+ Breast Cancer. We found that in these models, our vaccine platform could elicit robust HER2-specific T-cell and B-cell responses, capable of eliciting ADCC and CDC against tumor cells. Notably, we found that ADCC responses elicited from vaccine-induced antibodies could be enhanced by PD-1 ICB mAbs. Critically, we found that while established HER2+ transgenic tumors were only modestly responsive to PD-1 ICB mAbs, HER2 vaccination in combination with PD-1 ICB synergistically enhanced anti-tumor responses, mediated by augmented HER2-specific immunity. Moreover, we found that viral vaccines targeting the oncogene HER2 outperformed identical vaccines targeting tumor-specific GFP in eliciting maximal anti-tumor efficacy. These studies demonstrate the potential of vaccines targeting oncogenic drivers and are currently the focus of a Phase II clinical trial that will test the efficacy of a viral HER2 vaccine in combination with an anti-PD-1 mAb, Pembrolizumab.