American Association for Cancer Research
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Figure S3 from Stimulation of Oncogene-Specific Tumor-Infiltrating T Cells through Combined Vaccine and αPD-1 Enable Sustained Antitumor Responses against Established HER2 Breast Cancer

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posted on 2023-03-31, 22:08 authored by Erika J. Crosby, Chaitanya R. Acharya, Anthony-Fayez Haddad, Christopher A. Rabiola, Gangjun Lei, Jun-Ping Wei, Xiao-Yi Yang, Tao Wang, Cong-Xiao Liu, Kay U. Wagner, William J. Muller, Lewis A. Chodosh, Gloria Broadwater, Terry Hyslop, Jonathan H. Shepherd, Daniel P. Hollern, Xiaping He, Charles M. Perou, Shengjie Chai, Benjamin K. Ashby, Benjamin G. Vincent, Joshua C. Snyder, Jeremy Force, Michael A. Morse, Herbert K. Lyerly, Zachary C. Hartman

Supplementary Figure 3

Funding

Susan G. Komen

Merck Sharp-Dohme Investigator

Department of Defense

NCI

Cancer Research Society

Canadian Institutes of Health Research

History

ARTICLE ABSTRACT

Despite promising advances in breast cancer immunotherapy, augmenting T-cell infiltration has remained a significant challenge. Although neither individual vaccines nor immune checkpoint blockade (ICB) have had broad success as monotherapies, we hypothesized that targeted vaccination against an oncogenic driver in combination with ICB could direct and enable antitumor immunity in advanced cancers. Our models of HER2+ breast cancer exhibit molecular signatures that are reflective of advanced human HER2+ breast cancer, with a small numbers of neoepitopes and elevated immunosuppressive markers. Using these, we vaccinated against the oncogenic HER2Δ16 isoform, a nondriver tumor-associated gene (GFP), and specific neoepitopes. We further tested the effect of vaccination or anti–PD-1, alone and in combination. We found that only vaccination targeting HER2Δ16, a driver of oncogenicity and HER2-therapeutic resistance, could elicit significant antitumor responses, while vaccines targeting a nondriver tumor-specific antigen or tumor neoepitopes did not. Vaccine-induced HER2-specific CD8+ T cells were essential for responses, which were more effective early in tumor development. Long-term tumor control of advanced cancers occurred only when HER2Δ16 vaccination was combined with αPD-1. Single-cell RNA sequencing of tumor-infiltrating T cells revealed that while vaccination expanded CD8 T cells, only the combination of vaccine with αPD-1 induced functional gene expression signatures in those CD8 T cells. Furthermore, we show that expanded clones are HER2-reactive, conclusively demonstrating the efficacy of this vaccination strategy in targeting HER2. Combining oncogenic driver targeted vaccines with selective ICB offers a rational paradigm for precision immunotherapy, which we are clinically evaluating in a phase II trial (NCT03632941).