Stimulation of Oncogene-Specific Tumor-Infiltrating T Cells through Combined Vaccine and αPD-1 Enable Sustained Antitumor Responses against Established HER2 Breast Cancer

Abstract

◥Purpose: 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.Experimental Design: Our models of HER2 þ breast cancer exhibit molecular signatures that are reflective of advanced human HER2 þ breast cancer, with a small numbers of neoepitopes and elevated immunosuppressive markers. Using these, we vaccinated against the oncogenic HER2D16 isoform, a nondriver tumorassociated gene (GFP), and specific neoepitopes. We further tested the effect of vaccination or anti-PD-1, alone and in combination.Results: We found that only vaccination targeting HER2D16, 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 þ T cells were essential for responses, which were more effective early in tumor development.Long-term tumor control of advanced cancers occurred only when HER2D16 vaccination was combined with aPD-1. Single-cell RNA sequencing of tumor-infiltrating T cells revealed that while vaccination expanded CD8 T cells, only the combination of vaccine with aPD-1 induced functional gene expression signatures in those CD8 T cells. Furthermore, we show that expanded clones are HER2reactive, conclusively demonstrating the efficacy of this vaccination strategy in targeting HER2.Conclusions: 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).

Best Practices for Spatial Profiling for Breast Cancer Research with the GeoMx® Digital Spatial Profiler

“…Within an individual tumor, heterogeneity occurs at the level of the genome, transcriptome and proteome, which leads to the diversity of cell populations and tissue morphology [3,9,14,15]. As an example, recent studies have shown that tumor-infiltrating lymphocytes (TILs) in the primary tumor play an important role in therapy response and prognosis in breast cancer [4,[16][17][18][19][20][21][22][23][24][25][26]]. Yet, improved clinical outcomes were associated with the presence of TILs in some but not all tumor types and in some but not all patients [4,[27][28][29][30].…”

A Novel Immune-Related Seventeen-Gene Signature for Predicting Early Stage Lung Squamous Cell Carcinoma Prognosis

“…It has been proved that the tumor-infiltrating immune cells were closely related to the prognosis of patients (6)(7)(8)(9)(10)(11)(12)(13). For example, stimulation of tumor-infiltrating CD8 T cells enabled sustained antitumor responses (14). The combination of signal transducer and activator of transcription 3 (STAT3) inhibition and wholebrain radiation therapy (WHRT) could induce dendritic cell and T cell interactions to enhance the therapeutic effect against glimas (15).…”

A combination of PD‑1/PD‑L1 inhibitors: The prospect of overcoming the weakness of tumor immunotherapy (Review)

“…A previous study (34) explored the synergistic effect of a vaccine targeting HER2Δ16 on anti-PD-1 therapy in enhancing antitumor immunity in a model of advanced HER2 + breast cancer. HER2Δ16 is a critical oncogenic pathway and spontaneous tumors driven by HER2Δ16 are reflective of clinically advanced immunosuppressive HER2 + breast cancer.…”