Vaccine-Induced Memory CD8+ T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study

Abstract

Purpose: Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T-cell infiltration of tumors include vaccines targeting established oncogenic drivers such as the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2).Patients and Methods: In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2 þ tumor cells and HER2-specific immune responses and antitumor function were evaluated. We tested VRP-HER2 in a phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of 3 doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy.Results: Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was 1 partial response and 2 patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n ¼ 4) and 32.7 months in cohort 2 (n ¼ 18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS.Conclusions: VRP-HER2 increased HER2-specific memory CD8 T cells and had antitumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T-cell activity by combining with anti-PD-1.There were 3 grade 3 AEs, but these AEs were not attributable to the VRP-HER2 vaccine. Crosby et al.

Long-term survival of patients with stage III colon cancer treated with VRP-CEA(6D), an alphavirus vector that increases the CD8+ effector memory T cell to Treg ratio

“…We recently reported on the use of CyTOF analysis to describe the changes occurring in peripheral blood immune cells after vaccination with a different VRP-based vaccine encoding the tumor antigen HER2 (VRP-HER2). 28 In that study, we also observed the expansion of an antigen-specific, cytolytic CD8 T cell population, suggesting that CyTOF may be a preferred approach for assessing immunogenicity of cancer vaccines. In the current study, CyTOF allowed us to determine that the terminally differentiated effector memory cells CD8+T EMRA were increased and Tregs were decreased in most patients following the immunizations, with the result that the CD8 T EMRA :Treg ratio increased, an important indicator of a favorable environment for antitumor immune responses.…”

HER2-LAMP vaccines effectively traffic to endolysosomal compartments and generate enhanced polyfunctional T cell responses that induce complete tumor regression

“…This mirrors preclinical and clinical studies with different immunotherapies in BC that demonstrate heterogeneous tumor regression associated with differences in T cell infiltration and local immunosuppression. 39 48 49 As our clinical studies suggest that the stimulation of HER2-specific memory CD8+ T cells is an important requirement for progression-free survival, 6 the use of HER2-LAMP vaccines may have a significant impact against treatment-resistant metastatic HER2+ BC. Given that effective local immunosuppression can still curtail these responses in a significant fraction of mice, HER2-LAMP vaccines may be effectively coupled with heterologous vaccines (such as our viral HER2 vectors) to further expand anti-HER2 immune responses, or with PD-1/PD-L1 immune checkpoint inhibitors to counterbalance local immunosuppression, which are the focus of our continuing investigations.…”

“…1 2 5 In our previous studies, we developed HER2-specific viral vaccines encoding inactivated and truncated forms of HER2 6 7 which we used to stimulate HER2-specific immune responses in patients with advanced HER2+ BC. 6 These studies demonstrated that viral vaccines encoding truncated forms of HER2 could break HER2specific tolerance in HER2+ BC patients, with the induction of significant HER2-specific T cell memory responses in a subset of patients. Notably, we found that these HER2-specific memory responses were associated with enhanced progression-free survival.…”

“…Notably, we found that these HER2-specific memory responses were associated with enhanced progression-free survival. 6 As the HER2 specific immune responses were only observed in a subset of patients, we wanted to explore strategies to enhance immune responses to HER2, and considered genetic modifications to our vaccine.…”

“…In the past, we explored the use of exosomal antigen trafficking and found that while it enhanced T cell and B cell responses to certain antigens, such as Carcinoembryonic Antigen, it did not strongly enhance responses compared with full length or truncated forms of HER2. 8 Due to our clinical success in HER2 vaccination, 6 we explored the endolysosomal trafficking of a HER2 vaccine through the incorporation of a LAMP trafficking motifs into a HER2 construct containing both the extracellular and intracellular domains (ECD/ICD) of the receptor. Our studies found that HER2-LAMP enhanced endolysosomal trafficking of HER2 compared with HER2-WT, which resulted in significantly decreased HER2 expression and enhanced both MHC class I and II presentation of LAMP-fusion peptides.…”