Sequential Anti-PD1 Therapy Following Dendritic Cell Vaccination Improves Survival in a HER2 Mammary Carcinoma Model and Identifies a Critical Role for CD4 T Cells in Mediating the Response

Abstract

Patients with metastatic HER2 breast cancer (MBC) often become resistant to HER 2 targeted therapy and have recurrence of disease. The Panacea trial suggested that HER2 MBC patients were more likely to respond to checkpoint therapy if TIL were present or if tumor expressed PD-L1. We assessed whether type I polarized dendritic cells (DC1) could improve checkpoint therapy in a preclinical model of HER2 + breast cancer. TUBO bearing mice were vaccinated with either MHC class I or class II HER2 peptide pulsed DC1 (class I or class II HER2-DC1) concurrently or sequentially with administration of anti-PD-1 or anti-PDL1. Infiltration of tumors by immune cells, induction of anti-HER2 immunity and response to therapy was evaluated. Class I or class II HER2-DC1 vaccinated mice generated anti-HER2 CD8 or CD4+ T cell immune responses and demonstrated delayed tumor growth. Combining both MHC class I and II HER2-pulsed DC1 did not further result in inhibition of tumor growth or enhanced survival compared to individual administration. Interestingly class II HER2-DC1 led to both increased CD4 and CD8 T cells in the tumor microenvironment while class I peptides typically resulted in only increased CD8 T cells. Anti-PD-1 but not anti-PD-L1 administered sequentially with class I or class II HER2-DC1 vaccine could improve the efficacy of HER2-DC1 vaccine as measured by tumor growth, survival, infiltration of tumors by T cells and increase in systemic anti-HER2 immune responses. Depletion of CD4+ T cells abrogated the anti-tumor efficacy of combination therapy with class II HER2-DC1 and anti-PD-1, suggesting that tumor regression was CD4 dependent. Since class II HER2-DC1 was as effective as class I, we combined class II HER2-DC1 vaccine with anti-rat neu antibodies and anti-PD-1 therapy. Combination therapy demonstrated further delay in tumor growth, and enhanced survival compared to control mice. In summary, Class II HER2-DC1 drives both a CD4 and CD8 T cell tumor infiltration that leads to increased survival, and in combination with anti-HER2 therapy and checkpoint blockade can improve survival in preclinical models of HER2 positive breast cancer and warrants exploration in patients with HER2 MBC.

Prospective, randomized, single-blinded, multi-center phase II trial of two HER2 peptide vaccines, GP2 and AE37, in breast cancer patients to prevent recurrence

“…A similar finding was demonstrated in a HER2 peptide derived vaccine on a dendritic cell platform that stimulates both CD8+ and CD4+ T cells. This MHC class 2 vaccine was also given in combination with anti-PD-1 therapy and demonstrated improved survival in a preclinical model [30]. It is worth exploring future trials of combinations of check point inhibitors and peptide-based vaccine strategies to improve DFS.…”

Local and distant tumor dormancy during early stage breast cancer are associated with the predominance of infiltrating T effector subsets

“…However, mortality remains high in patients with distant recurrence of the disease after initially successful treatment of early stage breast cancer. Recent advances in immunotherapy of cancer by means of antibody therapies [ 1 , 2 ] and immune checkpoint blockade [ 3 – 6 ] have prolonged survival of cancer patients, but many patients do not respond to these therapies [ 5 , 7 , 8 ] and those who respond would remain at risk of tumor recurrence [ 6 , 9 , 10 ]. Therefore, a relapse-free cancer cure remains a major challenge for cancer therapeutics.…”

Combined Vaccine-Immune-Checkpoint Inhibition Constitutes a Promising Strategy for Treatment of dMMR Tumors

“…Although complete remission was not achieved in all mice, we would like to stress the point that tumor burden massively reduced in the combination likely because of inducing a T cell-in amed tumor microenvironment. Other studies reported superior effects when checkpoint-inhibition was given after cessation of the vaccine [38]. Still, the signi cantly prolonged overall survival of MLH1 −/− mice achieved in this study argues in favor of concomitant application.…”