Oncolytic adeno-immunotherapy modulates the immune system enabling CAR T-cells to cure pancreatic tumors

Amanda Rosewell Shaw,Robin Parihar,Youngrock Jung,Caroline E Porter,Matthew Dysthe,Way-Champ Mah,Mary K Mckenna,Tiffany Yip,Malcolm K Brenner,Masataka Suzuki

doi:10.1038/s42003-021-01914-8

Abstract

High expression levels of human epidermal growth factor receptor 2 (HER2) have been associated with poor prognosis in patients with pancreatic adenocarcinoma (PDAC). However, HER2-targeting immunotherapies have been unsuccessful to date. Here we increase the breadth, potency, and duration of anti-PDAC HER2-specific CAR T-cell (HER2.CART) activity with an oncolytic adeno-immunotherapy that produces cytokine, immune checkpoint blockade, and a safety switch (CAdTrio). Combination treatment with CAdTrio and HER2.CARTs cured tumors in two PDAC xenograft models and produced durable tumor responses in humanized mice. Modifications to the tumor immune microenvironment contributed to the antitumor activity of our combination immunotherapy, as intratumoral CAdTrio treatment induced chemotaxis to enable HER2.CART migration to the tumor site. Using an advanced PDAC model in humanized mice, we found that local CAdTrio treatment of primary tumor stimulated systemic host immune responses that repolarized distant tumor microenvironments, improving HER2.CART anti-tumor activity. Overall, our data demonstrate that CAdTrio and HER2.CARTs provide complementary activities to eradicate metastatic PDAC and may represent a promising co-operative therapy for PDAC patients.

Highlights

High expression levels of human epidermal growth factor receptor 2 (HER2) have been associated with poor prognosis in patients with pancreatic adenocarcinoma (PDAC)
Monoclonal antibody therapy targeting HER2 previously failed for PDAC patients[9], HER2.CARTs have higher avidity and ability to directly kill tumor cells through cytolytic proteins as opposed to antibodydependent cellular cytotoxicity through infiltrating immune cells
Since PDAC patients have been safely treated with oncolytic viruses[16,17], we confirmed that our oncolytic adeno-immunotherapy, comprised of an oncolytic adenovirus (OAd) and a helper-dependent adenoviral vector (HDAd) encoding human interleukin 12p70, programmed death ligand 1 (PDL1) blocking miniantibody, and herpes simplex virus thymidine kinase (HSVtk) safety switch expression cassettes (CAdTrio), lysed PDAC lines (Fig. 1b)

Summary

Introduction

High expression levels of human epidermal growth factor receptor 2 (HER2) have been associated with poor prognosis in patients with pancreatic adenocarcinoma (PDAC). We increase the breadth, potency, and duration of anti-PDAC HER2-specific CAR T-cell (HER2.CART) activity with an oncolytic adeno-immunotherapy that produces cytokine, immune checkpoint blockade, and a safety switch (CAdTrio). Using an advanced PDAC model in humanized mice, we found that local CAdTrio treatment of primary tumor stimulated systemic host immune responses that repolarized distant tumor microenvironments, improving HER2.CART anti-tumor activity. In a phase II clinical trial, patients with metastatic PDAC with grade 3 HER2 expression by immunohistochemistry were treated with the HER2 monoclonal antibody Trastuzumab (Herceptin) in combination with fluorouracil[9] This HER2-targeting therapy was tolerated but did not improve progression-free or overall survival in these patients. We tested whether our combination immunotherapy with HER2.CART and CAd expressing IL-12, PD-L1 blocking antibody, and safety switch HSVtk (CAdTrio) could resolve HER2-positive PDAC tumors

Methods

Results

Conclusion