IL-18R supported CAR T cells targeting oncofetal tenascin C for the immunotherapy of pediatric sarcoma and brain tumors.

in Journal for immunotherapy of cancer by Elizabeth Wickman, Shannon Lange, Jessica Wagner, Jorge Ibanez, Liqing Tian, Meifen Lu, Heather Sheppard, Jason Chiang, Selene C Koo, Peter Vogel, Deanna Langfitt, S Scott Perry, Raghuvaran Shanmugam, Matthew Bell, Timothy I Shaw, Giedre Krenciute, Jinghui Zhang, Stephen Gottschalk

TLDR

  • The study demonstrates the potential of targeting the oncofetal TNC-C domain with CAR T cells in pediatric cancers, with improved activity achieved through the addition of a novel cytokine receptor component.

Abstract

Oncofetal splice variants of extracellular matrix (ECM) proteins present a unique group of target antigens for the immunotherapy of pediatric cancers. However, limited data is available if these splice variants can be targeted with T cells expressing chimeric antigen receptors (CARs). To determine the expression of the oncofetal version of tenascin C (TNC) encoding the C domain (C.TNC) in pediatric brain and solid tumors, we used quantitative reverse transcription PCR and immunohistochemistry. Genetically modified T cells were generated from human peripheral blood mononuclear cells and evaluated in vitro and in vivo. We demonstrate that C.TNC is expressed on a protein level in pediatric tumors, including diffuse intrinsic pontine glioma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. We generate C.TNC-CAR T cells and establish that these recognize and kill C.TNC-positive tumor cells. However, their antitumor activity in vivo is limited. To improve the effector function of C.TNC-CAR T cells, we design a leucine zipper-based chimeric cytokine receptor that activates interleukin-18 signaling pathways (Zip18R). Expression of Zip18R in C.TNC-CAR T cells improves their ability to secrete cytokines and expand in repeat stimulation assays. C.TNC-CAR.Zip18R T cells also have significantly greater antitumor activity in vivo compared with unmodified C.TNC-CAR T cells. Our study identifies the C domain of the ECM protein TNC as a promising CAR T-cell therapy for pediatric solid tumors and brain tumors. While we focus here on pediatric cancer, our work has relevance to a broad range of adult cancers that express C.TNC.

Overview

  • The study focuses on the oncofetal splice variant of tenascin C (TNC) as a target antigen for immunotherapy in pediatric cancers.
  • The researchers used quantitative reverse transcription PCR and immunohistochemistry to determine the expression of C.TNC in pediatric brain and solid tumors.
  • The study aims to generate genetically modified T cells expressing a chimeric antigen receptor (CAR) against C.TNC and evaluate their antitumor activity in vitro and in vivo.

Comparative Analysis & Findings

  • The study shows that C.TNC is expressed on a protein level in pediatric tumors, including diffuse intrinsic pontine glioma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma.
  • The genetically modified T cells targeting C.TNC (C.TNC-CAR T cells) can recognize and kill C.TNC-positive tumor cells, but their antitumor activity in vivo is limited.
  • The addition of a leucine zipper-based chimeric cytokine receptor (Zip18R) to C.TNC-CAR T cells improves their ability to secrete cytokines and expand in repeat stimulation assays, and increases their antitumor activity in vivo.

Implications and Future Directions

  • The study identifies the C domain of TNC as a promising target for CAR T-cell therapy in pediatric solid tumors and brain tumors.
  • The findings have relevance to a broad range of adult cancers that express C.TNC, suggesting potential applications beyond pediatric cancers.
  • Future studies can focus on further optimizing the Zip18R component and evaluating its combination with other immunotherapies to improve the efficacy of CAR T-cell therapy.
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