Infusion Product TNFα, Th2, and STAT3 Activities Are Associated with Clinical Responses to Transgenic T-cell Receptor Cell Therapy

Author:

Nowicki Theodore S.12345ORCID,Peters Cole W.1ORCID,Quiros Crystal1ORCID,Kidd Conner K.1ORCID,Kawakami Moe1ORCID,Klomhaus Alexandra M.6ORCID,Baselga-Carretero Ignacio7ORCID,Kaplan-Lefko Paula7ORCID,Macabali Mignonette H.7ORCID,Perez Garcilazo Ivan7ORCID,Berent-Maoz Beata7ORCID,Comin-Anduix Begoña38ORCID,Ribas Antoni34789ORCID

Affiliation:

1. 1Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, California.

2. 2Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, California.

3. 3Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California.

4. 4Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, California.

5. 5Molecular Biology Institute, University of California Los Angeles, Los Angeles, California.

6. 6Department of General Internal Medicine and Health Services Research, University of California, Los Angeles, California.

7. 7Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, California.

8. 8Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, California.

9. 9Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California.

Abstract

Abstract Transgenic T-cell receptor (TCR) T cell–based adoptive cell therapies for solid tumors are associated with dramatic initial response rates, but there remain many instances of treatment failure and disease relapse. The association of infusion product cytokine profiles with clinical response has not been explored in the context of TCR T-cell therapy products. Single-cell antigen-dependent secretomic and proteomic analysis of preinfusion clinical TCR T-cell therapy products revealed that TNFα cytokine functionality of CD8+ T cells and phospho-STAT3 signaling in these cells were both associated with superior clinical responsiveness to therapy. By contrast, CD4+ T-helper 2 cell cytokine profiles were associated with inferior clinical responses. In parallel, preinfusion levels of IL15, Flt3-L, and CX3CL1 were all found to be associated with clinical response to therapy. These results have implications for the development of therapeutic biomarkers and identify potential targets for enrichment in the design of transgenic TCR T-cell therapies for solid tumors.

Funder

National Cancer Institute

California Institute for Regenerative Medicine

Hyundai Hope On Wheels

Ruby Family Foundation

Parker Institute for Cancer Immunotherapy

Ressler Family Fund

Ken and Donna Schultz

Todd and Donna Jones

Thomas Stutz

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Immunology

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