Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy

Sabina Kaczanowska; Tara Murty; Ahmad Alimadadi; Cristina F Contreras; Caroline Duault; Priyanka B Subrahmanyam; Warren Reynolds; Norma A Gutierrez; Reema Baskar; Catherine J Wu; Franziska Michor; Jennifer Altreuter; Yang Liu; Aashna Jhaveri; Vandon Duong; Hima Anbunathan; Claire Ong; Hua Zhang; Radim Moravec; Joyce Yu; Roshni Biswas; Stephen Van Nostrand; James Lindsay; Mina Pichavant; Elena Sotillo; Donna Bernstein; Amanda Carbonell; Joanne Derdak; Jacquelyn Klicka-Skeels; Julia E Segal; Eva Dombi; Stephanie A Harmon; Baris Turkbey; Bita Sahaf; Sean Bendall; Holden Maecker; Steven L Highfill; David Stroncek; John Glod; Melinda Merchant; Catherine C Hedrick; Crystal L Mackall; Sneha Ramakrishna; Rosandra N Kaplan

doi:10.1016/j.ccell.2023.11.011

Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy

Cancer Cell. 2024 Jan 8;42(1):35-51.e8. doi: 10.1016/j.ccell.2023.11.011. Epub 2023 Dec 21.

Authors

Sabina Kaczanowska¹, Tara Murty², Ahmad Alimadadi³, Cristina F Contreras⁴, Caroline Duault⁵, Priyanka B Subrahmanyam⁵, Warren Reynolds², Norma A Gutierrez⁶, Reema Baskar⁷, Catherine J Wu⁸, Franziska Michor⁹, Jennifer Altreuter⁹, Yang Liu⁹, Aashna Jhaveri⁹, Vandon Duong², Hima Anbunathan², Claire Ong¹, Hua Zhang¹, Radim Moravec¹⁰, Joyce Yu¹¹, Roshni Biswas¹¹, Stephen Van Nostrand¹¹, James Lindsay¹¹, Mina Pichavant¹², Elena Sotillo², Donna Bernstein¹, Amanda Carbonell¹, Joanne Derdak¹, Jacquelyn Klicka-Skeels¹, Julia E Segal¹, Eva Dombi¹, Stephanie A Harmon¹³, Baris Turkbey¹³, Bita Sahaf², Sean Bendall¹⁴, Holden Maecker¹², Steven L Highfill¹⁵, David Stroncek¹⁵, John Glod¹, Melinda Merchant¹, Catherine C Hedrick³, Crystal L Mackall², Sneha Ramakrishna¹⁶, Rosandra N Kaplan¹⁷

Affiliations

¹ Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
² Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
³ La Jolla Institute for Immunology, La Jolla, CA, USA; Immunology Center of Georgia, Augusta University, Augusta, GA, USA; Georgia Cancer Center, Medical College of Georgia at Augusta University, Augusta, GA, USA.
⁴ Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Department of Oncology, University of Oxford, Oxford, UK.
⁵ Stanford Human Immune Monitoring Center, Stanford University School of Medicine, Stanford, CA, USA.
⁶ La Jolla Institute for Immunology, La Jolla, CA, USA.
⁷ Department of Pathology, Stanford University, Stanford, CA, USA.
⁸ Broad Institute, Cambridge, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA.
⁹ Broad Institute, Cambridge, MA, USA.
¹⁰ Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹¹ Dana-Farber Cancer Institute, Boston, MA, USA.
¹² Immunology Center of Georgia, Augusta University, Augusta, GA, USA.
¹³ Artificial Intelligence Resource, Molecular Imaging Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁴ Georgia Cancer Center, Medical College of Georgia at Augusta University, Augusta, GA, USA.
¹⁵ Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health Clinical Center, Bethesda, MD, USA.
¹⁶ Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: ramakrs@stanford.edu.
¹⁷ Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: rosie.kaplan@nih.gov.

PMID: 38134936
PMCID: PMC10947809 (available on 2025-01-08)
DOI: 10.1016/j.ccell.2023.11.011

Abstract

Chimeric antigen receptor T cells (CAR-Ts) have remarkable efficacy in liquid tumors, but limited responses in solid tumors. We conducted a Phase I trial (NCT02107963) of GD2 CAR-Ts (GD2-CAR.OX40.28.z.iC9), demonstrating feasibility and safety of administration in children and young adults with osteosarcoma and neuroblastoma. Since CAR-T efficacy requires adequate CAR-T expansion, patients were grouped into good or poor expanders across dose levels. Patient samples were evaluated by multi-dimensional proteomic, transcriptomic, and epigenetic analyses. T cell assessments identified naive T cells in pre-treatment apheresis associated with good expansion, and exhausted T cells in CAR-T products with poor expansion. Myeloid cell assessment identified CXCR3⁺ monocytes in pre-treatment apheresis associated with good expansion. Longitudinal analysis of post-treatment samples identified increased CXCR3^- classical monocytes in all groups as CAR-T numbers waned. Together, our data uncover mediators of CAR-T biology and correlates of expansion that could be utilized to advance immunotherapies for solid tumor patients.

Keywords: CAR-T cells; cancer; chimeric antigen receptor; correlative studies; immune suppression; immunotherapy; monocytes; myeloid cells; osteosarcoma; pediatric oncology; solid tumor.

Published by Elsevier Inc.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural

MeSH terms

Cell- and Tissue-Based Therapy
Child
Humans
Immunotherapy, Adoptive / adverse effects
Immunotherapy, Adoptive / methods
Neuroblastoma* / pathology
Proteomics
Receptors, Antigen, T-Cell / genetics
Receptors, Chimeric Antigen* / genetics
T-Lymphocytes
Young Adult

Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy

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