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

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 YuRoshni 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

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English (US)
Pages (from-to)	35-51.e8
Journal	Cancer Cell
Volume	42
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2023.11.011
State	Published - Jan 8 2024
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2023.11.011

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Kaczanowska, S., Murty, T., Alimadadi, A., Contreras, C. F., Duault, C., Subrahmanyam, P. B., Reynolds, W., Gutierrez, N. A., Baskar, R., Wu, C. J., Michor, F., Altreuter, J., Liu, Y., Jhaveri, A., Duong, V., Anbunathan, H., Ong, C., Zhang, H., Moravec, R., ... Kaplan, R. N. (2024). Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy. Cancer Cell, 42(1), 35-51.e8. https://doi.org/10.1016/j.ccell.2023.11.011

Kaczanowska, S, Murty, T, Alimadadi, A, Contreras, CF, Duault, C, Subrahmanyam, PB, Reynolds, W, Gutierrez, NA, Baskar, R, Wu, CJ, Michor, F, Altreuter, J, Liu, Y, Jhaveri, A, Duong, V, Anbunathan, H, Ong, C, Zhang, H, Moravec, R, Yu, J, Biswas, R, Van Nostrand, S, Lindsay, J, Pichavant, M, Sotillo, E, Bernstein, D, Carbonell, A, Derdak, J, Klicka-Skeels, J, Segal, JE, Dombi, E, Harmon, SA, Turkbey, B, Sahaf, B, Bendall, S, Maecker, H, Highfill, SL, Stroncek, D, Glod, J, Merchant, M, Hedrick, CC, Mackall, CL, Ramakrishna, S & Kaplan, RN 2024, 'Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy', Cancer Cell, vol. 42, no. 1, pp. 35-51.e8. https://doi.org/10.1016/j.ccell.2023.11.011

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title = "Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy",

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",

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

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doi = "10.1016/j.ccell.2023.11.011",

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AU - Kaczanowska, Sabina

AU - Murty, Tara

AU - Alimadadi, Ahmad

AU - Contreras, Cristina F.

AU - Duault, Caroline

AU - Subrahmanyam, Priyanka B.

AU - Reynolds, Warren

AU - Gutierrez, Norma A.

AU - Baskar, Reema

AU - Wu, Catherine J.

AU - Michor, Franziska

AU - Altreuter, Jennifer

AU - Liu, Yang

AU - Jhaveri, Aashna

AU - Duong, Vandon

AU - Anbunathan, Hima

AU - Ong, Claire

AU - Zhang, Hua

AU - Moravec, Radim

AU - Yu, Joyce

AU - Biswas, Roshni

AU - Van Nostrand, Stephen

AU - Lindsay, James

AU - Pichavant, Mina

AU - Sotillo, Elena

AU - Bernstein, Donna

AU - Carbonell, Amanda

AU - Derdak, Joanne

AU - Klicka-Skeels, Jacquelyn

AU - Segal, Julia E.

AU - Dombi, Eva

AU - Harmon, Stephanie A.

AU - Turkbey, Baris

AU - Sahaf, Bita

AU - Bendall, Sean

AU - Maecker, Holden

AU - Highfill, Steven L.

AU - Stroncek, David

AU - Glod, John

AU - Merchant, Melinda

AU - Hedrick, Catherine C.

AU - Mackall, Crystal L.

AU - Ramakrishna, Sneha

AU - Kaplan, Rosandra N.

PY - 2024/1/8

Y1 - 2024/1/8

N2 - 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.

AB - 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.

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KW - cancer

KW - chimeric antigen receptor

KW - correlative studies

KW - immune suppression

KW - immunotherapy

KW - monocytes

KW - myeloid cells

KW - osteosarcoma

KW - pediatric oncology

KW - solid tumor

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SN - 1535-6108

VL - 42

SP - 35-51.e8

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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