Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas

Brian J Sworder; David M Kurtz; Stefan K Alig; Matthew J Frank; Navika Shukla; Andrea Garofalo; Charles W Macaulay; Mohammad Shahrokh Esfahani; Mari N Olsen; James Hamilton; Hitomi Hosoya; Mark Hamilton; Jay Y Spiegel; John H Baird; Takeshi Sugio; Mia Carleton; Alexander F M Craig; Sheren F Younes; Bita Sahaf; Natasha D Sheybani; Joseph G Schroers-Martin; Chih Long Liu; Jean S Oak; Michael C Jin; Sara Beygi; Andreas Hüttmann; Christine Hanoun; Ulrich Dührsen; Jason R Westin; Michael S Khodadoust; Yasodha Natkunam; Robbie G Majzner; Crystal L Mackall; Maximilian Diehn; David B Miklos; Ash A Alizadeh

doi:10.1016/j.ccell.2022.12.005

Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas

Cancer Cell. 2023 Jan 9;41(1):210-225.e5. doi: 10.1016/j.ccell.2022.12.005. Epub 2022 Dec 29.

Authors

Brian J Sworder¹, David M Kurtz², Stefan K Alig¹, Matthew J Frank³, Navika Shukla¹, Andrea Garofalo¹, Charles W Macaulay¹, Mohammad Shahrokh Esfahani¹, Mari N Olsen¹, James Hamilton¹, Hitomi Hosoya⁴, Mark Hamilton⁵, Jay Y Spiegel³, John H Baird³, Takeshi Sugio¹, Mia Carleton¹, Alexander F M Craig¹, Sheren F Younes⁶, Bita Sahaf³, Natasha D Sheybani¹, Joseph G Schroers-Martin⁷, Chih Long Liu¹, Jean S Oak⁶, Michael C Jin¹, Sara Beygi¹, Andreas Hüttmann⁸, Christine Hanoun⁸, Ulrich Dührsen⁸, Jason R Westin⁹, Michael S Khodadoust², Yasodha Natkunam⁶, Robbie G Majzner¹⁰, Crystal L Mackall¹¹, Maximilian Diehn¹², David B Miklos³, Ash A Alizadeh¹³

Affiliations

¹ Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
² Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
³ Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford, CA 94305, USA.
⁴ Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
⁵ Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA; Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁷ Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA; Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
⁸ Department of Hematology, University Hospital of Essen, Essen, Germany.
⁹ Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford, CA 94305, USA; Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹¹ Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford, CA 94305, USA; Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹² Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA; Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
¹³ Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA; Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: arasha@stanford.edu.

Abstract

Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.

Keywords: MRD; cell-free DNA; chimeric antigen receptor T cells; circulating tumor DNA; ctDNA; genomics; immunotherapy; large B cell lymphoma; oncology; precision medicine.

Publication types

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

MeSH terms

Antigens, CD19 / genetics
Humans
Immunotherapy, Adoptive / methods
Lymphoma, Large B-Cell, Diffuse* / drug therapy
Lymphoma, Large B-Cell, Diffuse* / therapy
Neoplasm Recurrence, Local / drug therapy
Receptors, Chimeric Antigen* / genetics
T-Lymphocytes
Tumor Microenvironment

Substances

Receptors, Chimeric Antigen
Antigens, CD19

Abstract

Publication types

MeSH terms

Substances

Grants and funding