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Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas.
Sworder, Brian J; Kurtz, David M; Alig, Stefan K; Frank, Matthew J; Shukla, Navika; Garofalo, Andrea; Macaulay, Charles W; Shahrokh Esfahani, Mohammad; Olsen, Mari N; Hamilton, James; Hosoya, Hitomi; Hamilton, Mark; Spiegel, Jay Y; Baird, John H; Sugio, Takeshi; Carleton, Mia; Craig, Alexander F M; Younes, Sheren F; Sahaf, Bita; Sheybani, Natasha D; Schroers-Martin, Joseph G; Liu, Chih Long; Oak, Jean S; Jin, Michael C; Beygi, Sara; Hüttmann, Andreas; Hanoun, Christine; Dührsen, Ulrich; Westin, Jason R; Khodadoust, Michael S; Natkunam, Yasodha; Majzner, Robbie G; Mackall, Crystal L; Diehn, Maximilian; Miklos, David B; Alizadeh, Ash A.
Affiliation
  • Sworder BJ; Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
  • Kurtz DM; Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
  • Alig SK; Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
  • Frank MJ; 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.
  • Shukla N; Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
  • Garofalo A; Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
  • Macaulay CW; Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
  • Shahrokh Esfahani M; Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
  • Olsen MN; Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
  • Hamilton J; Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
  • Hosoya H; Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
  • Hamilton M; 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.
  • Spiegel JY; 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.
  • Baird JH; 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.
  • Sugio T; Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
  • Carleton M; Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
  • Craig AFM; Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
  • Younes SF; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Sahaf B; 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.
  • Sheybani ND; Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
  • Schroers-Martin JG; 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.
  • Liu CL; Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
  • Oak JS; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Jin MC; Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
  • Beygi S; Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
  • Hüttmann A; Department of Hematology, University Hospital of Essen, Essen, Germany.
  • Hanoun C; Department of Hematology, University Hospital of Essen, Essen, Germany.
  • Dührsen U; Department of Hematology, University Hospital of Essen, Essen, Germany.
  • Westin JR; Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Khodadoust MS; Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
  • Natkunam Y; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Majzner RG; 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.
  • Mackall CL; 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,
  • Diehn M; 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.
  • Miklos DB; 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.
  • Alizadeh AA; 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
Cancer Cell ; 41(1): 210-225.e5, 2023 01 09.
Article in En | MEDLINE | ID: mdl-36584673
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Lymphoma, Large B-Cell, Diffuse / Receptors, Chimeric Antigen Type of study: Prognostic_studies Limits: Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2023 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Lymphoma, Large B-Cell, Diffuse / Receptors, Chimeric Antigen Type of study: Prognostic_studies Limits: Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2023 Document type: Article Affiliation country: United States