To overcome the poor persistence and progressive loss of functionality of TCR-engineered T cells, in vivo, Nowicki et al. evaluated tandem treatment with autologous blood-derived T cells and hematopoietic stem cells (HSCs), both engineered with an NY-ESO-TCR. The HSCs also contained the suicide/reporter gene sr39TK to allow for in vivo visualization. In a first-in-human clinical trial in patients with solid tumors, treatment was both safe and feasible (despite clinical difficulties), with early evidence of tumor regression. In circulation, T cell progeny derived from HSCs expressed the engineered TCRs and showed antigen-specific functionality. In vivo imaging aligned with peripheral blood samples.
Contributed by Lauren Hitchings
ABSTRACT: Adoptive transfer of genetically engineered T cells expressing a tumor-antigen-specific transgenic T cell receptor (TCR) can result in clinical responses in a variety of malignancies. However, these responses are frequently short-lived, and patients typically relapse within several months. This phenomenon is largely due to poor persistence of the transgenic T cells, as well as a progressive loss of their functionality and terminal differentiation in vivo. This underscores the need for cell therapy approaches able to sustain the initial antitumor efficacy and lead to long-term antitumor efficacy. Herein, we report the use of tandem cell therapies involving autologous T cells and hematopoietic stem cells engineered to express the NY-ESO-1 TCR for the treatment of solid tumors in a first-in-human phase I clinical trial (NCT03240861). This therapy is shown to be safe, feasible, and leads to initial tumor regression activity. T cell progeny from the HSC progenitors is shown to provide circulating transgenic NY-ESO-1 TCR-T cells, which display tumor-antigen-specific antitumor functionality, without any evidence of anergy or exhaustion. These results demonstrate the utility of transgenic HSCs to generate a self-renewing source of tumor-specific cellular immunotherapy in human participants. Clinicaltrials.gov: NCT NCT03240861.
Author Info: (1) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. Department of Microbi
Author Info: (1) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. tnowicki@mednet.ucla.edu. (2) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (3) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. (4) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA. Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA. (5) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (6) Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA. Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA, USA. (7) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (8) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (9) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (10) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (11) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (12) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (13) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (14) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (15) David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (16) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. (17) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. (18) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (19) Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA. (20) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (21) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (22) Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (23) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Department of Orthopaedic Surgery, University of California Los Angeles, Los Angeles, CA, USA. (24) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (25) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (26) David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA. (27) Department of Medicine Statistics Core, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (28) Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (29) Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA. (30) Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. (31) Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA. Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. (32) Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA, USA. (33) Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA. Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA, USA. Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA.
