Patient-Specific Targeting of the T-Cell Receptor Variable Region as a Therapeutic Strategy in Clonal T-Cell Diseases.

Autor:	Lucero OM; Department of Dermatology, Oregon Health & Science University, Portland, Oregon.; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon., Lee JA; Clinical and Translational Science Institute, David Geffen School of Medicine, University of California, Los Angeles, California., Bowman J; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.; Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon., Johnson K; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.; Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon., Sapparapu G; Clinical and Translational Science Institute, David Geffen School of Medicine, University of California, Los Angeles, California., Thomas JK; Clinical and Translational Science Institute, David Geffen School of Medicine, University of California, Los Angeles, California., Fan G; Department of Pathology and Clinical Laboratory Medicine, Oregon Health & Science University, Portland, Oregon., Chang BH; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.; Division of Pediatric Hematology and Oncology, Oregon Health & Science University, Portland, Oregon., Thiel-Klare K; Division of Pediatric Hematology and Oncology, Oregon Health & Science University, Portland, Oregon., Eide CA; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.; Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon., Okada C; Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon., Palazzolo M; Clinical and Translational Science Institute, David Geffen School of Medicine, University of California, Los Angeles, California., Lind E; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.; Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon.; Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon., Kosaka Y; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.; Division of Pediatric Hematology and Oncology, Oregon Health & Science University, Portland, Oregon., Druker BJ; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.; Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon.; VB Therapeutics LLC, Jackson, Wyoming., Lydon N; VB Therapeutics LLC, Jackson, Wyoming., Bowers PM; Therapeutic Antibody Laboratory, Department of Pulmonology and Critical Care, David Geffen School of Medicine, Los Angeles, California.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Oct 13; Vol. 29 (20), pp. 4230-4241.
DOI:	10.1158/1078-0432.CCR-22-0906
Abstrakt:	Purpose: Targeted therapeutics are a goal of medicine. Methods for targeting T-cell lymphoma lack specificity for the malignant cell, leading to elimination of healthy cells. The T-cell receptor (TCR) is designed for antigen recognition. T-cell malignancies expand from a single clone that expresses one of 48 TCR variable beta (Vβ) genes, providing a distinct therapeutic target. We hypothesized that a mAb that is exclusive to a specific Vβ would eliminate the malignant clone while having minimal effects on healthy T cells. Experimental Design: We identified a patient with large granular T-cell leukemia and sequenced his circulating T-cell population, 95% of which expressed Vβ13.3. We developed a panel of anti-Vβ13.3 antibodies to test for binding and elimination of the malignant T-cell clone. Results: Therapeutic antibody candidates bound the malignant clone with high affinity. Antibodies killed engineered cell lines expressing the patient TCR Vβ13.3 by antibody-dependent cellular cytotoxicity and TCR-mediated activation-induced cell death, and exhibited specific killing of patient malignant T cells in combination with exogenous natural killer cells. EL4 cells expressing the patient's TCR Vβ13.3 were also killed by antibody administration in an in vivo murine model. Conclusions: This approach serves as an outline for development of therapeutics that can treat clonal T-cell-based malignancies and potentially other T-cell-mediated diseases. See related commentary by Varma and Diefenbach, p. 4024. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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