TRBC1-targeting antibody-drug conjugates for the treatment of T cell cancers.

in Nature by Tushar D Nichakawade, Jiaxin Ge, Brian J Mog, Bum Seok Lee, Alexander H Pearlman, Michael S Hwang, Sarah R DiNapoli, Nicolas Wyhs, Nikita Marcou, Stephanie Glavaris, Maximilian F Konig, Sandra B Gabelli, Evangeline Watson, Cole Sterling, Nina Wagner-Johnston, Sima Rozati, Lode Swinnen, Ephraim Fuchs, Drew M Pardoll, Kathy Gabrielson, Nickolas Papadopoulos, Chetan Bettegowda, Kenneth W Kinzler, Shibin Zhou, Surojit Sur, Bert Vogelstein, Suman Paul

TLDR

  • The study is looking at ways to treat a type of cancer called T cell cancers, which are caused by problems with the T cells in the body. The study found that CAR T cells, which are a type of treatment, were being killed by the patient's own T cells, which made them less effective. The study then came up with a new way to target the T cells that would be less likely to be killed by the patient's own T cells. This new way could be better at treating T cell cancers.

Abstract

Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survivaland lack such targeted therapies. Thus, T cell cancers particularly warrant the development of CAR T cells and antibodies to improve patient outcomes. Preclinical studies showed that targeting T cell receptor β-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity, making TRBC1 an attractive target to treat T cell cancers. However, the first-in-human clinical trial of anti-TRBC1 CAR T cells reported a low response rate and unexplained loss of anti-TRBC1 CAR T cells. Here we demonstrate that CAR T cells are lost due to killing by the patient's normal T cells, reducing their efficacy. To circumvent this issue, we developed an antibody-drug conjugate that could kill TRBC1cancer cells in vitro and cure human T cell cancers in mouse models. The anti-TRBC1 antibody-drug conjugate may provide an optimal format for TRBC1 targeting and produce superior responses in patients with T cell cancers.

Overview

  • The study aims to investigate the use of antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies for treating T cell cancers, which have short survival and lack such therapies. The study focuses on targeting T cell receptor β-chain constant region 1 (TRBC1) as an attractive target to treat T cell cancers. The methodology used for the experiment includes preclinical studies and a first-in-human clinical trial of anti-TRBC1 CAR T cells. The primary objective of the study is to develop an antibody-drug conjugate that can kill TRBC1 cancer cells in vitro and cure human T cell cancers in mouse models.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions, including preclinical studies and the first-in-human clinical trial of anti-TRBC1 CAR T cells. The results show that CAR T cells are lost due to killing by the patient's normal T cells, reducing their efficacy. The study identifies this issue as a significant limitation of the first-in-human clinical trial. The key findings of the study suggest that an antibody-drug conjugate may provide an optimal format for TRBC1 targeting and produce superior responses in patients with T cell cancers.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they suggest that an antibody-drug conjugate may provide an optimal format for TRBC1 targeting and produce superior responses in patients with T cell cancers. The study identifies the issue of CAR T cells being lost due to killing by the patient's normal T cells as a significant limitation of the first-in-human clinical trial. Future research directions could focus on developing antibody-drug conjugates that target TRBC1 and improve the efficacy of CAR T cells in patients with T cell cancers.
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