Progress and Pitfalls of Chimeric Antigen Receptor T Cell Immunotherapy against T Cell Malignancies

Angelos, Mathew G.; Patel, Ruchi P.; Ruella, Marco; Barta, Stefan K.

doi:10.1016/j.jtct.2023.10.013

Cited by 5 publications

(3 citation statements)

References 127 publications

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“…We initially tested the role of CD5 KO in CAR T cells against T cell neoplasms because there are no US Food and Drug Administration (FDA)–approved CAR T therapies for this orphan disease ( 15 ). CD5 is a T cell neoplasm target that is highly and homogeneously expressed in about 85% of patients with TCL and T-ALL (fig.…”

Section: Resultsmentioning

confidence: 99%

“…Despite these results, most patients treated with CAR T either do not respond or eventually relapse ( 4 – 10 ). Moreover, CAR T therapy has not yet demonstrated significant responses in solid cancers ( 11 ) and in several hematological malignancies, such as T cell lymphoma (TCL)/acute lymphoblastic leukemia (T-ALL) and others ( 12 – 15 ). Thus, there is a dire need to enhance the currently available CAR T products and extend this effective approach to successfully treat more types of cancer.…”

Section: Introductionmentioning

confidence: 99%

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CD5 deletion enhances the antitumor activity of adoptive T cell therapies

Patel,

Ghilardi,

Zhang

et al. 2024

Sci. Immunol.

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Most patients treated with US Food and Drug Administration (FDA)–approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CD5 deletion enhances the antitumor activity of adoptive T cell therapies

Patel,

Ghilardi,

Zhang

et al. 2024

Sci. Immunol.

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“…Raikar et al [ 10 ] employed CRISPR-Cas9 technology to knock down CD5 in primary T cells, followed by transduction with CD5-CAR, enhancing both the surface expression of CAR and its antitumor efficacy while reducing self-activation. Similarly, Angelos et al [ 11 ] developed a novel Senza5 CAR-T-cell product, which, by knocking down autologous CD5, showed high specificity and low off-target risks, maintained pathogen responsiveness, and has been utilized in phase I trials for treating R/R CD5-positive T-cell lymphomas. Recently, Hill L.C.…”

Section: Exploration Of Car-t-cell Therapy Targets In T-cell Malignan...mentioning

confidence: 99%

Advances in CAR-T-cell therapy in T-cell malignancies

Zheng,

Zhu,

Xiao

2024

J Hematol Oncol

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Significant advances have been made in chimeric antigen receptor T (CAR-T)-cell therapy for the treatment of recurrent or refractory B-cell hematologic malignancies. However, CAR-T-cell therapy has not yet achieved comparable success in the management of aggressive T-cell malignancies. This article reviews the challenges of CAR-T-cell therapy in treating T-cell malignancies and summarizes the progress of preclinical and clinical studies in this area. We present an analysis of clinical trials of CAR-T-cell therapies for the treatment of T-cell malignancies grouped by target antigen classification. Moreover, this review focuses on the major challenges encountered by CAR-T-cell therapies, including the nonspecific killing due to T-cell target antigen sharing and contamination with cell products during preparation. This review discusses strategies to overcome these challenges, presenting novel therapeutic approaches that could enhance the efficacy and applicability of CAR-T-cell therapy in the treatment of T-cell malignancies. These ideas and strategies provide important information for future studies to promote the further development and application of CAR-T-cell therapy in this field.

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