CAR T cell therapy: looking back and looking forward

Editorial Material Biotechnology & Applied Microbiology

Preliminary outcomes reported from three randomized controlled trials of CD19 CAR-T cell therapies in large B cell lymphoma

Michael D. Jain

MOLECULAR THERAPY (2022)

Article Multidisciplinary Sciences

Decade-long leukaemia remissions with persistence of CD4(+) CAR T cells

J. Joseph Melenhorst et al.

Summary: CAR T cells redirected to target CD19 demonstrated long-lasting potential and clonal stability in two patients with chronic lymphocytic leukaemia. Highly activated CD4(+) cells emerged and dominated the CAR T cell population at later time points. These unexpected CAR T cell populations provide novel insights into anti-cancer response and long-term remission in leukaemia.

NATURE (2022)

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Article Medicine, General & Internal

Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma

F. L. Locke et al.

Summary: This international phase 3 trial showed that axicabtagene ciloleucel therapy significantly improved event-free survival and response in patients with early relapsed or refractory large B-cell lymphoma compared to standard care, despite the expected high-grade toxic effects.

NEW ENGLAND JOURNAL OF MEDICINE (2022)

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Article Hematology

Whole-genome sequencing reveals complex genomic features underlying anti-CD19 CAR T-cell treatment failures in lymphoma

Michael D. Jain et al.

Summary: This study revealed the mechanisms of resistance to CAR-19 T cell therapy for large B-cell lymphomas through whole-genome sequencing. Pretreatment complex structural variants, APOBEC mutational signatures, and genomic damage from reactive oxygen species were found to predict CAR-19 resistance. In addition, the loss of the RHOA tumor suppressor gene through recurrent 3p21.31 chromosomal deletion was commonly observed in patients who failed CAR T-cell therapy. The reduced expression or monoallelic loss of CD19 before treatment did not affect the efficacy, suggesting the success and resistance of CAR-19 therapy are related to multiple mechanisms.

BLOOD (2022)

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Article Biochemistry & Molecular Biology

Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results

Changsong Qi et al.

Summary: The interim analysis results of a phase 1 clinical trial show that CLDN18.2-targeted CAR T cell therapy has promising efficacy and an acceptable safety profile in previously treated, CLDN18.2-positive digestive system cancer patients. Particularly, it shows significant efficacy in patients with gastric cancer.

NATURE MEDICINE (2022)

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Article Biochemistry & Molecular Biology

PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial

Vivek Narayan et al.

Summary: CAR T cells show promising efficacy in hematologic malignancies, but face challenges in solid tumors due to the immunosuppressive tumor microenvironment. This study reports results from a phase 1 trial using engineered CAR T cells resistant to TGF-beta signaling in castration-resistant prostate cancer patients, showing both efficacy and dose-dependent toxicity. Future studies should explore multipronged approaches to improve outcomes in this setting.

NATURE MEDICINE (2022)

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Article Medicine, General & Internal

Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial

Manali Kamdar et al.

LANCET (2022)

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Article Biochemistry & Molecular Biology

Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy

Zinaida Good et al.

Summary: Single-cell proteomic profiling of circulating CAR T cells in patients treated with CD19-CAR reveals that CD4(+)Helios(+) CAR T cells on day 7 after infusion are associated with progressive disease and less severe neurotoxicity.

NATURE MEDICINE (2022)

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Article Biochemistry & Molecular Biology

Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma

Nicholas J. Haradhvala et al.

Summary: This study reveals the role of CAR-T regulatory cells in treatment relapse and the different molecular phenotypes of CAR-T cells with different designs.

NATURE MEDICINE (2022)

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Article Biochemistry & Molecular Biology

Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma

Nathalie Scholler et al.

Summary: This study evaluates the impact of Axicabtagene ciloleucel (axi-cel) on the treatment outcomes of large B cell lymphoma (LBCL) patients. The results show that the immune contexture of the tumor microenvironment plays a significant role in clinical responses, and different T cell-related characteristics are associated with pre- and post-treatment clinical responses and neurologic toxicity.

NATURE MEDICINE (2022)

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Article Medicine, General & Internal

GPRC5D-Targeted CAR T Cells for Myeloma

Sham Mailankody et al.

Summary: The study demonstrates that GPRC5D is an active immunotherapeutic target in multiple myeloma, and GPRC5D-targeted CAR T-cell therapy shows promising efficacy in heavily pretreated patients, including those who relapsed after BCMA CAR T-cell therapy.

NEW ENGLAND JOURNAL OF MEDICINE (2022)

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Article Hematology

Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma

Michael D. Jain et al.

Summary: This study found that in LBCL tumors, IFN signaling is associated with the expression of immune checkpoint ligands, and it is related to lack of durable response to CAR-T therapy. Immune dysregulation promotes axi-cel resistance via multiple mechanistic programs, including insufficient axi-cel expansion due to circulating M-MDSC and tumor IFN signaling.

BLOOD (2021)

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Article Oncology