Current understanding and management of CAR T cell-associated toxicities

Brudno, Jennifer N.; Kochenderfer, James N.

doi:10.1038/s41571-024-00903-0

Cited by 23 publications

(3 citation statements)

References 171 publications

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“…Specifically, CAR-T cells targeting CD5 and CD7, has shown promise in treating T-cell malignancies [2,3]. However, patients often suffer from adverse events, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), virus reactivation, and T-cell aplasia post-CAR-T cell infusion [4][5][6]. These complications present substantial challenges to the wider application of CAR-T cell therapy in T-cell malignancies, necessitating the development of safety switch systems to attenuate potentially life-threatening side effects and to restore immune function after tumor elimination.…”

Section: Dear Editormentioning

confidence: 99%

Anti-CD5 CAR-T cells with a tEGFR safety switch exhibit potent toxicity control

Lin,

Cheng,

Zhu

et al. 2024

Blood Cancer J.

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Section: Dear Editormentioning

confidence: 99%

Anti-CD5 CAR-T cells with a tEGFR safety switch exhibit potent toxicity control

Lin,

Cheng,

Zhu

et al. 2024

Blood Cancer J.

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“…Besides the dangerous safety risk, viral vector-based manufacturing of CAR-T has a relatively high incidence of side effects such as CRS. A safer version of CAR-T is urgently needed to minimize safety issues and more importantly, unleash the full potentials of CAR-T cell therapy in noncancerous indications which is extremely sensitive to risk-benefit balance 1,11,17 . mRNA platform offers an ideal strategy to avoid the risks stem from viral vectors, genome integration, and permanent transgene expression of traditional CAR-T technologies 21 .…”

Section: Discussionmentioning

confidence: 99%

“…Despite these remarkable advances, currently approved CAR-T cell therapies are continually raising major safety concerns, including serious cytokine-release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), ontarget/off-tumor toxicity, and insertion mutation-related secondary cancers [10][11][12][13][14][15][16] . Many of these side effects can be largely attributed to the viral vector-based CAR engineering technologies which inevitably lead to vector-related side effects and risks from genome integration and permanent CAR expression on T cells 17 .…”

Section: Introductionmentioning

confidence: 99%

Scarless circular mRNA-based CAR-T cell therapy elicits superior anti-tumor efficacy

Hu,

Zhao,

Zhou

et al. 2024

Preprint

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Messenger RNA (mRNA)-based transient expression of CAR shows optimal safety profiles and provides promising opportunities to address existing challenges of viral vector-based CAR-T therapies and to meet emerging medical needs in noncancerous indications. However, linear mRNAs are intrinsically unstable and thus just achieve compromised efficacy. Here, we engineered a permuted intron exon (PIE) platform to synthesize scarless circular mRNA (cmRNA) for potent CAR expression and long-lasting efficacy. cmRNA significantly increased amount and duration of anti-CD19 CAR expression on human T cells. cmRNA-based anti-CD19 CAR-T cells elicit superior anti-tumor efficacy over linear mRNA counterparts, demonstrated by parallel lines of evidence includingin vitrospecific cell-killing, cytokine release, transcriptomics patterns, andin vivotumor elimination and survival benefit. We found that cmRNA-based anti-CD19 CAR-T efficiently eliminated target cellsin vivoand provide long-lasting antitumor efficacy. These results suggested that cmRNA could be a potent platform for unleashing full potential of mRNA technologies in cell therapies.

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CAR T Cells and T-Cell Therapies for Cancer

Brudno,

Maus,

Hinrichs

2024

JAMA

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ImportanceChimeric antigen receptor (CAR) T cells are T lymphocytes that are genetically engineered to express a synthetic receptor that recognizes a tumor cell surface antigen and causes the T cell to kill the tumor cell. CAR T treatments improve overall survival for patients with large B-cell lymphoma and progression-free survival for patients with multiple myeloma.ObservationsSix CAR T-cell products are approved by the US Food and Drug Administration (FDA) for 6 hematologic malignancies: B-cell acute lymphoblastic leukemia, large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, and multiple myeloma. Compared with standard chemotherapy followed by stem cell transplant, CAR T cells improved 4-year overall survival in patients with large B-cell lymphoma (54.6% vs 46.0%). Patients with pediatric acute lymphoblastic leukemia achieved durable remission after CAR T-cell therapy. At 3-year follow-up, 48% of patients were alive and relapse free. In people with multiple myeloma treated previously with 1 to 4 types of non–CAR T-cell therapy, CAR T-cell therapy prolonged treatment-free remissions compared with standard treatments (in 1 trial, CAR T-cell therapy was associated with progression-free survival of 13.3 months compared with 4.4 months with standard therapy). CAR T-cell therapy is associated with reversible acute toxicities, such as cytokine release syndrome in approximately 40% to 95% of patients, and neurologic disorders in approximately 15% to 65%. New CAR T-cell therapies in development aim to increase efficacy, decrease adverse effects, and treat other types of cancer. No CAR T-cell therapies are FDA approved for solid tumors, but recently, 2 other T lymphocyte–based treatments gained approvals: 1 for melanoma and 1 for synovial cell sarcoma. Additional cellular therapies have attained responses for certain solid tumors, including pediatric neuroblastoma, synovial cell sarcoma, melanoma, and human papillomavirus–associated cancers. A common adverse effect occurring with these T lymphocyte–based therapies is capillary leak syndrome, which is characterized by fluid retention, pulmonary edema, and kidney dysfunction.Conclusions and RelevanceCAR T-cell therapy is an FDA-approved therapy that has improved progression-free survival for multiple myeloma, improved overall survival for large B-cell lymphoma, and attained high rates of cancer remission for other hematologic malignancies such as acute lymphoblastic leukemia, follicular lymphoma, and mantle cell lymphoma. Recently approved T lymphocyte–based therapies demonstrated the potential for improved outcomes in solid tumor malignancies.

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Current understanding and management of CAR T cell-associated toxicities

Cited by 23 publications

References 171 publications

Anti-CD5 CAR-T cells with a tEGFR safety switch exhibit potent toxicity control

Anti-CD5 CAR-T cells with a tEGFR safety switch exhibit potent toxicity control

Scarless circular mRNA-based CAR-T cell therapy elicits superior anti-tumor efficacy

CAR T Cells and T-Cell Therapies for Cancer

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