Impact of Manufacturing Procedures on CAR T Cell Functionality

Watanabe, Norihiro; Mo, Feiyan; McKenna, Mary K.

doi:10.3389/fimmu.2022.876339

Cited by 88 publications

(74 citation statements)

References 100 publications

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“…Cai et al reported the rates of GIAEs were 13% and 10% following tisagenlecleucel and axicel infusion, respectively. significantly more reports of tisagenlecleucel and axi-cel compared to liso-cel and KTE-X19 mainly due to earlier approval time by FDA, which were 2017 and 2021 for tisagenlecleucel and axi-cel ( 8), and liso-cel and KTE-X19 (26), respectively. Overall, males accounted for a larger portion compared with females in all the reports of CAR-T-related GIAEs (57.38% vs. 37.94%).…”

Section: Discussionmentioning

confidence: 99%

Gastrointestinal infections are underestimated but fatal in chimeric antigen receptor T-cell therapy: a real-world study leveraging FDA adverse event reporting system from 2017 to 2021

Song

Liu

et al. 2022

Preprint

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Clinical trials are underpowered to detect infrequent toxicities following chimeric antigen receptor T-cell (CAR-T) therapy such as gastrointestinal adverse events (GIAEs). Here, we extensively revealed the GIAEs following four U.S. Food and Drug Administration (FDA)-approved CD19-targeted CAR-T products using FDA adverse event reporting system, tisagenlecleucel, axicabtagene-ciloleucel, lisocabtagene maraleucel, and brexucabtagene autoleucel. The disproportionality analyses were performed using reporting odds ratios (ROR) and information component (IC) and the lower bounds of the ROR and IC 95% confidence interval (CI) (ROR025 and IC025) exceeding one and zero were deemed significant, respectively. Among 105,087,611 reports in FAERS between January 2017 and December 2021, 1518 CAR-T-associated GIAEs reports were identified. 23 GIAEs (n = 281, 18.51%) were significantly overreported following CAR-T therapy compared with the full database, of which 11 GIAEs (n = 156, 10.28%) were associated with gastrointestinal infection such as clostridium difficile colitis (n = 44 [2.90%], ROR = 5.55 [95% CI: 4.12-7.46]), enterovirus infection (n = 23 [1.52%], ROR = 20.02 [13.15-30.48]), and mucormycosis (n = 15 [0.99%], ROR = 5.13 [3.09-8.54], all IC025 > 0). Overall, the fatality rate of 11 overreported infection-related GIAEs was 29.49%, which was higher following tisagenlecleucel compared with axicabtagene-ciloleucel (31.45% vs. 24.14%). In this largest post-marketing study to date, we firstly analyzed the CAR-T-associated GIAEs comprehensively and found that gastrointestinal infections were underestimated but led to substantial mortality in CAR-T recipients, which provided a deeper understanding of CAR-T therapy and early alert of those rare but life-threatening GIAEs for the clinician.

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Section: Discussionmentioning

confidence: 99%

Gastrointestinal infections are underestimated but fatal in chimeric antigen receptor T-cell therapy: a real-world study leveraging FDA adverse event reporting system from 2017 to 2021

Song

Liu

et al. 2022

Preprint

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“…Watanabe et al. summarized that co-culturing of T cells with some pharmacological inhibitors (e.g., the IKT inhibitor ibrutinib, BET inhibitor JQ-1) can specifically suppress T cell exhaustion ( 58 ). All of these studies suggested that T cells modifications and cytokines/pharmacal supplementation may significantly improve the efficacy of the final infusion product.…”

Section: Limitation and Recent Advances In Car T Cell Therapies For S...mentioning

confidence: 99%

Chimeric antigen receptor T cells applied to solid tumors

Zhou

Tao

et al. 2022

Front. Immunol.

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Chimeric antigen receptor T cell (CAR-T) therapy is novel tumor immunotherapy that enables autologous T to express synthetic receptors to specifically recognize the surface tumor-associated antigens for exerting subsequent antitumor effects, and eliminating the resistance, metastases and recurrence of cancer. Although CAR T cells have exhibited success in eradicating hematologic malignancies, their applications to solid tumors has not yet been achieved due to obstacles such as the immune-suppressor tumor microenvironment and lack of tumor specific target antigens. In this review, we presented advancements in the development of CAR T cell therapy in solid tumors, and offered a brief summary of the challenges, as well as novel engineering and pharmaceutical interventions to overcome these barriers. Looking forward, we discussed the latest studies which are expected to reach the clinicals in the next few years, including CRISPR screens-based CAR modification and CAR T cells driven from progenitor-like T cells. Collectively, this review may inspire researchers and clinicians to develop clinical available strategies of CAR T cell therapies in solid tumor.

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“…CAR T cells have been shown to have remarkable activity in several hematologic malignancies (91). There are four anti-CD19 CAR T products currently approved for use in B cell acute lymphoblastic leukemia (brexucabtagene autoleucel and tisagenelcleucel) and non-Hodgkin B cell lymphomas (axicabtagene ciloleucel and lisocabtagene maraleucel) (92). The first CAR T product for relapsed MM, idecabtagene vicleucel (idecel), was approved in 2021 for patients who have received 4 or more prior lines including an IMiD, a PI, and a CD38-directed MoAb.…”

Section: Car T Cellsmentioning

confidence: 99%

Harnessing the T Cell to Treat Multiple Myeloma: Dawn of a New Therapeutic Paradigm

Keller

Sherbenou²,

Forsberg³

et al. 2022

Front. Oncol.

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Multiple myeloma is an incurable hematologic malignancy. The typical disease course for myeloma patients is characterized by initial response to treatment followed by eventual development of resistance. Subsequent cycles of remission and relapse proceed as long as patients have new lines of therapy available to them. This reality has prompted development of many novel immunotherapeutics. Many of these drugs exploit the cytotoxic capabilities of the patients’ own T cells, effectively redirecting them to myeloma cells that are otherwise evading immune attack. Approaches including CAR T cell therapy and bispecific antibodies have displayed impressive efficacy in clinical trials for myeloma patients. This review examines the different approaches that utilize T cells in multiple myeloma therapy and investigates the benefits and risks of these exciting new strategies.

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Impact of Manufacturing Procedures on CAR T Cell Functionality

Cited by 88 publications

References 100 publications

Gastrointestinal infections are underestimated but fatal in chimeric antigen receptor T-cell therapy: a real-world study leveraging FDA adverse event reporting system from 2017 to 2021

Gastrointestinal infections are underestimated but fatal in chimeric antigen receptor T-cell therapy: a real-world study leveraging FDA adverse event reporting system from 2017 to 2021

Chimeric antigen receptor T cells applied to solid tumors

Harnessing the T Cell to Treat Multiple Myeloma: Dawn of a New Therapeutic Paradigm

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