Chimeric antigen receptor (CAR) T-cell treatment for mantle cell lymphoma (MCL)

Tbakhi, Bushra; Reagan, Patrick M.

doi:10.1177/20406207221080738

Cited by 10 publications

(5 citation statements)

References 83 publications

(131 reference statements)

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“…Mantle cell lymphoma (MCL) is a rare, yet aggressive type of B-cell lymphoma with a poor prognosis despite available therapeutic strategies. CAR-T cell therapies have demonstrated efficacy in high-risk MCL [136,137]. Brexucabtagene autoleucel (Tecartus ® ) is the only FDAapproved CAR T-cell therapy for adult patients with r/r mantle cell lymphoma [107,138,139].…”

Section: Mantle Cell Lymphomamentioning

confidence: 99%

Harnessing the potential of CAR-T cell therapy: progress, challenges, and future directions in hematological and solid tumor treatments

et al. 2023

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Traditional cancer treatments use nonspecific drugs and monoclonal antibodies to target tumor cells. Chimeric antigen receptor (CAR)-T cell therapy, however, leverages the immune system's T-cells to recognize and attack tumor cells. T-cells are isolated from patients and modified to target tumor-associated antigens. CAR-T therapy has achieved FDA approval for treating blood cancers like B-cell acute lymphoblastic leukemia, large B-cell lymphoma, and multiple myeloma by targeting CD-19 and B-cell maturation antigens. Bi-specific chimeric antigen receptors may contribute to mitigating tumor antigen escape, but their efficacy could be limited in cases where certain tumor cells do not express the targeted antigens. Despite success in blood cancers, CAR-T technology faces challenges in solid tumors, including lack of reliable tumor-associated antigens, hypoxic cores, immunosuppressive tumor environments, enhanced reactive oxygen species, and decreased T-cell infiltration. To overcome these challenges, current research aims to identify reliable tumor-associated antigens and develop cost-effective, tumor microenvironment-specific CAR-T cells. This review covers the evolution of CAR-T therapy against various tumors, including hematological and solid tumors, highlights challenges faced by CAR-T cell therapy, and suggests strategies to overcome these obstacles, such as utilizing single-cell RNA sequencing and artificial intelligence to optimize clinical-grade CAR-T cells.

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Section: Mantle Cell Lymphomamentioning

confidence: 99%

Harnessing the potential of CAR-T cell therapy: progress, challenges, and future directions in hematological and solid tumor treatments

et al. 2023

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“…Similarly, axi-cel, liso-cel, and KTE-X19 also achieved remarkable overall response rates with 83% (5), 73% (6), and 71% (7), respectively. These promising results contribute to the approval of tisagenlecleucel, axicel, liso-cel, and KTE-X19 for r/r B-ALL and/or LBCL (8) (9)(10)(11)(12). Despite these remarkable results of CD19-directed CAR-T therapy compared with traditional chemotherapy (13), it also resulted in serious and even fatal adverse events (AEs).…”

Section: Cd19-targeted Chimeric Antigen Receptor T-cell (Car-t) Thera...mentioning

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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“…The overall prognosis and long‐term survival for R/R patients after multiple lines of therapy are often poor [ 7 , 8 , 9 ]. CAR T‐cell therapy provides impressive response rates in heavily pretreated R/R follicular and other B‐cell NHLs, but toxicities, complicated logistics, limited access, and delays in delivering treatment may limit use of this therapy in many patients [ 10 , 11 , 12 ]. The development of more effective and tolerable therapies for R/R NHL represents a high unmet medical need.…”

Section: Introductionmentioning

confidence: 99%

A phase 1 first‐in‐human study of GS‐0189, an anti‐signal regulatory protein alpha (SIRPα) monoclonal antibody, in patients with relapsed/refractory (R/R) non‐Hodgkin lymphoma (NHL)

Narkhede

Bartlett

Ibrahimi

et al. 2023

eJHaem

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Signal regulatory protein alpha (SIRPα) is the receptor for cluster of differentiation (CD)47, a potent “don't eat me” signal for macrophages. Disruption of CD47‐SIRPα signaling in the presence of prophagocytic signals can lead to enhanced phagocytosis of tumor cells, resulting in a direct antitumor effect; agents targeting this pathway have shown efficacy in non‐Hodgkin lymphoma (NHL) and other tumor types. GS‐0189 is a novel anti‐SIRPα humanized monoclonal antibody. Here we report: (1) clinical safety, preliminary activity, and pharmacokinetics of GS‐0189 as monotherapy and in combination with rituximab from a phase 1 clinical trial in patients with relapsed/refractory NHL (NCT04502706, SRP001); (2) in vitro characterization of GS‐0189 binding to SIRPα; and (3) in vitro phagocytic activity. Clinically, GS‐0189 was well tolerated in patients with relapsed/refractory NHL with evidence of clinical activity in combination with rituximab. Receptor occupancy (RO) of GS‐0189 was highly variable in NHL patients; binding affinity studies showed significantly higher affinity for SIRPα variant 1 than variant 2, consistent with RO in patient and healthy donor samples. In vitro phagocytosis induced by GS‐0189 was also SIRPα variant–dependent. Although clinical development of GS‐0189 was discontinued, the CD47‐SIRPα signaling pathway remains a promising therapeutic target and should continue to be explored.

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Chimeric antigen receptor (CAR) T-cell treatment for mantle cell lymphoma (MCL)

Cited by 10 publications

References 83 publications

Harnessing the potential of CAR-T cell therapy: progress, challenges, and future directions in hematological and solid tumor treatments

Harnessing the potential of CAR-T cell therapy: progress, challenges, and future directions in hematological and solid tumor treatments

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

A phase 1 first‐in‐human study of GS‐0189, an anti‐signal regulatory protein alpha (SIRPα) monoclonal antibody, in patients with relapsed/refractory (R/R) non‐Hodgkin lymphoma (NHL)

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