GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma (POLARIS): a first-in-human, single-centre, single-arm, phase 1 trial

Zhang, Mingming; Wei, Guoqing; Zhou, Linghui; Zhou, Jinqiu; Chen, Siye; Zhang, Wei; Wang, Dongrui; Luo, Xueping; Cui, Jiazhen; Huang, Simao; Fu, Shan; Zhou, Xinkai; Tang, Yu; Ding, Xiaomin; Kuang, Jiao; He, Xiaowen; Hu, Yongxian; Huang, He

doi:10.1016/s2352-3026(22)00372-6

Cited by 83 publications

(56 citation statements)

References 24 publications

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“…Most of the above targets are still in the preclinical stage ( 18 – 23 ), and only a few targets are explored in clinical trials, such as CD138, CD38, CD19, GPRC5D, SLAMF7, and integrin β7 ( 24 – 27 ) (NCT03778346). Among them, GPRC5D is the most potential target for CAR-T cell therapy in R/R MM patients at present ( 24 , 28 , 29 ). Recent, two phase 1 trials have reported the encouraging efficacy of anti-GPRC5D CAR-T cell therapy.…”

Section: Resistance To Anti-bcma Car-t Cell Therapy In Multiple Myelo...mentioning

confidence: 99%

“…In a phase 1 dose-escalation study, 17 R/R MM patients received anti-GPRC5D CAR-T cell infusion at four dose levels and 71% of them achieved a clinical responses ( 24 ). In another single-center, phase 1 trial, 10 R/R MM patients were treated with anti-GPRC5D CAR-T cells (OriCAR-017), and 100% of them showed clinical responses and 60% of them achieved a stringent complete response (sCR) ( 29 ). More importantly, these anti-GPRC5D CAR-T cells were also effective in R/R MM patients who were refractory to previous anti-BCMA CAR-T cell therapy ( 24 , 29 ).…”

Section: Resistance To Anti-bcma Car-t Cell Therapy In Multiple Myelo...mentioning

confidence: 99%

“…In another single-center, phase 1 trial, 10 R/R MM patients were treated with anti-GPRC5D CAR-T cells (OriCAR-017), and 100% of them showed clinical responses and 60% of them achieved a stringent complete response (sCR) ( 29 ). More importantly, these anti-GPRC5D CAR-T cells were also effective in R/R MM patients who were refractory to previous anti-BCMA CAR-T cell therapy ( 24 , 29 ). However, due to the relatively short median follow‐up time, the efficacy and safety of anti-GPRC5D CAR-T cell therapy in R/R MM remain to be evaluated in large-scale multicenter studies.…”

Section: Resistance To Anti-bcma Car-t Cell Therapy In Multiple Myelo...mentioning

confidence: 99%

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CAR-T cell therapy in multiple myeloma: Current limitations and potential strategies

Zhang

Zhang²,

Lan³

et al. 2023

Front. Immunol.

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Over the last decade, the survival outcome of patients with multiple myeloma (MM) has been substantially improved with the emergence of novel therapeutic agents, such as proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, selective inhibitors of nuclear export (SINEs), and T cell redirecting bispecific antibodies. However, MM remains an incurable neoplastic plasma cell disorder, and almost all MM patients inevitably relapse due to drug resistance. Encouragingly, B cell maturation antigen (BCMA)-targeted chimeric antigen receptor T (CAR-T) cell therapy has achieved impressive success in the treatment of relapsed/refractory (R/R) MM and brought new hopes for R/R MM patients in recent years. Due to antigen escape, the poor persistence of CAR-T cells, and the complicated tumor microenvironment, a significant population of MM patients still experience relapse after anti-BCMA CAR-T cell therapy. Additionally, the high manufacturing costs and time-consuming manufacturing processes caused by the personalized manufacturing procedures also limit the broad clinical application of CAR-T cell therapy. Therefore, in this review, we discuss current limitations of CAR-T cell therapy in MM, such as the resistance to CAR-T cell therapy and the limited accessibility of CAR-T cell therapy, and summarize some optimization strategies to overcome these challenges, including optimizing CAR structure, such as utilizing dual-targeted/multi-targeted CAR-T cells and armored CAR-T cells, optimizing manufacturing processes, combing CAR-T cell therapy with existing or emerging therapeutic approaches, and performing subsequent anti-myeloma therapy after CAR-T cell therapy as salvage therapy or maintenance/consolidation therapy.

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Section: Resistance To Anti-bcma Car-t Cell Therapy In Multiple Myelo...mentioning

confidence: 99%

Section: Resistance To Anti-bcma Car-t Cell Therapy In Multiple Myelo...mentioning

confidence: 99%

Section: Resistance To Anti-bcma Car-t Cell Therapy In Multiple Myelo...mentioning

confidence: 99%

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CAR-T cell therapy in multiple myeloma: Current limitations and potential strategies

Zhang

Zhang²,

Lan³

et al. 2023

Front. Immunol.

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“…48 Several phase I studies of GPRC5D-directed CAR T cells have shown high response rates (71%-100%). [44][45][46][47] Likewise, the GPRC5D/CD3 BsAbs talquetamab and RG6234 have demonstrated ORRs in the 60%-70% range. 31,32 Finally, Fc receptorlike 5 (FcRH5) has also proven to be a target of interest in MM.…”

Section: Efficacymentioning

confidence: 99%

Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapy in Multiple Myeloma: Moving Into the Future

Holstein

Grant

Wildes

2023

JCO

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Historically, the outcomes for individuals with triple-class refractory and penta-drug refractory multiple myeloma (MM) have been poor because of a dearth of effective treatment options. However, the advent of chimeric antigen receptor (CAR) T-cell and T-cell redirecting bispecific antibody (BsAb) therapies has led to unprecedented response rates and durations of response in heavily relapsed/refractory (R/R) populations. Currently, two B-cell maturation antigen (BCMA)–directed CAR T-cell therapies (idecabtagene vicleucel and ciltacabtagene autoleucel) as well as one BCMA/CD3 BsAb (teclistamab) have been approved for late-line (greater than four previous lines) R/R MM in the United States. The purpose of this review is to analyze the recent data for these approved therapies as well as provide an overview of other related CAR T-cell and BsAb therapies under development, including non–BCMA-targeting agents. We review efficacy and safety considerations, with particular focus on cytokine release syndrome, neurotoxicity, and infection risk. The relative merits and limitations of each class of therapy are discussed, as well as the areas of unmet need with respect to optimal sequencing and supportive care measures. We examine the factors that challenge equitable access to these novel therapies across minoritized racial, ethnic, and socioeconomic populations. Although it is evident that CAR T-cell and BsAb therapies will transform treatment paradigms in MM for years to come, significant work remains to identify the optimal utilization of these novel therapies and ensure equitable access.

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“…Several clinical trials address the safety and efficacy of GPRC5D CAR T cells in the treatment of RRMM (NCT05749133, NCT05759793, NCT05739188, NCT05219721, and NCT05016778). First results from the POLARIS trial, which is a first‐in‐human phase 1 trial of GPCR5D‐targeted CAR T cells, demonstrated that GPRC5D is a promising treatment modality for RRMM patients, since all of the 10 treated patients showed a response, with 60% showing a sCR and 40% a VGPR 25 . Furthermore, results from a phase 2 clinical trial in China showed that GPRC5D CAR T cells have an encouraging clinical efficacy with a manageable safety profile in RRMM 26 .…”

Section: Car T Cells Targeting Gprc5dmentioning

confidence: 99%

CAR T cell therapy in multiple myeloma, where are we now and where are we heading for?

Fischer,

Grieb,

Platzbecker

et al. 2023

European J of Haematology

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The introduction of chimeric antigen receptor (CAR) T cells revolutionized treatment of relapsed and refractory multiple myeloma (RRMM) in recent years. Currently, two CAR T cell products—idecabtagene vicleucel and ciltacabtagene autoleucel—are approved in the United States and the European Union to treat patients with three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti‐CD38 antibody. Moreover, seminal phase III trials of both agents in earlier lines of therapy have been published recently. Despite unprecedented rates of deep and lasting remissions in RRMM, there are still areas of uncertainty regarding the optimal use and distribution of CAR T cells in multiple myeloma. In the current review, we discuss the available data on approved CAR T cell products as well as unmet clinical needs and ongoing developments to optimize usage of this promising treatment modality in multiple myeloma.

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GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma (POLARIS): a first-in-human, single-centre, single-arm, phase 1 trial

Cited by 83 publications

References 24 publications

CAR-T cell therapy in multiple myeloma: Current limitations and potential strategies

CAR-T cell therapy in multiple myeloma: Current limitations and potential strategies

Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapy in Multiple Myeloma: Moving Into the Future

CAR T cell therapy in multiple myeloma, where are we now and where are we heading for?

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