Anti-BCMA/CD19 CAR T Cells with Early Immunomodulatory Maintenance for Multiple Myeloma Responding to Initial or Later-Line Therapy

Garfall, Alfred L.; Cohen, Adam D.; Susanibar-Adaniya, Sandra P.; Hwang, Wei–Ting; Vogl, Dan T.; Waxman, Adam; Lacey, Simon F.; Gonzalez, Vanessa; Fraietta, Joseph A.; Gupta, Minnal; Kulikovskaya, Irina; Tian, Lifeng; Chen, Fang; Koterba, Natalka; Patchin, Margaret; Xu, Rong; Plesa, Gabriela; Siegel, Donald L.; Brennan, Andrea; Nelson, Anne Marie; Ferthio, Regina; Cosey, Angela; Shea, Kim-Marie; Leskowitz, Rachel; Four, Megan; Wilson, Wesley V.; Miao, Fei; Lancaster, Eric; Carreño, Beatriz M.; Linette, Gerald P.; Hexner, Elizabeth O.; Young, Regina M.; Bu, De-xiu; Mansfield, Keith G.; Brogdon, Jennifer L.; June, Carl H.; Milone, Michael C.; Stadtmauer, Edward A.

doi:10.1158/2643-3230.bcd-22-0074

Cited by 29 publications

(20 citation statements)

References 42 publications

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“…In this clinical trial, 92% of patients had a clinical response and 60% of them achieved CR with a median follow-up of 21.3 months ( 27 ). In addition, a recent study has explored the efficacy and safety of the combination of anti-CD19 and anti-BCMA CAR-T cell therapy in 10 newly diagnosed MM patients with high-risk factors, and all patients achieved a clinical response ( 32 ). In preclinical studies, BCMA/GPRC5D and BCMA/CS1 bispecific CAR-T cells showed robust anti-tumor activities against MM cells, and they could overcome BCMA-negative antigen escape ( 36 , 37 ).…”

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

confidence: 99%

“…In addition, there are few recommendations for maintenance/consolidation therapy after CAR-T cell infusion, but it seems that maintenance treatment after CAR-T therapy may provide potential clinical benefits for high-risk MM patients. Recent studies have demonstrated that maintenance therapy with lenalidomide and pomalidomide is able to facilitate CAR-T cell re-expansion in high-risk MM patients ( 32 , 35 ). Moreover, in a phase I study, the efficacy and safety of selinexor in R/R MM patients with EMD after the fully humanized anti-BCMA CAR-T therapy is being tested (NCT05201118).…”

Section: Subsequent Anti-myeloma Therapy After Car-t Therapymentioning

confidence: 99%

“…Dual-targeted CAR-T cell therapy are also observed in preclinical and clinical studies, and they are available in a variety of forms, including combined infusion of 2 single-targeted CAR-T cells, and application of bispecific CAR-T cells which incorporate two distinct scFvs into two CARs separately or a single CAR structure simultaneously, the latter also known as tandem CAR-T cells. In several clinical trials, CD38 and CD19 were applied in combination with BCMA to develop dual-targeted CAR-T cells for the treatment of R/R MM (26,27,(30)(31)(32)(33) (Table 1). In a phase I clinical trial, 23 R/R MM patients received BCMA/CD38 bispecific CAR-T cells, and 87% of them achieved clinical a response and 52%…”

Section: Overcoming Antigen Escapementioning

confidence: 99%

“…of them achieved complete response (CR) with a median follow-up of 9.0 months (30). In another clinical trial, 16 patients with R/R MM were treated with BCMA/CD38 bispecific CAR-T cells, and 14 of them had clinical response and 13 of them achieved CR after a median follow-up of 11.5 months (31). In addition to BCMA/CD38 bispecific CAR-T cells, the combination of anti-CD38 and anti-BCMA CAR-T cell therapy was also performed.…”

Section: Overcoming Antigen Escapementioning

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: Subsequent Anti-myeloma Therapy After Car-t Therapymentioning

confidence: 99%

Section: Overcoming Antigen Escapementioning

confidence: 99%

Section: Overcoming Antigen Escapementioning

confidence: 99%

See 2 more Smart Citations

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

Zhang

Zhang²,

Lan³

et al. 2023

Front. Immunol.

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“…CAR T cells were manufactured as previously described. 27 Brie y, engineered CAR T cells were manufactured at the Cell and Vaccine Production Facility (CVPF) at the University of Pennsylvania (Philadelphia, PA), A Foundation for the Accreditation of Cellular Therapy (FACT)-accredited facility. The leukapheresis product collected at the University of Pennsylvania Apheresis Center was processed at CVPF to obtain the T cell starting population.…”

Section: Car T Manufacturingmentioning

confidence: 99%

Phase I study of repeated peripheral infusions of anti-EGFRvIII CAR T cells in combination with pembrolizumab in patients with newly diagnosed, MGMT-unmethylated glioblastoma

Bagley

Binder

Desai

et al. 2023

Preprint

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Treatment efficacy with chimeric antigen receptor (CAR) T cell therapy in glioblastoma (GBM) is undermined by an immunosuppressive tumor microenvironment (TME). We previously showed that CAR T cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces anti-tumor activity against recurrent GBM and causes upregulation of programmed death-ligand 1 (PD-L1) in the TME. Here, we conducted a phase I trial to study the impact of CART-EGFRvIII cells administered concomitantly with the PD-1 inhibitor pembrolizumab in patients (n = 7) with newly diagnosed, EGFRvIII + GBM. Treatment was well tolerated without incidence of dose-limiting toxicity. However, no signal of efficacy was detected with a median progression-free survival of 5.2 months (90% CI, 2.9–6.0 months) and median overall survival of 11.8 months (90% CI, 9.2–14.2 months). In addition, PD-1 expression in the CART-EGFRvIII infusion product did not correlate with outcomes, and peripheral CAR T cell engraftment was relatively short-lived. Together, these findings show the safety of combining CAR T cells and PD-1 inhibition in GBM but given the lack of efficacy, also indicate a need to consider alternative combinatorial strategies. ClinicalTrials.gov registration: NCT03726515.

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CAR T‐Cell Therapy for Multiple Myeloma: A Clinical Practice‐Oriented Review

Sadek,

Costa,

Nath

et al. 2023

Clin Pharma and Therapeutics

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The emergence of chimeric antigen receptor (CAR) T‐cell therapy has revolutionized the treatment of hematologic malignancies, including multiple myeloma (MM). Two B‐cell maturation antigen (BCMA)‐directed CAR T‐cell products — idecabtagene vicleucel (ide‐cel) and ciltacabtagene autoleucel (cilta‐cel) — have received Food and Drug Administration (FDA) approval for patients with relapsed/refractory MM who underwent four or more prior lines of therapy (including an immunomodulatory agent, a proteasome inhibitor, and an anti‐CD38 monoclonal antibody). Despite producing unprecedented response rates in an otherwise difficult to treat patient population, CAR T‐cell therapies are commonly associated with immune‐related adverse events (e.g., cytokine release syndrome and neurotoxicity), cytopenias and infections. Moreover, many patients continue to exhibit relapse post‐treatment, with resistance mechanisms yet to be fully understood. Ongoing basic, translational, and clinical research efforts are poised to generate deeper insights into the optimal utilization of these therapies, improve their efficacy, minimize associated toxicity, and identify new target antigens in MM patients.

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Anti-BCMA/CD19 CAR T Cells with Early Immunomodulatory Maintenance for Multiple Myeloma Responding to Initial or Later-Line Therapy

Cited by 29 publications

References 42 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

Phase I study of repeated peripheral infusions of anti-EGFRvIII CAR T cells in combination with pembrolizumab in patients with newly diagnosed, MGMT-unmethylated glioblastoma

CAR T‐Cell Therapy for Multiple Myeloma: A Clinical Practice‐Oriented Review

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