All-trans retinoic acid works synergistically with the γ-secretase inhibitor crenigacestat to augment BCMA on multiple myeloma and the efficacy of BCMA-CAR T cells

García-Guerrero, Estefanía; Rodríguez‐Lobato, Luis Gerardo; Sierro-Martínez, Belén; Danhof, Sophia; Bates, Stephan; Frenz, Silke; Härtle, Larissa; Götz, Roland; Sauer, Markus; Rasche, Leo; Kortüm, K. Martin; Pérez-Simón, Josè Antonio; Einsele, Hermann; Hudecek, Michael; Prommersberger, Sabrina

doi:10.3324/haematol.2022.281339

Cited by 16 publications

(9 citation statements)

References 53 publications

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“…Besides targeting distinct antigens, increasing target antigen density on MM cells also appears to be an appealing strategy. Several studies have proved that γ-secretase inhibitors and all-trans retinoic acid (ATRA) could upregulate BCMA expression on MM cells and facilitate their recognition by anti-BCMA CAR-T cells ( 40 , 41 ). In addition, ATRA could promote CD38 expression on MM cells ( 42 ).…”

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

confidence: 99%

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%

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

Zhang

Zhang²,

Lan³

et al. 2023

Front. Immunol.

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“…However, responders had signi cantly higher baseline levels of surface BCMA expression compared to non-responders. In line with this observation, a recent preclinical study found out that increasing BCMA surface density by augmenting its expression with all-trans retinoic acid and preventing its shedding through gamma secretase inhibition improves e cacy of anti-BCMA CAR T cells 40 . Longitudinal single cell sequencing of peripheral blood allowed a detailed characterization of tiding malignant plasma cell clones and T cells.…”

Section: Discussionmentioning

confidence: 73%

Single Cell Multi-Omic Dissection of Response and Resistance to Chimeric Antigen Receptor T Cells Against BCMA in Relapsed Multiple Myeloma

Merz,

Fischer,

Sia

et al. 2023

Blood

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Background: Chimeric antigen receptor (CAR) T cell therapy has revolutionized treatment of relapsed/refractory multiple myeloma (RRMM). Robust variables that predict long-term response are currently missing. Limited data are especially available on the impact of bridging therapies on manufacturing and outcome. We conducted a longitudinal single-cell multi-omics study to identify factors that predict response to BCMA-directed CAR T cells. Changes in the immune microenvironment associated with response were analyzed as well as the impact of prior bridging therapy with bispecific antibodies on subsequent CAR T cell manufacturing and outcome. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 29 consecutive MM patients treated with commercially available anti-BCMA CAR T cells on the day of leukapheresis as well as days 30 and 100 after CAR T cell infusion. PBMCs were subjected to single cell RNA, T-cell receptor (TCR) and B-cell receptor (BCR) sequencing. A custom panel of 57 oligonucleotide-coupled antibodies was used to study surface proteomics. Downstream analyses were performed with Seurat. Differences in cellular compositions at all three time points were analyzed with scCODA. To analyze CAR T cell functionality, CAR T cells from peripheral blood were isolated 7 days after infusion and subjected to an in vitro cytotoxicity assay after expansion and stimulation. Patients were grouped based on their best response following CAR T cell infusion (CR: n=12, non CR: n=17). Results: In total, 375,338 cells were sequenced (median 7246 cells/sample, range 1,569-10,972 cells) and 354,878 cells (94.5%) passed quality assessment. Quantitative and qualitative differences in the cellular composition of peripheral blood between CR and non CR patients were detected at the time of leukapheresis as well as on days 30 and 100 following infusion. CR patients harbored significantly more CD8+ effector memory T cells (TEM) at leukapheresis and less NK cells on day 30 after therapy compared to non CR patients. Regulatory T cells isolated at the time of leukapheresis from non CR patients exhibited significantly higher surface protein levels of CXCR3, CD40, CD95 and KLRG1 (p<0.015, respectively) that have been associated with T cell senescence and impaired tumor immunity. No significant differences in cell numbers between CR and non CR were detected on day 100 after CAR T cell infusion. However, single cell TCR analysis revealed an increasing diversity in the TCR repertoire over time in patients with CR, while Shannon diversity decreased from leukapheresis over day 30 to day 100 in non CR patients (p=0.004). The prior administration of the bispecific antibody teclistamab had no significant impact on the quantitative cellular composition at the time of leukapheresis. However, termination of manufacturing in the first attempt occurred in all patients with a close proximity of teclistimab administration and apheresis. Differential gene expression analysis showed that the application of teclistamab was associated with impaired T cell activation and exhaustion indicated by upregulation of e.g. CTLA4, TIGIT, LAG3 and GZMK. After discontinuation of teclistamab (median 4 weeks) and successful manufacturing of CAR T cells, we found no significant differences for in vitro cytotoxicity and in vivo expansion of CAR T cells. CAR T cells isolated at day 7 post-infusion from patients in CR, non CR or with prior teclistamab exposure, effectively eliminated MM cells (U-266). Tracking of single CAR T cells over time showed that the majority of CAR+ cells were CD8+ TEMs regardless of remission achievement or prior teclistamab exposure. Conclusion: We demonstrate that differences between MM patients achieving a CR and patients with suboptimal response upon anti-BCMA CAR T cell therapy can already be identified at the time of leukapheresis. Long-term changes associated with CR include a diversification of the TCR repertoire. Successful CAR T cell manufacturing is hampered by exposure to bispecific antibodies but can be successfully achieved by allowing for a wash-out phase of ca. 4 weeks.

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“…The heterogenous expression of B-cell maturation antigen (BCMA), which is the primary CAR target in multiple myeloma, and BCMA shutdown under CAR-T-cell pressure pose crucial issues in the CAR-T-cell therapy of multiple myeloma [22,23]. Using the epigenetic modulator all-trans retinoic acid (ATRA) (Figure 1), BCMA expression could be augmented in multiple myeloma cell lines and primary multiple myeloma cells [24]. Additionally, the pharmacological upregulation of BCMA in myeloma cells eventuated in enhanced reactivity of BCMA-CAR-T cells in vitro and in vivo [24].…”

Section: Upregulation Of Target Antigensmentioning

confidence: 99%

“…Using the epigenetic modulator all-trans retinoic acid (ATRA) (Figure 1), BCMA expression could be augmented in multiple myeloma cell lines and primary multiple myeloma cells [24]. Additionally, the pharmacological upregulation of BCMA in myeloma cells eventuated in enhanced reactivity of BCMA-CAR-T cells in vitro and in vivo [24]. A combined treatment of myeloma cells with ATRA and the γ-secretase inhibitor crenigacestat (Figure 1) could further increase BCMA expression, inducing even stronger antigen-specific targeting by BCMA-specific CAR-T cells [24].…”

Section: Upregulation Of Target Antigensmentioning

confidence: 99%

CARs and Drugs: Pharmacological Ways of Boosting CAR-T-Cell Therapy

Harrer

Dörrie

Schaft

2023

IJMS

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The development of chimeric antigen receptor T cells (CAR-T cells) has marked a new era in cancer immunotherapy. Based on a multitude of durable complete remissions in patients with hematological malignancies, FDA and EMA approval was issued to several CAR products targeting lymphoid leukemias and lymphomas. Nevertheless, about 50% of patients treated with these approved CAR products experience relapse or refractory disease necessitating salvage strategies. Moreover, in the vast majority of patients suffering from solid tumors, CAR-T-cell infusions could not induce durable complete remissions so far. Crucial obstacles to CAR-T-cell therapy resulting in a priori CAR-T-cell refractory disease or relapse after initially successful CAR-T-cell therapy encompass antigen shutdown and CAR-T-cell dysfunctionality. Antigen shutdown predominately rationalizes disease relapse in hematological malignancies, and CAR-T-cell dysfunctionality is characterized by insufficient CAR-T-cell proliferation and cytotoxicity frequently observed in patients with solid tumors. Thus, strategies to surmount those obstacles are being developed with high urgency. In this review, we want to highlight different approaches to combine CAR-T cells with drugs, such as small molecules and antibodies, to pharmacologically boost CAR-T-cell therapy. In particular, we discuss how certain drugs may help to counteract antigen shutdown and CAR-T-cell dysfunctionality in both hematological malignancies and solid tumors.

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All-trans retinoic acid works synergistically with the γ-secretase inhibitor crenigacestat to augment BCMA on multiple myeloma and the efficacy of BCMA-CAR T cells

Cited by 16 publications

References 53 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

Single Cell Multi-Omic Dissection of Response and Resistance to Chimeric Antigen Receptor T Cells Against BCMA in Relapsed Multiple Myeloma

CARs and Drugs: Pharmacological Ways of Boosting CAR-T-Cell Therapy

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