Paving the Way toward Successful Multiple Myeloma Treatment: Chimeric Antigen Receptor T-Cell Therapy

Grywalska, Ewelina; Sosnowska‐Pasiarska, Barbara; Smok-Kalwat, Jolanta; Pasiarski, Marcin; Niedźwiedzka-Rystwej, Paulina; Roliński, Jacek

doi:10.3390/cells9040983

Cited by 10 publications

(9 citation statements)

References 121 publications

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“…The therapeutic landscape for MM has been rapidly evolving due to introduction of targeted precision medicines, IMiDs, monoclonal antibodies, BiTEs, and CAR-T cells into multi-modality treatment strategies that have improved the survival outcomes [ 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 ].…”

Section: Discussionmentioning

confidence: 99%

Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

Uckun

2021

Cancers

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SeverFigurel cellular elements of the bone marrow (BM) microenvironment in multiple myeloma (MM) patients contribute to the immune evasion, proliferation, and drug resistance of MM cells, including myeloid-derived suppressor cells (MDSCs), tumor-associated M2-like, “alternatively activated” macrophages, CD38+ regulatory B-cells (Bregs), and regulatory T-cells (Tregs). These immunosuppressive elements in bidirectional and multi-directional crosstalk with each other inhibit both memory and cytotoxic effector T-cell populations as well as natural killer (NK) cells. Immunomodulatory imide drugs (IMiDs), protease inhibitors (PI), monoclonal antibodies (MoAb), adoptive T-cell/NK cell therapy, and inhibitors of anti-apoptotic signaling pathways have emerged as promising therapeutic platforms that can be employed in various combinations as part of a rationally designed immunomodulatory strategy against an immunosuppressive tumor microenvironment (TME) in MM. These platforms provide the foundation for a new therapeutic paradigm for achieving improved survival of high-risk newly diagnosed as well as relapsed/refractory MM patients. Here we review the scientific rationale and clinical proof of concept for each of these platforms.

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Section: Discussionmentioning

confidence: 99%

Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

Uckun

2021

Cancers

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“…The pooled incidence of grade 3–4 CRS was 6.6% and neurotoxicity was 2.2%. With prompt recognition and anti-IL-6 treatment, the therapy-related mortality of CAR T is extremely low in fact [ 4 ]. There were some concerns about the safety of CAR T therapy among elderly patients due to their poor tolerance.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive meta-analysis of anti-BCMA chimeric antigen receptor T-cell therapy in relapsed or refractory multiple myeloma

Zhang

Shen

et al. 2021

Annals of Medicine

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Background Chimeric antigen receptor (CAR) T-cell therapy shows impressive results in clinical trials. We conducted a meta-analysis based on the most recent data to systematically describe the efficacy and safety of anti-BCMA CAR T therapy for patients with relapsed or refractory multiple myeloma (R/R MM). Methods PubMed, Embase, Web of Science, Cochrane library, ClinicalTrials.gov, China Biology Medicine disc (CBM disc) and Wanfang Data were searched on 8 November 2020. Registration number of PROSPERO was CRD42020219127. Results From 763 articles, we identified 22 appropriate studies with 681 patients. The pooled overall response rate (ORR) was 85.2% (95%CI 0.797–0.910), complete response rate (CRR) was 47.0% (95%CI 0.378–0.583), and minimal residual disease (MRD) negativity rate was 97.8% (95%CI 0.935–1.022). The pooled incidence of grade 3–4 cytokine release syndrome was 6.6% (95%CI 0.036–0.096) and neurotoxicity was 2.2% (95%CI 0.006–0.038). The median progression-free survival (PFS) was 14.0 months and median overall survival (OS) was 24.0 months. Subgroup analysis showed dual epitope-binding CAR T cells achieved the best therapy outcomes and humanized CAR T cells had the best safety profile. Patients who were older, heavily pre-treated or received lower dose of CAR T cells had worse ORR. There was no significant difference in ORR, CRR and PFS between patients with and without high-risk cytogenetic features. The PFS and CRR of non-extramedullary disease (EMD) group was superior to those of EMD group. Conclusion Anti-BCMA CAR T therapy is effective and safe for patients with R/R MM. It can improve the prognosis of patients with high-risk cytogenetic features while the prognosis of patients with EMD remains poor. Moreover, patients are likely to benefit from an earlier use of CAR T therapy and human-derived CAR T cells have obvious advantages based on the existing data.

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“…The significant clinical outcomes of anti-CD19 CAR-T cells in MM justified the creation of CAR-T cells targeting other antigens expressed on myeloma cells, including CD38 ( 83 ), CD138 ( 84 ), SLAMF7 ( 85 ), SLAMF3 ( 86 ), CD56 ( 87 ), NKG2D ( 88 ), and most successfully BCMA ( 89 ). However, despite their early success, CAR-T cells are not exempt from limitations such as Graft-versus-Host disease (GvHD), cytokine release syndrome, neurotoxicity and off-tumor/on target toxicity ( 90 , 91 ) that threaten patient safety. CAR-NK cells were developed to overcome some of the limitations of CAR-T cells.…”

Section: Restoring Nk Cells For MM Therapymentioning

confidence: 99%

Targeting NK Cell Inhibitory Receptors for Precision Multiple Myeloma Immunotherapy

et al. 2020

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Innate immune surveillance of cancer involves multiple types of immune cells including the innate lymphoid cells (ILCs). Natural killer (NK) cells are considered the most active ILC subset for tumor elimination because of their ability to target infected and malignant cells without prior sensitization. NK cells are equipped with an array of activating and inhibitory receptors (IRs); hence NK cell activity is controlled by balanced signals between the activating and IRs. Multiple myeloma (MM) is a hematological malignancy that is known for its altered immune landscape. Despite improvements in therapeutic options for MM, this disease remains incurable. An emerging trend to improve clinical outcomes in MM involves harnessing the inherent ability of NK cells to kill malignant cells by recruiting NK cells and enhancing their cytotoxicity toward the malignant MM cells. Following the clinical success of blocking T cell IRs in multiple cancers, targeting NK cell IRs is drawing increasing attention. Relevant NK cell IRs that are attractive candidates for checkpoint blockades include KIRs, NKG2A, LAG-3, TIGIT, PD-1, and TIM-3 receptors. Investigating these NK cell IRs as pathogenic agents and therapeutic targets could lead to promising applications in MM therapy. This review describes the critical role of enhancing NK cell activity in MM and discusses the potential of blocking NK cell IRs as a future MM therapy.

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Paving the Way toward Successful Multiple Myeloma Treatment: Chimeric Antigen Receptor T-Cell Therapy

Cited by 10 publications

References 121 publications

Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

Comprehensive meta-analysis of anti-BCMA chimeric antigen receptor T-cell therapy in relapsed or refractory multiple myeloma

Targeting NK Cell Inhibitory Receptors for Precision Multiple Myeloma Immunotherapy

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