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

Article Oncology

Idecabtagene Vicleucel for Relapsed/Refractory Multiple Myeloma: Real-World Experience From the Myeloma CAR T Consortium

Doris K. Hansen et al.

Summary: A retrospective analysis showed that the safety and efficacy of standard-of-care ide-cel therapy in RRMM patients were similar to those seen in the phase II KarMMa trial, despite most patients not meeting the trial eligibility criteria.

JOURNAL OF CLINICAL ONCOLOGY (2023)

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Article Oncology

Th17.1 cell driven sarcoidosis-like inflammation after anti-BCMA CAR T cells in multiple myeloma

Alexander M. Leipold et al.

Summary: This article presents a case study on pulmonary flare-up after Ide-cel therapy and identifies a Th17.1 driven autoimmune mechanism as the cause. The study also reveals transcriptomic similarities between post CAR T pulmonary lesions and sarcoidosis. Furthermore, a noninvasive PET diagnostic approach using multiple tracers is explored, which helps discriminate between immune-mediated changes and true relapse after CAR T-cell treatment.

LEUKEMIA (2023)

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Article Biochemistry & Molecular Biology

Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results

Sham Mailankody et al.

Summary: In an interim phase 1 trial analysis, escalating doses of off-the-shelf allogeneic anti-BCMA CAR T cells, in combination with an anti-CD52 antibody-containing lymphodepletion regimen, were shown to be feasible and safe for the treatment of relapsed or refractory multiple myeloma.

NATURE MEDICINE (2023)

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Article Oncology

Ciltacabtagene Autoleucel, an Anti-B-cell Maturation Antigen Chimeric Antigen Receptor T-Cell Therapy, for Relapsed/Refractory Multiple Myeloma: CARTITUDE-1 2-Year Follow-Up

Thomas Martin et al.

Summary: PURPOSECARTITUDE-1, a phase Ib/II study, evaluated the safety and efficacy of Ciltacabtagene Autoleucel in heavily treated patients with relapsed/refractory multiple myeloma. The study showed early, deep, and durable responses at 12 months, with updated results at 2 years. Patients received a single infusion of Ciltacabtagene Autoleucel and responses were assessed.

JOURNAL OF CLINICAL ONCOLOGY (2023)

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Article Hematology

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

Mingming Zhang et al.

Lancet Haematology (2023)

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Article Oncology

Anti-G Protein-Coupled Receptor, Class C Group 5 Member D Chimeric Antigen Receptor T Cells in Patients With Relapsed or Refractory Multiple Myeloma: A Single-Arm, Phase II Trial

Jieyun Xia et al.

Summary: This study evaluated the efficacy and safety of anti-GPRC5D chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory multiple myeloma (MM). The results showed that anti-GPRC5D CAR T-cell therapy had good clinical efficacy and manageable safety in patients, especially for those who were previously unresponsive to anti-BCMA CAR T-cell therapy.

JOURNAL OF CLINICAL ONCOLOGY (2023)

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Article Medicine, General & Internal

Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma

Jesus San-Miguel et al.

Summary: In patients with lenalidomide-refractory multiple myeloma, Ciltacabtagene autoleucel (CAR-T cell therapy) showed a lower risk of disease progression or death compared to standard care, highlighting its effectiveness in this patient population.

NEW ENGLAND JOURNAL OF MEDICINE (2023)

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Article Medicine, General & Internal

Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma

Paula Rodriguez-Otero et al.

Summary: In this international phase 3 trial, idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, was found to significantly prolong progression-free survival and improve response compared to standard regimens in patients with relapsed and refractory multiple myeloma. The toxicity of ide-cel was consistent with previous reports.

NEW ENGLAND JOURNAL OF MEDICINE (2023)

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Article Hematology

Interventions and outcomes of patients with multiple myeloma receiving salvage therapy after BCMA-directed CAR T therapy

Oliver Van Oekelen et al.

Summary: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR T) therapy has shown remarkable efficacy in relapsed/refractory multiple myeloma patients. However, most patients eventually relapse despite high initial response rates. This study analyzed the salvage treatments and outcomes of patients with disease recurrence after BCMA-directed CAR T therapy.

BLOOD (2023)

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Article Cell & Tissue Engineering

Challenges in αCD38-chimeric antigen receptor (CAR)-expressing natural killer (NK) cell-based immunotherapy in multiple myeloma: Harnessing the CD38dim phenotype of cytokine-stimulated NK cells as a strategy to prevent fratricide

Maria Karvouni et al.

Summary: In this study, CAR-NK cells targeting CD38 in multiple myeloma (MM) were generated by utilizing the CD38dim phenotype occurring during long-term cytokine stimulation of primary NK cells. These CAR-NK cells demonstrated potent cytotoxicity against CD38+ cell lines and primary MM cells, suggesting their potential as a therapeutic strategy for MM.

CYTOTHERAPY (2023)

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Article Oncology

Neurological Adverse Effects of Immune Checkpoint Inhibitors and Chimeric Antigen Receptor T-Cell Therapy

Farhan Khalid et al.

Summary: Immune checkpoint inhibitors (ICPIs) and chimeric antigen receptor (CAR) T-cell therapies are novel treatments for various cancers. These therapies can cause immune-related complications, including neurological ones. This literature review focuses on the uncommon neurological complications and emphasizes the importance of early recognition and treatment to optimize the outcomes of ICPI and CAR T-cell therapies.

WORLD JOURNAL OF ONCOLOGY (2023)

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Review Oncology

CAR-NK cells for cancer immunotherapy: from bench to bedside

Leisheng Zhang et al.

Summary: This article mainly focuses on the latest updates, opportunities, and challenges of CAR-NK cell-based tactics in cancer immunotherapy. CAR-NK cells have the potential to improve efficacy and control adverse effects, while also meeting the demand for large-scale manufacture.

BIOMARKER RESEARCH (2022)

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Article Medicine, General & Internal

GPRC5D-Targeted CAR T Cells for Myeloma

Sham Mailankody et al.

Summary: The study demonstrates that GPRC5D is an active immunotherapeutic target in multiple myeloma, and GPRC5D-targeted CAR T-cell therapy shows promising efficacy in heavily pretreated patients, including those who relapsed after BCMA CAR T-cell therapy.

NEW ENGLAND JOURNAL OF MEDICINE (2022)

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Article Hematology

Access to and affordability of CAR T-cell therapy in multiple myeloma: an EBMT position paper

Nico Gagelmann et al.

Lancet Haematology (2022)

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Article Medicine, General & Internal

Geographic and Racial Disparities in Access to Chimeric Antigen Receptor-T Cells and Bispecific Antibodies Trials for Multiple Myeloma

Raghad Alqazaqi et al.

Summary: This study examines the geographic distribution of CAR-T therapy and bispecific antibodies for multiple myeloma and its impact on access for Black patients. The findings suggest that there may be disparities in accessing advanced clinical trials for new multiple myeloma therapies, particularly for Black populations.

JAMA NETWORK OPEN (2022)

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Meeting Abstract Hematology

Anti-BCMA-CAR NK Cells Expressing Soluble TRAIL: Promising Therapeutic Approach for Multiple Myeloma in Combination with Bortezomib and.-Secretase Inhibitors

Benjamin Motais et al.

BLOOD (2022)

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Meeting Abstract Hematology

Interim Phase I Clinical Data of FT576 As Monotherapy and in Combination with Daratumumab in Subjects with Relapsed/Refractory Multiple Myeloma

Binod Dhakal et al.

BLOOD (2022)

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Letter Biophysics

Impact of age on outcome of CAR-T cell therapies for large B-cell lymphoma: the GLA/DRST experience

Peter Dreger et al.

BONE MARROW TRANSPLANTATION (2022)

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Article Medicine, Research & Experimental

CAR T cell manufacturing from naive/stem memory T lymphocytes enhances antitumor responses while curtailing cytokine release syndrome

Silvia Arcangeli et al.

Summary: This study investigated the efficacy and safety profiles of CAR T cell products generated from preselected naive/stem memory T cells (TN/SCM). The results showed that CAR TN/SCM cells exhibited stronger antitumor activity and were able to prevent leukemia relapse. Furthermore, CAR TN/SCM cells had a lower risk of inducing severe cytokine release syndrome, indicating a higher therapeutic index.

JOURNAL OF CLINICAL INVESTIGATION (2022)

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Article Hematology

A phase 1 study of a novel fully human BCMA-targeting CAR (CT103A) in patients with relapsed/refractory multiple myeloma

Di Wang et al.

Summary: CT103A, a fully human BCMA-specific CAR T-cell therapy, has shown safety and high efficacy in patients with relapsed/refractory multiple myeloma, including those who had prior exposures to murine BCMA CAR therapy. Its overall response rate reaches 100%, with a significant portion achieving complete response or stringent complete response. Hematologic toxicities are common adverse events, but no immune effector cell-associated neurotoxicity syndrome was observed. Detection of CAR transgenes and median CAR transgene persistence support the potential of CT103A as a promising therapy for RRMM.

BLOOD (2021)

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Meeting Abstract Hematology

Bortezomib, Lenalidomide and Dexamethasone (VRd) Followed By Ciltacabtagene Autoleucel Versus Vrd Followed By Lenalidomide and Dexamethasone (Rd) Maintenance in Patients with Newly Diagnosed Multiple Myeloma Not Intended for Transplant: A Randomized, Phase 3 Study (CARTITUDE-5)

Dominik Dytfeld et al.

BLOOD (2021)

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Article Biotechnology & Applied Microbiology

Switching CAR-T cells on and off

Sarah Crunkhorn

NATURE REVIEWS DRUG DISCOVERY (2021)

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Article Biochemistry & Molecular Biology

Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy

Oliver Van Oekelen et al.

Summary: The study presents a case of a multiple myeloma patient who developed parkinsonism symptoms after receiving BCMA-targeted CAR-T cell therapy, highlighting the importance of close neurological monitoring for patients on such therapies.

NATURE MEDICINE (2021)

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Article Biochemistry & Molecular Biology

Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma

Matteo C. Da Via et al.

Summary: BCMA serves as a target for immunotherapies and a biomarker for tumor load in MM. The study found a correlation between TNFRSF17 loss and BCMA loss, leading to immune escape. Heterozygous TNFRSF17 deletion at baseline in high hyperhaploid MM patients may increase the risk of BCMA loss after immunotherapy.

NATURE MEDICINE (2021)

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Article Medicine, General & Internal

Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma

Nikhil C. Munshi et al.

Summary: The phase 2 study confirmed the efficacy and safety of ide-cel in patients with relapsed and refractory myeloma, with a majority of patients achieving responses and 26% achieving MRD-negative status. Despite the high response rate, almost all patients experienced grade 3 or 4 toxic effects, including hematologic toxic effects and cytokine release syndrome.

NEW ENGLAND JOURNAL OF MEDICINE (2021)

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Review Immunology

Taking T-Cell Oncotheraphy Off-the-Shelf

Feiyan Mo et al.

Summary: Banked allogeneic or 'off-the-shelf' (OTS) T cells from healthy human donors are being developed to address the limitations of autologous cell therapies. Potential challenges of OTS T cell therapies are associated with their allogeneic origin and the possibility of graft-versus-host disease (GvHD) and host-versus-graft immune reactions. While approaches to prevent immune rejection of OTS cells are at an earlier stage of development, the risk of GvHD from OTS T cells has been proved to be manageable in clinical studies.

TRENDS IN IMMUNOLOGY (2021)

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Article Multidisciplinary Sciences

Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma

Mehmet Kemal Samur et al.

Summary: Relapse following BCMA targeted CAR T-cell therapy in multiple myeloma patients is often due to biallelic loss of BCMA, which hinders the proliferation of CAR T cells and results in lack of response to retreatment. Single cell genomic characterization is essential for detecting BCMA gene alterations to improve treatment outcomes.

NATURE COMMUNICATIONS (2021)

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Article Hematology

Requirements for operational cure in multiple myeloma

Mohamad Mohty et al.

Summary: With recent therapeutic advancements, operational cure for multiple myeloma is becoming a realistic goal. The correlation between MRD negativity and improved patient outcomes suggests MRD as a surrogate for potential long-term cure. Various parameters influence the value and impact of MRD, with different treatment approaches leading to potential operational cure in both younger and older patients.

BLOOD (2021)

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Article Medicine, General & Internal

Ciltacabtagene autoleucel, a B-cell maturation antigendirected chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study

Jesus G. Berdeja et al.

Summary: The study aimed to evaluate the safety and clinical activity of cilta-cel in patients with relapsed or refractory multiple myeloma, and the results showed that cilta-cel treatment achieved good efficacy and safety with short treatment duration, deep response, and long duration of response.

LANCET (2021)

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Article Oncology

NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma

Alejandra Leivas et al.

Summary: CAR-T-cell therapy has shown promising results against multiple myeloma, but with serious toxicities, while CAR-NK cells may have less toxicity against resistant myeloma cells. By using receptors like NKG2D, CAR-NK cells can exhibit broad target specificity. The study demonstrates the effective modification of autologous NKAE cells from MM patients to safely express a NKG2D-CAR, showing enhanced antimyeloma activity and supporting the development of NKG2D-CAR-NK-cell therapy for MM.

BLOOD CANCER JOURNAL (2021)

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Article Hematology

Effective anti-BCMA retreatment in multiple myeloma

Nicolas Gazeau et al.

Summary: The recent emergence of anti-B-cell maturation antigen (BCMA) therapies, including CAR T cells, bispecific antibodies, and antibody-drug conjugates, holds great promise in changing the strategy for treating multiple myeloma. Understanding the different mechanisms of resistance to these therapies, such as antigen escape and T-cell exhaustion, will be crucial in guiding sequential treatments with anti-BCMA therapies.

BLOOD ADVANCES (2021)

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Review Oncology