ReviewCurrent state and next-generation CAR-T cells in multiple myeloma
Introduction
Multiple myeloma (MM) is the second most frequent hematological malignancy with an incidence of 6.5 per 100,000 persons per year. Despite considerable advances in treatment options, including new generations of proteasome inhibitors, immunomodulatory drugs, and immunotherapies with anti-CD38 antibodies, MM remains an incurable disease with a 5 years relative survival of 55.6% in 2011–2017 [1]. A substantial proportion of patients either do not respond to current therapies or acquire resistance to treatment highlighting an unmet need for improved therapeutic options for MM. Typically, patients with triple-class or penta-class refractory MM have an overall survival (OS) of 9.2 and 5.6 months, respectively [2]. The new treatment approaches have focused on immunotherapies to address this unmet need, including development of antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor (CAR) T cells. Their evaluation in phase 1 dose escalation studies have demonstrated high response rates in late-stage refractory MM.
CAR-T cells are T cells modified ex vivo to express a chimeric receptor with an antigen receptor containing a single chain variable fragment (scFv) and an intracellular T-cell receptor (TCR) signaling domain. The scFv is the recognition domain directed to target tumor cells. The intracellular domain of CAR contains various components with CD3-zeta (first generation), in addition to a costimulatory domain such as CD28 or 41bb (second generation) or both (third generation). A fourth-generation CAR-T cells is known as armored CAR-T cells and co-express key cytokines or suicide genes to enhance the efficacy and safety of CAR-T therapy. Notably, CAR-T target cell recognition does not require HLA presentation of antigens. To this end, the patient's own T cells are isolated and genetically modified to express the CAR, redirecting T cell specificity to the tumor-associated antigen. Adoptively transferred CAR-T cells are therefore equipped to induce and sustain remissions through a synergy of antibody-based target cell recognition and the memory and effector function of T cells. These results represent a substantial improvement compared to conventional therapies yielding complete and durable response rate.
B cell maturation antigen (BCMA) is currently the main target for CAR-T cells in MM as it is predominantly expressed on differentiated B cells including malignant plasma cells. BCMA, also known as TNF receptor superfamily 17 (TNFRSF17), delivers pro-survival signaling upon binding to its ligands - B cell activator of the TNF family (BAFF) and a proliferation inducing ligand (APRIL) - participating in the survival and proliferation of MM cells. BCMA is shed from the surface of MM cells by γ-secretase, releasing a soluble form BCMA (sBCMA), which serves as a biomarker of MM tumor burden. Additionally, soluble BCMA can limit therapeutic efficacy of membrane-bound BCMA-targeted therapies.
This review discusses the primary clinical data on anti-BCMA CAR-T cells in MM and known mechanisms of resistance and next generations CAR-T cells that are currently under research.
Section snippets
Clinical trials of CAR-T cells in myeloma
Since the development of CAR-T cells in MM, several clinical trials have been reported for this indication. So far, all CAR-T cells used in MM target BCMA. Most of them are autologous, but some allogenic products are emerging, they bear human or chimeric scFv and have various manufacturing processes. The main clinical trials data are reported here (Table 1).
Mechanisms of resistance to CAR-T cells
The main mechanism of resistance to CAR-T cells are either antigen dependent (antigen escape, antigen shedding or anti-CAR antibodies) or T cell driven (CAR-T cell exhaustion and a non-permissive microenvironment), (Fig. 1). Their precise knowledge will help guide medical decisions [13] and improve the next generation of CAR-T cells.
Next generation CARs
A major limiting factor of adoptive CAR-T therapy is poor in vivo persistence, lineage stability of infused CAR-T cells, properties that are known to be critical for generating robust and durable Treg-mediated functional responses. Additionally, current methods of CAR-T cell therapy are limited for broader use by the risk of severe adverse events, including CRS and neurotoxicity. Hence, the next-generation CAR-T cell-based therapies are focused on designing CAR-T with improving efficacy while
Conclusion
The rapid development of BCMA-targeting CAR-T cells in MM since their first administration in 2014 to the FDA and EMA approvals of ide-cel in 2021 holds great expectation for the future of myeloma treatments. BCMA-targeting CAR-T cells have demonstrated remarkable efficacy in the context of relapsed and refractory MM. Current studies are evaluating CAR-T cells in earlier lines of treatment, including frontline, with the hope of achieving long-lasting remission in MM. Many different approaches
Practice points
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Autologous BCMA-directed CAR-T cells used in multiple myeloma induce an overall response rate above 80% and median progression free-survivals from 12 to 22 months, in late stage refractory setting of the disease.
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New generation CAR-T cells with humanized scFv, alternative manufacturing or generated from allogenic T cells are effective.
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Loss of BCMA is observed in about 4% of the cases at relapse, with some bi-allelic deletions of BCMA on chromosome 16p13.13.
Research agenda
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Understanding the impact of the immune microenvironment in response and resistance to CAR-T cells.
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Determining the nature of resistant myeloma cells to CAR-T cells, despite high rates of MRD negativity.
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Improving CAR-T cells efficacy with newer approaches such as commuting CARs or knock-out of immune checkpoints.
Future considerations
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Future clinical trials will evaluate the efficacy of CAR-T cells in early line of treatments, including frontline and in combination with other treatment.
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Learning how to sequence anti-BCMA therapies will be important in clinical practice with future approvals of bispecific antibodies and antibody-drug conjugate.
References (78)
Efficacy and safety of Idecabtagene Vicleucel (ide-cel, bb2121) in elderly patients with relapsed and refractory multiple myeloma: KarMMa subgroup analysis
Blood
(2020)- et al.
Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study
Lancet Lond Engl
(2021) Results from Lummicar-2: a phase 1b/2 study of fully human B-cell maturation antigen-specific CAR T cells (CT053) in patients with relapsed and/or refractory multiple myeloma
Blood
(2020)Updated results from the phase I CRB-402 study of Anti-Bcma CAR-T cell therapy bb21217 in patients with relapsed and refractory multiple myeloma: correlation of expansion and duration of response with T cell phenotypes
Blood
(2020)Clinical results of a multicenter study of the first-in-human dual BCMA and CD19 targeted novel platform fast CAR-T cell therapy for patients with relapsed/refractory multiple myeloma
Blood
(2020)Universal updated phase 1 data validates the feasibility of allogeneic anti-BCMA ALLO-715 therapy for relapsed/refractory multiple myeloma
Blood
(2021)- et al.
Effective anti-BCMA retreatment in multiple myeloma
Blood Adv
(2021) - et al.
Target expression, generation, preclinical activity, and pharmacokinetics of the BCMA-T cell bispecific antibody EM801 for multiple myeloma treatment
Cancer Cell
(2017) Idecabtagene Vicleucel (ide-cel, bb2121) responses are characterized by early and temporally consistent activation and expansion of CAR T cells with a T effector phenotype
Blood
(2020)- et al.
Selinexor, Pomalidomide, and dexamethasone (SPd) in patients with relapsed or refractory multiple myeloma
Blood
(2019)
Results from CARTITUDE-1: a phase 1b/2 study of JNJ-4528, a CAR-T cell therapy directed against B-cell maturation antigen (BCMA), in patients with relapsed and/or refractory multiple myeloma (R/R MM)
Blood
T-cell phenotypes associated with effective CAR T-cell therapy in postinduction vs relapsed multiple myeloma
Blood Adv
Clinical overview of anti-CD19 BiTE(®) and ex vivo data from anti-CD33 BiTE(®) as examples for retargeting T cells in hematologic malignancies
Mol Immunol
Augmentation of antitumor immunity by human and mouse CAR T cells secreting IL-18
Cell Rep
CAR T and CAR NK cells in multiple myeloma: expanding the targets
Best Pract Res Clin Haematol
Precision tumor recognition by T cells with combinatorial antigen-sensing circuits
Cell
A phase 1 study with point-of-care manufacturing of dual targeted, tandem Anti-CD19, Anti-CD20 chimeric antigen receptor modified T (CAR-T) cells for relapsed, refractory
Non-Hodgkin Lymphoma Blood
Reversal of tumor immune inhibition using a chimeric cytokine receptor
Mol Ther
Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using Interleukin-4*
J Biol Chem
Chimeric antigen receptor–T cells with cytokine neutralizing capacity
Blood Adv
Positive conversion of negative signaling of CTLA4 potentiates antitumor efficacy of adoptive T-cell therapy in murine tumor models
Blood
Human Vdelta1 gamma-delta T cells exert potent specific cytotoxicity against primary multiple myeloma cells
Cytotherapy
γδT cells kill myeloma cells by sensing mevalonate metabolites and ICAM-1 molecules on cell surface
Biochem Biophys Res Commun
Chimeric antigen receptor-engineered human gamma delta T cells: enhanced cytotoxicity with retention of cross presentation
Mol Ther J Am Soc Gene Ther
Recent progress in and challenges in cellular therapy using NK cells for hematological malignancies
Blood Rev
SEER cancer statistics review, 1975–2018
Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy
Leukemia
Idecabtagene vicleucel in relapsed and refractory multiple myeloma
N Engl J Med
Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy
Nat Med
Orvacabtagene autoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T cell therapy for patients (pts) with relapsed/refractory multiple myeloma (RRMM): update of the phase 1/2 EVOLVE study (NCT03430011)
J Clin Oncol
Phase 1/2 study of the safety and response of P-BCMA-101 CAR-T cells in patients with relapsed/refractory (r/r)
BCMA is essential for the survival of long-lived bone marrow plasma cells
J Exp Med
Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma
Nat Med
Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma
Nat Commun
T-cell therapy bb2121 in relapsed or refractory multiple myeloma | NEJM
γ-Secretase directly sheds the survival receptor BCMA from plasma cells
Nat Commun
Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival
Br J Haematol
Serum B-cell maturation antigen: a novel biomarker to predict outcomes for multiple myeloma patients
Haematologica
Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma
Proc Natl Acad Sci U S A
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These authors contributed equally.