Preclinical Evaluation of Allogeneic CAR T Cells Targeting BCMA for the Treatment of Multiple Myeloma

Sommer, Cesar; Boldajipour, Bijan; Kuo, Tracy C.; Bentley, Trevor; Sutton, Janette; Chen, Amy; Geng, Tao; Dong, Holly; Galetto, Román; Valton, Julien; Pertel, Thomas; Juillerat, Alexandre; Gariboldi, Annabelle; Pascua, Edward; Brown, Colleen; Chin, Sherman M.; Sai, Tao; Ni, Yajin; Duchâteau, Philippe; Smith, Julianne; Rajpal, Arvind; Blarcom, Thomas Van; Chaparro‐Riggers, Javier; Sasu, Barbra J.

doi:10.1016/j.ymthe.2019.04.001

Cited by 112 publications

(96 citation statements)

References 61 publications

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“…This prolonged manufacturing time can lead to disease progression between leukapheresis and CAR T-cell infusion [37]. The development of allogeneic off-the-shelf CAR T cells with reduced risk of graft-versus-host disease could significantly change the workflow of CAR T-cell therapy if these treatments become available to patients without the requirements for standard CAR T-cell manufacturing [84][85][86][87][88]. Another potential drawback of CAR T-cell therapy is the use of preconditioning lymphodepletion regimens.…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

et al. 2020

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Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.

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Section: Discussion and Future Perspectivesmentioning

confidence: 99%

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

et al. 2020

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“…Advances in gene-editing techniques are leading to a new scenario in CAR T-cell therapy resulting in the development of universal CAR T-cells from allogeneic healthy donors. In this regard, preclinical results of allogenic second-generation BCMA CAR T-cells, called ALLO-715, were reported (150). In this study the authors, after CAR-transduction, transfected CAR T-cells with messenger RNA of TALEN.…”

Section: Increasing Car T-cell Persistencementioning

confidence: 98%

Overcoming Chimeric Antigen Receptor (CAR) Modified T-Cell Therapy Limitations in Multiple Myeloma

2020

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Multiple myeloma (MM) remains an incurable disease regardless of recent advances in the field. Therefore, a substantial unmet need exists to treat patients with relapsed/refractory myeloma. The use of novel agents such as daratumumab, elotuzumab, carfilzomib, or pomalidomide, among others, usually cannot completely eradicate myeloma cells. Although these new drugs have had a significant impact on the prognosis of MM patients, the vast majority ultimately become refractory or can no longer be treated due to toxicity of prior treatment, and thus succumb to the disease. Cellular therapies represent a novel approach with a unique mechanism of action against myeloma with the potential to defeat drug resistance and achieve long-term remissions. Genetic modification of cells to express a novel receptor with tumor antigen specificity is currently being explored in myeloma. Chimeric antigen receptor gene-modified T-cells (CAR T-cells) have shown to be the most promising approach so far. CAR T-cells have shown to induce durable complete remissions in other advanced hematologic malignancies like acute lymphocytic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). With this background, significant efforts are underway to develop CAR-based therapies for MM. Currently, several antigen targets, including CD138, CD19, immunoglobulin kappa (Ig-Kappa) and B-cell maturation antigen (BCMA), are being used in clinical trials to treat myeloma patients. Some of these trials have shown promising results, especially in terms of response rates. However, the absence of a plateau is observed in most studies which correlates with the absence of durable remissions. Therefore, several potential limitations such as lack of effectiveness, off-tumor toxicities, and antigen loss or interference with soluble proteins could hamper the efficacy of CAR T-cells in myeloma. In this review, we will focus on clinical outcomes reported with CAR T-cells in myeloma, as well as on CAR T-cell limitations and how to overcome them with next generation of CAR T-cells.

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“…TR depleted CAR-T cells generated through the transcription activator-like effector nuclease (TALEN) technique were further transduced with a CD20 mimotope (antigen-mimicking peptide) expressing gene. In this system, overactivated CAR-T cells could be targeted by rituximab that recognizes the CD20 mimotope and blocks activation signal, and thereby the cells are eliminated [60]. This is especially useful in reducing the death rate induced by cytokine releasing syndrome during CAR-T therapy.…”

Section: Tr Deletionmentioning

confidence: 99%

Recent Advances in Allogeneic CAR-T Cells

Kim

Cho

2020

Biomolecules

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In recent decades, great advances have been made in the field of tumor treatment. Especially, cell-based therapy targeting tumor associated antigen (TAA) has developed tremendously. T cells were engineered to have the ability to attack tumor cells by generating CAR constructs consisting of genes encoding scFv, a co-stimulatory domain (CD28 or TNFRSF9), and CD247 signaling domains for T cell proliferation and activation. Principally, CAR-T cells are activated by recognizing TAA by scFv on the T cell surface, and then signaling domains inside cells connected by scFv are subsequently activated to induce downstream signaling pathways involving T cell proliferation, activation, and production of cytokines. Many efforts have been made to increase the efficacy and persistence and also to decrease T cell exhaustion. Overall, allogeneic and universal CAR-T generation has attracted much attention because of their wide and prompt usage for patients. In this review, we summarized the current techniques for generation of allogeneic and universal CAR-T cells along with their disadvantages and limitations that still need to be overcome.

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Preclinical Evaluation of Allogeneic CAR T Cells Targeting BCMA for the Treatment of Multiple Myeloma

Cited by 112 publications

References 61 publications

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

Overcoming Chimeric Antigen Receptor (CAR) Modified T-Cell Therapy Limitations in Multiple Myeloma

Recent Advances in Allogeneic CAR-T Cells

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