Novel BCMA-OR-CD38 tandem-dual chimeric antigen receptor T cells robustly control multiple myeloma

Feng, Yaru; Liu, Xiuying; Li, Xiaorui; Zhou, Yating; Song, Zhiru; Zhang, Jing; Shi, Bingjie; Wang, Jianxun

doi:10.1080/2162402x.2021.1959102

Cited by 32 publications

(16 citation statements)

References 50 publications

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“…Combination of CD38 CAR T with CD38 transcriptional activators, such as ATRA, further improve therapeutic efficacy in mouse xenografts, emphasizing the importance of optimal induction of CD38 expression in cancer cells. Designing tandem dual CAR Ts, which targets multiple antigens simultaneously, can increase specificity of effector cells and potentially circumvent to antigen escape [ 132 ]. Clinical trials are ongoing to evaluate the single dose escalation safety and efficacy outcomes of CD38 CAR-T-cell therapy in relapsed or refractory MM patients (NCT03464916 and NCT03767751).…”

Section: Discussionmentioning

confidence: 99%

Molecular Determinants Underlying the Anti-Cancer Efficacy of CD38 Monoclonal Antibodies in Hematological Malignancies

Mustafa

Azaman

et al. 2022

Biomolecules

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CD38 was first discovered as a T-cell antigen and has since been found ubiquitously expressed in various hematopoietic cells, including plasma cells, NK cells, B cells, and granulocytes. More importantly, CD38 expression levels on malignant hematopoietic cells are significantly higher than counterpart healthy cells, thus presenting itself as a promising therapeutic target. In fact, for many aggressive hematological cancers, including CLL, DLBCL, T-ALL, and NKTL, CD38 expression is significantly associated with poorer prognosis and a hyperproliferative or metastatic phenotype. Studies have shown that, beyond being a biomarker, CD38 functionally mediates dysregulated survival, adhesion, and migration signaling pathways, as well as promotes an immunosuppressive microenvironment conducive for tumors to thrive. Thus, targeting CD38 is a rational approach to overcoming these malignancies. However, clinical trials have surprisingly shown that daratumumab monotherapy has not been very effective in these other blood malignancies. Furthermore, extensive use of daratumumab in MM is giving rise to a subset of patients now refractory to daratumumab treatment. Thus, it is important to consider factors modulating the determinants of response to CD38 targeting across different blood malignancies, encompassing both the transcriptional and post-transcriptional levels so that we can diversify the strategy to enhance daratumumab therapeutic efficacy, which can ultimately improve patient outcomes.

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Section: Discussionmentioning

confidence: 99%

Molecular Determinants Underlying the Anti-Cancer Efficacy of CD38 Monoclonal Antibodies in Hematological Malignancies

Mustafa

Azaman

et al. 2022

Biomolecules

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“…Combinatorial targets include explorations of GPRC5D, SLAMF7, CD38, CD19, TACI and BAFF-R. [40][41][42][43][44][45][46][47] Other future directions include combinatorial targeting with CAR T cells and microenvironment modulation or the exploration of enhanced manufacturing modalities that favor the long-term function and persistence of adoptively transferred T cells.…”

Section: Discussionmentioning

confidence: 99%

Rapid BCMA downmodulation on myeloma cells upon CAR T cell contact is mediated by trogocytosis and BCMA internalization

Camviel

Wolf

Croce

et al. 2022

Preprint

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Background: Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) on multiple myeloma (MM) produces fast but not long-lasting responses. Reasons for treatment failure are poorly understood. CARs simultaneously targeting two antigens may represent an alternative. Here, we (1) designed and characterized novel A proliferation inducing ligand (APRIL) based dual-antigen targeting CARs, and (2) investigated mechanisms of resistance to CAR T cells with three different BCMA-binding moieties (APRIL, single-chain-variable-fragment, heavy-chain-only). Methods: Three new APRIL-CARs were designed and characterized. Human APRIL-CAR T cells were evaluated for their cytotoxic function in vitro and in vivo, for their polyfunctionality, immune synapse formation, memory, exhaustion phenotype and tonic signaling activity. To investigate resistance mechanisms, we analyzed BCMA levels and cellular localization and quantified CAR T cell/ target cell interactions by live microscopy. Impact on pathway activation and tumor cell proliferation was assessed in vitro and in vivo. Results: APRIL-BBz CAR T cells in a trimeric ligand binding conformation conferred the best polyfunctionality, immune synapse formation and fast anti-tumor function in vivo in two different mouse xenograft models. Upon CAR T cell/ myeloma cell contact, we found rapid BCMA downmodulation on target cells with all three evaluated binding moieties. CAR T cells acquired BCMA on their cell surface by trogocytosis, and BCMA on MM cells was rapidly internalized. Since trogocytosis can lead to CAR T cell exhaustion and presence of CAR T cells does not protect patients from relapse, we investigated whether non-functional CAR T cells play a role in tumor progression. While CAR T cell/ MM cell interactions activated BCMA pathway, we did not find enhanced tumor growth in vitro or in vivo. Conclusion: We designed and characterized distinct APRIL-CAR T cells for dual-antigen targeting of MM. Rapid BCMA downmodulation occurred upon CAR T cell/ tumor cell encounter independently of whether an APRIL or antibody-based binding moiety was used. BCMA internalization mostly contributed to this effect, but trogocytosis by CAR T cells was also observed. Our study sheds light on the mechanisms underlying CAR T cell failure in MM and can inform the development of improved treatment strategies.

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“…The synergistic effect may be caused by binding two or more antigens simultaneously, which may enhance the signal transduction of immune synapses ( 10 ). When compared to traditional CARs with only one scFv, TanCAR-T cells have a higher anti-tumor effect and can limit tumor cell immune evasion ( 10 – 13 ).…”

Section: Optimize the Recognition Ability Of Carsmentioning

confidence: 99%

Special Chimeric Antigen Receptor (CAR) Modifications of T Cells: A Review

et al. 2022

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Chimeric antigen receptor (CAR) -T cell therapy has become one of the hot topics in tumor immunity research in recent years. Although CAR-T cell therapy is highly effective in treating hematological malignancies, there are numerous obstacles that prevent CAR-T cells from having anti-tumor effects. Traditional CARs, from the first to the fourth generation, are incapable of completely overcoming these challenges. Therefore, identifying ways to boost the efficacy of CAR-T cells by utilizing the limited tumor surface antigens has become an urgent area of research. Certain special CARs that have special structures, special systems, or are greatly improved on the basis of traditional CARs, such as tandem CAR, dual-signaling CARs, AND-gate CARs, inhibitory CAR, AND-NOT CARs, CARs with three scFvs, ON/OFF-switch CARs, and universal CARs have been introduced. This study aims to use these special CARs to improve the anti-tumor ability, accuracy, and safety of CAR-T cells. In addition to summarizing various special CARs of T cells, this paper also expounds some of our own conjectures, aiming to provide reference and inspiration for CARs researchers.

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Novel BCMA-OR-CD38 tandem-dual chimeric antigen receptor T cells robustly control multiple myeloma

Cited by 32 publications

References 50 publications

Molecular Determinants Underlying the Anti-Cancer Efficacy of CD38 Monoclonal Antibodies in Hematological Malignancies

Molecular Determinants Underlying the Anti-Cancer Efficacy of CD38 Monoclonal Antibodies in Hematological Malignancies

Rapid BCMA downmodulation on myeloma cells upon CAR T cell contact is mediated by trogocytosis and BCMA internalization

Special Chimeric Antigen Receptor (CAR) Modifications of T Cells: A Review

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