A BAFF ligand-based CAR-T cell targeting three receptors and multiple B cell cancers

Wong, Derek P.; Roy, Nand Kishor; Zhang, Keman; Anukanth, Anusha; Asthana, Abhishek; Shirkey-Son, Nicole J.; Dunmire, Samantha K.; Jones, Bonnie; Lahr, Walker S.; Webber, Beau R.; Moriarity, Branden S.; Caimi, Paolo; Parameswaran, Reshmi

doi:10.1038/s41467-021-27853-w

Cited by 47 publications

(30 citation statements)

References 59 publications

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“…33 Further, efficacy may be increased with dual antigen targeting CARs that combine BCMA targeting with a second antigen that is involved in myelomgenesis but through a different pathway. Combinatorial targets include explorations of Open access 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: Open Accessmentioning

confidence: 99%

Both APRIL and antibody-fragment-based CAR T cells for myeloma induce BCMA downmodulation by trogocytosis and internalization

Camviel

Wolf

Croce

et al. 2022

J Immunother Cancer

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BackgroundChimeric 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).MethodsThree 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.ResultsAPRIL-CAR T cells in a trimeric ligand binding conformation conferred fast but not sustained antitumor responses in vivo in mouse xenograft models. In vitro trimer-BBζ CAR T cells were more polyfunctional and formed stronger immune synapses than monomer-BBζ CAR T cells. After CAR T cell–myeloma cell contact, BCMA was rapidly downmodulated on target cells with all evaluated binding moieties. CAR T cells acquired BCMA by trogocytosis, and BCMA on MM cells was rapidly internalized. Since BCMA can be re-expressed during progression and persisting CAR T cells may 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.ConclusionAntitumor responses with APRIL-CAR T cells were fast but not sustained. Rapid BCMA downmodulation occurred 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 when targeting BCMA and can inform the development of improved treatment strategies.

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Section: Open Accessmentioning

confidence: 99%

Both APRIL and antibody-fragment-based CAR T cells for myeloma induce BCMA downmodulation by trogocytosis and internalization

Camviel

Wolf

Croce

et al. 2022

J Immunother Cancer

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“…33 Further, efficacy may be increased with dual antigen targeting CARs that combine BCMA targeting with a second antigen that is involved in myeloma-genesis but through a different pathway. Combinatorial targets include explorations of GPRC5D, SLAMF7, CD38, CD19, TACI and BAFF-R. 40-47 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%

“…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 multi-targeted CAR-T cells have also been explored. It has been demonstrated that the tri-specific CD19-CD20-CD22-targeting CAR-T cells could rapidly eliminate B cell lymphoma in a preclinical study (181), and BAFF ligand-based CAR-T cells simultaneously target three receptors, including BAFF-R, BCMA, and TACI (182). In addition to simultaneously targeting different antigens, increasing immunogenicity of target cells might be a feasible strategy.…”

Section: Overcoming Antigen Escapementioning

confidence: 99%

CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges

et al. 2022

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Chimeric antigen receptor T (CAR-T) cell therapy represents a major breakthrough in cancer treatment, and it has achieved unprecedented success in hematological malignancies, especially in relapsed/refractory (R/R) B cell malignancies. At present, CD19 and BCMA are the most common targets in CAR-T cell therapy, and numerous novel therapeutic targets are being explored. However, the adverse events related to CAR-T cell therapy might be serious or even life-threatening, such as cytokine release syndrome (CRS), CAR-T-cell-related encephalopathy syndrome (CRES), infections, cytopenia, and CRS-related coagulopathy. In addition, due to antigen escape, the limited CAR-T cell persistence, and immunosuppressive tumor microenvironment, a considerable proportion of patients relapse after CAR-T cell therapy. Thus, in this review, we focus on the progress and challenges of CAR-T cell therapy in hematological malignancies, such as attractive therapeutic targets, CAR-T related toxicities, and resistance to CAR-T cell therapy, and provide some practical recommendations.

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A BAFF ligand-based CAR-T cell targeting three receptors and multiple B cell cancers

Cited by 47 publications

References 59 publications

Both APRIL and antibody-fragment-based CAR T cells for myeloma induce BCMA downmodulation by trogocytosis and internalization

Both APRIL and antibody-fragment-based CAR T cells for myeloma induce BCMA downmodulation by trogocytosis and internalization

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

CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges

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