CD38 knockout natural killer cells expressing an affinity optimized CD38 chimeric antigen receptor successfully target acute myeloid leukemia with reduced effector cell fratricide

Gurney, Mark E.; Stikvoort, Arwen; Nolan, Emma; Kirkham-McCarthy, Lucy; Khoruzhenko, Stanislav; Shivakumar, Rama; Zweegman, Sonja; Donk, Niels W.C.J. van de; Mutis, Tuna; Szegezdi, Éva; Sarkar, Subhashis; O’Dwyer, Michael

doi:10.3324/haematol.2020.271908

Cited by 68 publications

(53 citation statements)

References 31 publications

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“…Since CD38 is also expressed by some key immune cell population, the on-target off-tumor effects of CD38-targeted CAR-T cells including Tan CAR-T in the treatment of MM has become a problem that cannot be neglected. Researchers have made many attempts to address this issue, such as optimizing the design of the antigen recognition domain of CD38 CARs, 46 designing doxycycline (DOX) inducible Tet-on CD38-CARs, 47 knocking out 48 or block CD38 molecules. 49 In previous research, we found that shRNA-mediated knockdown of CD38 for CD38 CAR-T cells exhibited similar proliferative capacity with CD38 CAR-T cells, possibly due to the lack of expression of CD38 in CD38 CAR-T cells (unpublished observation) .…”

Section: Discussionmentioning

confidence: 99%

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

Feng

Liu

et al. 2021

OncoImmunology

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BCMA-targeting chimeric antigen receptor (CAR)-T cell therapy has shown remarkable clinical efficacy against multiple myeloma, yet antigen escape and tumor relapse still occur after the use of these therapies. Designing CAR-T therapies that targets multiple antigens simultaneously seems a feasible way to avoid antigen escape, and it has been extensively studied elsewhere. Here, we report novel BCMA-OR-CD38 Tan CAR T cells that can trigger robust cytotoxicity against target cells expressing either BCMA or CD38. We demonstrate that, in in vitro studies, these BCMA-OR-CD38 Tan CAR T cells exhibit similar CAR expression, superior cytotoxicity and antigen-stimulated T cell proliferation as compared to single-targeted CAR T cells or CD38-OR-BCMA Tan CAR T cells. Importantly, these BCMA-OR-CD38 Tan CAR-T cells can achieve complete tumor clearance in myeloma-bearing mice with no relapse observed through the course of these experiments. Finally, this BCMA-OR-CD38 Tan CAR was fully compatible with existing clinical grade T cell manufacturing procedures and can be implemented using current clinical protocols. Taken together, our results present an effective solution to the challenge of antigen escape in BCMA CAR T-cell therapies.

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Section: Discussionmentioning

confidence: 99%

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

Feng

Liu

et al. 2021

OncoImmunology

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“…CAR-T cells have been extensively investigated in preclinical and clinical models of AML. 9 However, there are limited preclinical animal studies 36,37 and only 3 active clinical trials (NCT04623944, NCT05008575, NCT02742727) testing CAR-NK cells as AML therapy. There is a single completed anti-AML CAR-NK cell trial with evaluable data (NCT02944162).…”

Section: Discussionmentioning

confidence: 99%

Engineering CAR-NK cells to secrete IL15 sustains their anti-AML functionality, but is associated with systemic toxicities

Christodoulou

Marple

et al. 2021

Preprint

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Background: The prognosis of patients with recurrent/refractory acute myelogenous leukemia (AML) remains poor and cell-based immunotherapies hold promise to improve outcomes. NK cells can elicit an anti-leukemic response via a repertoire of activating receptors that bind AML surface ligands. NK cell adoptive transfer is safe but thus far has shown limited anti-AML efficacy. Here, we aimed to overcome this limitation by engineering NK cells to express chimeric antigen receptors (CARs) to boost their anti-AML activity, and interleukin-15 (IL15) to enhance their persistence. Methods: We characterized in detail NK cell populations expressing a panel of AML (CD123)-specific CARs and/or IL15 in vitro and in AML xenograft models. Results: CARs with 2B4.ζ or 4-1BB.ζ signaling domains demonstrated greater cell surface expression and endowed NK cells with improved anti-AML activity in vitro. Initial in vivo testing revealed that only 2B4.ζ CAR-NK cells had improved anti-AML activity in comparison to untransduced (UTD) and 4-1BB.ζ CAR-NK cells. However, the benefit was transient due to limited CAR-NK cell persistence. Transgenic expression of secretory (s)IL15 in 2B4.ζ CAR and UTD NK cells improved their effector function in the setting of chronic antigen simulation in vitro. Multiparameter flow analysis after chronic antigen exposure identified the expansion of unique NK cell subsets. 2B4.ζ/sIL15 CAR and sIL15 NK cells maintained an overall activated NK cell phenotype. This was confirmed by transcriptomic analysis, which revealed a highly proliferative and activated signature in these NK cell groups. In vivo, 2B4.ζ/sIL15 CAR-NK cells had potent anti-AML activity in one model, while 2B4.ζ/sIL15 CAR and sIL15 NK cells induced lethal toxicity in a second model. Conclusion: Transgenic expression of CD123-CARs and sIL15 enabled NK cells to function in the setting of chronic antigen exposure but was associated with systemic toxicities. Thus, our study provides the impetus to explore inducible and controllable expression systems to provide cytokine signals to AML-specific CAR-NK cells before embarking on early phase clinical testing.

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“…Whether CD38‐directed cell therapy could achieve more stringent PC elimination compared to mAbs may be answered in the coming years. CD38 CAR T cells and CAR NK cells are in preclinical and clinical stages of development 113‐115 . However, toxicity due to recognition of CD38 on non‐PCs including non‐hematopoietic cells is a major concern 116,117 .…”

Section: Cd38‐directed Immunotherapymentioning

confidence: 99%

On the road to eliminating long‐lived plasma cells—“are we there yet?”

Markmann

Bhoj

2021

Immunological Reviews

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Central to protective humoral immunity is the activation of B cells and their terminal differentiation into antibody‐secreting plasma cells. Long‐lived plasma cells (LLPC) may survive for years to decades. Such long‐lived plasma cells are also responsible for producing pathogenic antibodies that cause a variety of challenges such as autoimmunity, allograft rejection, and drug neutralization. Up to now, various therapeutic strategies aimed at durably eliminating pathogenic antibodies have failed, in large part due to their inability to efficiently target LLPCs. Several antibody‐based therapies have recently gained regulatory approval or are in clinical phases of development for the treatment of multiple myeloma, a malignancy of plasma cells. We discuss the exciting potential of using these emerging cancer immunotherapies to solve the antibody problem.

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CD38 knockout natural killer cells expressing an affinity optimized CD38 chimeric antigen receptor successfully target acute myeloid leukemia with reduced effector cell fratricide

Cited by 68 publications

References 31 publications

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

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

Engineering CAR-NK cells to secrete IL15 sustains their anti-AML functionality, but is associated with systemic toxicities

On the road to eliminating long‐lived plasma cells—“are we there yet?”

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