Preclinical Evaluation of Invariant Natural Killer T Cells Modified with CD38 or BCMA Chimeric Antigen Receptors for Multiple Myeloma

Poels, Renée; Drent, Esther; Lameris, Roeland; Katsarou, Afroditi; Themeli, Maria; Vliet, Hans J. van der; Gruijl, Tanja D. de; Donk, Niels W.C.J. van de; Mutis, Tuna

doi:10.3390/ijms22031096

Cited by 33 publications

(28 citation statements)

References 59 publications

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“…A limitation of belantamab mafodotin is the frequent development of keratopathy, which may substantially impair quality of life (146). Other cell types, with different killing mechanisms, such as NK cells, invariant NKT cells, γδ T cells, or myeloid cells, can also be engineered to express a CAR (149,150). However, at this moment, in the absence of clinical data, it is unknown whether adoptive therapy with alternative cell types will be able to overcome resistance conferred by the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Determinants of Response and Mechanisms of Resistance of CAR T-cell Therapy in Multiple Myeloma

Donk

Themeli

Usmani

2021

Blood Cancer Discovery

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B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cells have substantial therapeutic potential in multiple myeloma (MM), but most patients eventually relapse. Determinants of response and mechanisms of resistance are most likely multifactorial and include MM-related factors, premanufacturing T-cell characteristics, CAR T-cell-related features, and several components of the immunosuppressive microenvironment. Efforts to improve the potency and safety of CAR T-cell therapy include optimizing CAR design, combinatorial approaches to enhance persistence and activity, treatment of less heavily pretreated patients, and dual-antigen targeting to prevent antigen escape. We expect that these rationally designed strategies will contribute to further improvement in the clinical outcome of patients with MM.Significance: Although BCMA-specific CAR T-cell therapies are highly effective in heavily pretreated patients with MM, there has been, until now, no indication of a plateau in the survival curves. In this review, we provide an overview of the determinants of response and the mechanisms that contribute to the development of treatment failure after initial remission (acquired resistance). A better understanding of these mechanisms, underlying lack of disease response, and acquired resistance may lead to further improvements in the effectiveness of CAR T-cell therapy. iNtRODUctiONAlthough the introduction of new anti-multiple myeloma (MM) agents has markedly improved the survival of patients with MM, there is an unmet need for new drugs for patients who develop resistance to immunomodulatory drugs (IMiD), proteasome inhibitors (PI), and CD38-targeting antibodies (triple-class refractory disease), which carries a poor prognosis (1). Also, newly diagnosed patients with high-risk disease [e.g., presence of del(17p), t(4;14), or t(14;16)] or suboptimal response have an impaired outcome, and these patients may benefit from the incorporation of new drugs with novel mechanisms of action in first-line regimens.A promising new strategy is the reprogramming of T cells to target MM cells by introducing genes encoding chimeric antigen receptors (CAR). CARs are fusion proteins, combining an antigen-recognition moiety [commonly a monoclonal antibody-derived single-chain variable fragment (scFv), but other formats such as natural ligands are also possible; ref.2] with a T-cell activation domain, typically CD3ζ. These two parts are connected via an extracellular spacer region (hinge) and a transmembrane-spanning element. Second-generation CARs incorporating a costimulatory domain, such as CD28, 4-1BB, OX40, or ICOS, into the CAR endodomain result in enhanced antitumor activity of the modified T cells compared with first-generation CARs without such domain (Fig. 1; ref. 3). Importantly, CAR T cells eliminate tumor cells in a non-major histocompatibility complex (MHC)restricted manner.Most CAR T-cell products, currently evaluated in clinical trials for patients with MM, target B-cell maturation antigen (BCMA), which is...

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Section: Discussionmentioning

confidence: 99%

Determinants of Response and Mechanisms of Resistance of CAR T-cell Therapy in Multiple Myeloma

Donk

Themeli

Usmani

2021

Blood Cancer Discovery

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“… NKT cell source Activation Expansion Target CS Generation Cancer Phase Ref. or No.NCT Healthy donors Auto feeder cells pulsed with α-Galcer IL-2 GD2 CD28/4–1BB/CD28+4–1BB Second/third Neuroblastoma Preclinical [69] Healthy donors Irradiated auto NKT-negative cells pulsed with α-Galcer IL-2 CD19 4–1BB Second B cell lymphoma Preclinical [94] Healthy donors Anti-CD3 antibody IL-2 CSPG4 CD28 Second melanoma Preclinical [72] Healthy donors Irradiated auto NKT-negative cells pulsed with α-Galcer IL-2, IL-7 and/or IL-21 CD19 4–1BB Second B cell lymphoma Preclinical [96] Healthy donors Irradiated auto PBMC pulsed with CD3/28 at 1:1 beads-to-cell IL-2 and/or IL-15 CD19 CD28/CD28+OX40 Second/third B cell lymphoma Preclinical [74] Healthy donors Irradiated auto NKT-negative cells pulsed with α-Galcer IL-2, IL-7 and/or IL-21 GD2 CD28/4–1BB/CD28/4–1BB Second/fourth Neuroblastoma Preclinical [71] Healthy donors Irradiated auto NKT-negative cells pulsed with α-Galcer IL-2, IL-7 and IL-15 CD38/BCMA CD28/4–1BB Second Multiple myeloma Preclinical [70] Autologous iNKT GD2 CD28 …”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

“…It is worth noting that CAR-iNKT cells containing 4–1BB costimulatory domain did not increase the production of IL-6, which is one of the important cytokines associated with cytokine release syndrome. 4–1BB may provide an effective co-stimulation for optimal expansion and function of iNKT cells [70] . At the same time, experiments have proved that 4–1BB costimulation leads to activation induced cell death (AICD) of CAR-iNKT cells, and found that the activity of death receptor dependent caspase-8 is higher than that containing CD28.…”

Section: Introductionmentioning

confidence: 99%

“…BCMA.CAR transduced iNKT cells can effectively reorient the killing function of iNKT cells to MM cells. Anti BCMA.CAR immunotherapy combined with iNKT cells has shown good early clinical efficacy, which proved the effectiveness and feasibility of CAR-iNKT in tumor treatment [ 70 , 73 ]. Recent study found that CAR.19-iNKT cells show enhanced dual cytotoxicity against CD1d-expressing lymphoma through targeting both CD19 by CD19.CAR and CD1d by endogenous iTCR respectively.…”

Section: Introductionmentioning

confidence: 99%

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iNKT: A new avenue for CAR-based cancer immunotherapy

Liu

Wang

Chai

et al. 2022

Translational Oncology

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Highlights Invariant natural killer cells are rare but pleiotropic immunoregulatory and effector cells, which show powerful antitumor responses through direct killing, adjuvant effects, superior tumor infiltration and tumor-associated macrophages inhibition. iNKT cells are considered as an attractive platform for CAR-based cancer immunotherapy. Allogenic iNKT cells don't cause GvHD, which render CAR-iNKT a great potential to develop universal therapeutic product.

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“…[22][23][24][25][26] The immune regulatory potential and the rapid cytokine production of iNKT cells suggest that these cells may be harnessed for redirection with CAR. To this end, Poels et al 27 expressed CD38 or B cell maturation antigen-directed CARs in Va24-iNKT cells and demonstrated effective elimination of multiple myeloma (MM) cells. Additionally, Xu et al 28 demonstrated potent anti-tumor activity by GD2-directed CAR NKT cells against neuroblastoma cells.…”

Section: Natural Killer T Cellsmentioning

confidence: 99%