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    Cellular and T cell engager Immunotherapy

    Category: Cellular and T cell engager Immunotherapy

    BCMA-Directed CAR-NK and BiKE Therapies Enhance NK Cell Cytotoxicity in Primary Multiple Myeloma

    (PA-001) BCMA-Directed CAR-NK and BiKE Therapies Enhance NK Cell Cytotoxicity in Primary Multiple Myeloma

    Wednesday, September 17, 2025
    Introduction: Multiple myeloma (MM), characterized by the uncontrolled expansion of malignant plasma cells in the bone marrow (BM), requires more innovative therapies. Chimeric Antigen Receptor (CAR) T cells and Bispecific T cell Engagers (BiTEs) have demonstrated success in MM but pose risks such as cytokine release syndrome (CRS) and neurotoxicity. Natural killer (NK) cells offer advantages including possibility to be used from allogeneic sources and reduced risk of CRS. Their combination with CAR and Bispecific NK Engagers (BiKEs) might present promising therapeutic strategies. BiKEs are engineered to bind an activating receptor on NK cells, such as NKp30, and a tumor antigen on malignant cells. B-cell maturation antigen (BCMA), highly expressed on myeloma cells, is a validated target antigen for MM immunotherapy. Membrane-bound BCMA can be shed into a soluble form through gamma-secretase activity. Inhibiting this process with gamma-secretase inhibitors (GSIs) may improve therapeutic response. Given NK cells’ potential in MM immunotherapy and the lack of preclinical studies using primary MM samples, this study investigates the anti-tumor potential of nanobody-based BCMA-targeted CAR-NK cells and BiKEs against pMM.

    Methods: BM mononuclear cells (BMNCs) were isolated from BM aspirates by RBC lysis. MM cells were confirmed by flow cytometry using CD38, CD138, CD45, CD56, CD19, and BCMA. CAR-NK cells were generated by lentiviral transduction, expanded, and co-incubated with target cells at varying E:T ratios for 4 h at 37°C. For BiKE assays, expanded NK cells from healthy donors were co-cultured with target cells with or without BCMA/NKp30 BiKEs. BCMA-positive and -negative controls were included. Surface CD107a was measured as a marker of NK activation. MM samples were pretreated with 10 or 50 nM GSI for 16h to evaluate the impact of BCMA expression on NK cell cytotoxicity. Data were analyzed by flow cytometry.

    Results: MM samples (n=14) showed diverse immunophenotypes. Despite this, BCMA-CAR NK cells significantly enhanced cytotoxicity against myeloma cells (E:T=1:2, NK vs. CAR-NK: 28.1% ± 3.9 vs. 50.7% ± 6.1; P< .001), with minimal effects on normal BMNCs (P=.46). Surface BCMA expression positively correlated with CAR-NK sensitivity (r= 0.596, r²= 0.356, P=.040), though other factors also influenced outcomes. BCMA-CAR NK cells showed higher CD107a expression than control NK cells (MFI 3159 vs. 2467). A low BiKE dose (5 nM) increased CD107a and NK cytotoxicity (NK vs. NK + BiKE: 21.6% ± 9.1 vs. 39.1% ± 10.4). GSI pretreatment stabilized surface BCMA and increased BiKEs specific killing in samples with low-BCMA expression from 1.47% to 9.0% and 14.2% (P< .01), without intrinsic toxicity.

    Conclusions: BCMA-CAR and BiKE enhance NK cells’ ability to recognize and eliminate MM cells while sparing non-malignant BMNCs. GSIs can further improve the efficacy of both BCMA-targeted CARs and BiKEs. Treatment outcomes may depend on MM cell characteristics.