Abstract: Natural killer (NK) cells are key mediators of antibody dependent cellular cytotoxicity (ADCC) via the CD16 Fc receptor. NK cellular therapies can effectively be targeted to tumor antigens when combined with tumor specific antibodies. Celularity Inc. is developing human placental CD34+-derived, cryopreserved, off-the-shelf, allogenic NK cells (CYNK-101) with high IgG binding affinity proteinase cleavage resistant CD16 variant (CD16VP) for cancer treatment. We hypothesize that expressing CD16VP augments anti-tumor ADCC activity. Here, we report the results of evaluating CYNK-101 in combination with Cetuximab, an anti-EGFR antibody, against EGFR+ non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinomas (HNSCC). Methods Human placental CD34+ cells were transduced with lentivirus expressing CD16VP and expanded in the presence of cytokines to generate CYNK-101 cells. The anti-tumor activity of CYNK-101 in combination with Cetuximab was assessed against EGFR+ NSCLC and HNSCC cell lines. The PI3K kinase inhibitor Wortmannin was used to investigate the molecular mechanisms underlying cytotoxicity of CYNK-101. Results In vitro ADCC activity of CYNK-101 against NSCLC and HNSCC targets was assessed in combination with Cetuximab. At 4h at the effector to target (E:T) ratio of 2.5:1, CYNK-101 displayed increased cytotoxicity against NSCLC lines SK-MES-1 and NCI-H226 at 78.7 ± 11.4% and 58.3 ± 10.0% with Cetuximab vs. 44.9 ± 9.2% and 41.7 ± 5.0% with IgG control, respectively (n=5 donors, p 〈 0.01). For HNSCC targets the cytolysis with Cetuximab compared to IgG control was 57.0 ± 14.1% vs. 23.3 ± 6.2% for CAL-27, 69.6 ± 13.7% vs. 34.0 ± 12.5% for FaDu, 41.6 ± 22.6% vs. 22.9 ± 14.9% for A-253, and 25.8 ± 29.1% vs. 4.2 ± 8.0% for SCC-25 (n=6 donors, p 〈 0.005 for first 3 targets). CYNK-101 (n=6 donors) in the presence of Cetuximab secreted higher levels of GM-CSF (p 〈 0.01), IFN-γ (p 〈 0.05), and TNF-α (p 〈 0.05) when co-cultured with the HNSCC lines A-253, FaDu, and SCC-25; and higher GM-CSF and IFN-γ levels (p 〈 0.01) when co-cultured with NCI-H226 compared to that of IgG control. The enhanced cytotoxicity of CYNK-101 was PI3K pathway-dependent as at an E:T ratio of 2.5:1 Wortmannin significantly decreased the cytotoxicity for NCI-H226 from 49.2 ± 18.1% to 27.7 ± 18.1% (p 〈 0.005) and for CAL-27 from 41.6 ± 20.7% to 19.4 ± 13.0% (p 〈 0.05) (n=4 donors). Conclusions Our results demonstrate that CYNK-101 have enhanced Cetuximab-mediated ADCC activity against EGFR+ NSCLC and HNSCC tumor cell lines. Further development of the combinational therapy for these solid tumor indications is warranted.

Abstract: Introduction: Overexpression of human epidermal growth factor receptor 2 (HER2) has been reported in ~20% of gastric cancer cases and correlated with poor outcome. Celularity is developing CYNK-101, an allogeneic, off-the-shelf human placental CD34+-derived NK cell product with genetically modified CD16 variant (CD16VP) for cancer treatment. CYNK-101 is designed to enhance the anti-tumor antibody dependent cellular cytotoxicity (ADCC) activity by expressing high-affinity and cleavage resistant CD16VP. Here we report the preclinical efficacy data of CYNK-101 plus Trastuzumab, an anti-HER2 monoclonal antibody, against HER2+ gastric cancer cells. Methods: Human placental CD34+ cells were transduced with lentivirus expressing CD16VP and cultured with cytokines to generate CYNK-101. ADCC activity of CYNK-101 plus Trastuzumab against HER2+ gastric cancer cells was measured by real-time xCELLigence, and cytokine secretion was quantified by Luminex. Ex vivo-CYNK-101 was isolated from NOD-scid IL2Rγnull immunodeficient (NSG) mice 13 days post CYNK-101 infusion. A subcutaneous NCI-N87 xenograft NSG-hIL15 transgenic mouse model was used for in vivo study. Results and conclusion: CYNK-101 was generated from multiple placental CD34+ donors (n=7) with & gt;90% CD56+CD3-and 74.1 ± 5.6% CD16 expression. While 4h PMAi treatment resulted in & gt;89% CD16 cleavage on non-transduced NK cells, & lt;11% cleavage from CYNK-101 demonstrated CD16 shedding resistance. At an effector to target (E:T) ratio of 1:1, CYNK-101 (n=7) showed enhanced lysis of NCI-N87 cells in the presence of Trastuzumab compared to IgG control, 59.6 ± 13.7% vs. 9.8 ± 3.2% at 4h, 97.1 ± 7.1% vs. 26.2 ± 16.1% at 24h, respectively (p & lt;0.001), and secreted increased GM-CSF, IFN-γ, and TNF-α at 24h. Ex vivo-CYNK-101 plus Trastuzumab exhibited enhanced cytotoxicity against NCI-N87 compared to IgG control (30.9% vs. 6.6% at 4h, 90.7% vs. 9.1% at 24h) at the E:T of 0.5:1, as well as increased production of GM-CSF, IFN-γ, and TNF-α at 24h. Compared to CYNK-101 pre-infusion, ex vivo-CYNK-101 showed not only a higher ADCC activity against NCI-N87, but also a more matured NK phenotype with increased expression of CD16, KIR, NKG2D, and CD94. In addition, CD16 shedding resistance was demonstrated on ex vivo-CYNK-101. CYNK-101 in vivo anti-tumor ADCC activity was assessed in a subcutaneous xenograft NCI-N87 mouse model. Significant tumor reduction was shown in the animals treated with CYNK-101 plus Trastuzumab compared to vehicle control, Trastuzumab or CYNK-101 alone (P & lt;0.0001, n=20 mice per group). In summary, our results demonstrated synergistic anti-tumor ADCC activities of CYNK-101 plus Trastuzumab against HER2+ gastric cancer cells in vitro, ex vivo and in vivo. Further development of CYNK-101 in combination with Trastuzumab for HER2+ gastric cancer immunotherapy is underway. Citation Format: Lin Kang, Shuyang He, Irene Raitman, Salvatore Rotondo, Joseph Gleason, Valentina Rousseva, Xuan Guo, Hemlata Rana, Qian Ye, Robert Hariri, Xiaokui Zhang. Potent immunotherapy of human placental CD34+-derived natural killer cells with high affinity and cleavage resistant CD16 (CYNK-101) plus Trastuzumab for HER2+ gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 58.

Abstract: Background: Natural killer (NK) cells exhibit anti-tumor activity in a non-antigen-specific manner without causing graft-versus-host disease. T cell and cord blood NK cells expressing chimeric antigen receptor (CAR) targeting CD19 have demonstrated remarkable clinical efficacies against B cell lymphomas (Maude et al, N Engl J Med 2018; Neelapu et al, N Engl J Med 2017; Liu et al, N Engl J Med 2020). Celularity has developed a platform for the expansion and differentiation of human placental CD34 + stem cells towards NK cells. The introduction of CD19 CAR enables generation of CAR19-CYNK cells that can be used as an off-the-shelf, cryopreserved, allogeneic cell therapy for CD19 + B cell malignancies. Reported here are the in vitro and in vivo results evaluating anti-tumor activity of CAR19-CYNK against CD19 + B cell malignancies. Methods: CAR19-CYNK cells were generated by retroviral transduction of human placental CD34 + cells with an anti-CD19 CAR (CD19scFv-CD28CD3ζ, Sorrento Therapeutics), followed by culture expansion in the presence of cytokines. CD19 CAR expression and phenotype of CAR19-CYNK cells were characterized by flow cytometry using the following surface markers: CD56, CD3, CD226, CD16, CD11a, CD94, NKG2D, NKp30, NKp44, NKp46. The in vitro anti-tumor activity of CAR19-CYNK against the B cell lymphoma cell lines, Daudi and Nalm-6, was assessed at various effector to target (E:T) ratios using a flow cytometry-based cytotoxicity assay and multiplex Luminex analysis for cytokine profiling. Non-transduced (NT) NK cells were used as control. In vivo efficacy of CAR19-CYNK was assessed using a disseminated B-cell lymphoma xenograft model in B-NDG-hIL15 mice. B-NDG-hIL15 mice lack T, B, and NK cells and are transgenic for human IL-15 to support CAR19-CYNK persistence and maturation. Luciferase expressing Daudi cells (3×10 6) were intravenously (IV) injected on Day 0 three days after the mice were preconditioned with a myeloablative dose of busulfan to allow for better tumor cell engraftment. CAR19-CYNK cells (1x10 7) were IV injected on Day 7. Tumor burden was assessed weekly by bioluminescence imaging (BLI) and the mice were followed for assessment of their survival (n=5 mice per group). Results: Placental CD34 + cells were genetically modified using a retroviral vector and achieved an average of 29.2% ± 12.4% (range 17.5% to 50.1%; n=5 donor lots) CD19 CAR expression on CAR19-CYNK cells at the end of 35-day culture. The average fold expansion of CAR19-CYNK was 6186 ± 2847 with the range of 2692 to 10626 (n=5 donor lots). Post-thaw evaluation of CAR19-CYNK (n=5 donor lots) revealed 93.8 ± 3.9% of CD56 +CD3 - NK cells, and transduction of CD19 CAR on CYNK did not significantly alter NK cell phenotype based on various activation and lineage markers (CD226, CD16, CD11a, CD94, NKG2D, NKp30, NKp44, NKp46). CAR19-CYNK displayed enhanced in vitro cytotoxicity against lymphoma cell lines, Daudi and Nalm-6, compared to that of NT NK cells. At the E:T ratio of 10:1, CAR19-CYNK (n=5 donor lots) elicited significant increased cytotoxicity against Nalm-6 compared to that of NT NK cells, with 75.9 ± 14.8% vs. 0.00 ± 0.00% at 24h (p & lt;0.005). Under the same condition, CAR19-CYNK (n=4 donor lots) showed higher cytotoxicity against Daudi compared to that of NT NK cells with 23.6 ± 18.9% vs. 4.9 ± 4.0%. When cocultured with tumor cell lines, CAR19-CYNK showed increased secretion of the proinflammatory cytokines GM-CSF (p & lt;0.05 for both Nalm-6 and Daudi), IFN-g (p & lt;0.05 for Nalm-6), and TNF-a compared to that of NT NK cells at an E:T ratio of 1:1 for 24h. To evaluate the in vivo efficacy of CAR19-CYNK, a disseminated Daudi xenograft B-NDG-hIL15 model was used. CAR19-CYNK treated mice demonstrated a significant survival benefit with a median survival of 39 days versus a median survival of 28 days for the vehicle treated group (p & lt;0.05). Conclusions: In summary, we have successfully established a process for generating CAR19-CYNK cells from human placental CD34 + cells. CAR19-CYNK demonstrated enhanced in vitro cytotoxicity against CD19 + B cell malignancies and in vivo survival benefit in a disseminated lymphoma xenograft B-NDG-hIL15 model. Further development of CAR19-CYNK for CD19 + B cell malignancies is warranted. Disclosures Gergues: Celularity Inc: Current Employment, Current equity holder in publicly-traded company. Raitman: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Gleason: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Rousseva: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. He: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Van Der Touw: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Ye: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Kang: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Zhang: Sorrento Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Pai: Sorrento Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Guo: Sorrento Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Ji: Sorrento Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Hariri: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Zhang: Celularity Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months.

Abstract: Background: Natural Killer (NK) cells are innate immune lymphocytes with cytotoxic function and are critical for immune surveillance. Unlike T cells which rely on antigen-specific responses, NK cells recognize transformed cells through a variety of NK cell-specific receptor-ligand interactions. Clinical studies have highlighted the therapeutic potential of NK cell-based therapies and Celularity has developed a GMP procedure for generating PNK-007: an off-the-shelf and allogeneic NK cell product culture-expanded and differentiated from human placental CD34+ stem cells. PNK-007 was evaluated as a single-dose allogeneic cell therapy in a phase I dose-escalation study for multiple myeloma (MM) patients receiving autologous stem cell transplant (ASCT) (NCT02955550). 12 of 15 patients received subcutaneous IL-2 every 48 hours for 10 days following PNK-007 cell infusion while 3 patients in a separate cohort did not receive IL-2. Here, we report translational studies evaluating post-treatment immune reconstitution, minimal residual disease (MRD) detection at 10-5 threshold, and serum profiling of cytokines and chemokines. Methods: Patient bone marrow aspirate was collected for EuroFlow MRD assessment and immune phenotyping by flow cytometry at baseline, 90-100 days, 6 months and 1 year post-ASCT. Peripheral blood was collected at baseline, then weekly for six weeks following PNK-007 infusion, at 6 months and at 1 year post-ASCT. PNK-007 persistence, leukocyte populations, and HLA antibody panels were determined by flow cytometry. Serum was analyzed by Luminex for panel cytokines, chemokines and soluble cytokine receptors. All patients and PNK-007 drug product were typed for HLA and killer-cell immunoglobulin-like (KIR) genotype. Results: PNK-007 infusion did not interfere with immune reconstitution kinetics post-ASCT. Cohorts receiving PNK infusion 14 days post-ASCT had already recovered white blood cell counts to normal levels. One cohort receiving 3x107 PNK cells/kg 7 days post-ASCT showed an immune deficient environment (0.05x103 ± 0.004x103 leukocytes/ml, n=3), but recovered their white blood cell counts by day 21 (6.8x103 ± 1.8x103 leukocytes/ml, n=3). Using a validated Euro-flow MRD assay, 4/15 patients were MRD(-) at pre-ASCT baseline, and by day 90, 10/15 pts were MRD(-). PNK-007 persistence was not detected in patients by flow cytometry with the earliest timepoint tested being 7 days post-infusion. Panel HLA serum antibodies were not detected at any timepoint indicating the absence of alloantibodies. Withholding IL-2 administration in one cohort allowed us to evaluate its potential effects on NK cell recovery and immune reconstitution. We found that subcutaneous IL-2 q.o.d. for 10 days following PNK-007 infusion did not affect recovery kinetics and concentration of endogenous NK cells. However, these patients showed a 5-10 fold increase in serum soluble IL-2RA from baseline and elevated regulatory T cell (Treg) count in the blood versus baseline (167 ± 107 Treg/mL vs. 61 ± 33 Treg/mL, p=0.0075). Patients not receiving IL-2 saw no change in serum soluble IL-2RA or blood Treg level from baseline. CD4 and CD8 T cells from all patients retained their ability to become activated in response to ex vivo stimulation and favored release of IL-2 and IFNg. T cell effector function was maintained in all patients post-ASCT but was lost in a subset of patients at 1 year. Serum analysis showed low levels of free IL-15 at the time of PNK dosing despite the transient lymphodepleted state associated with ASCT. Cytokines associated with myeloid inflammation and T cell immunity in the month post dosing were within normal homeostatic level. Serum TGFβ was significantly lower at the day of PNK infusion compared to normal homeostatic levels. Conclusion: Translational data from a Phase I study of PNK-007 in post-ASCT MM established that dosing up to 3x107 cells/kg at 14 or 7 days post-transplant did not impair engraftment or immune reconstitution. EuroFlow MRD assessment of the bone marrow showed conversion of 6/11 patients from MRD(+) to MRD(-) by day 90 post transplant. The administration of IL-2 in this clinical study did not appear to benefit NK cell reconstitution but instead favored soluble IL2RA antagonism and increased systemic levels of Treg. These results demonstrate the feasibility of allogeneic NK cell therapy in the MM + ASCT setting and will help inform the design of further clinical studies. Disclosures Van Der Touw: Celularity, Inc.: Employment, Patents & Royalties. Kang:Celularity, Inc.: Employment, Patents & Royalties. Stout:Celularity, Inc.: Employment. Voskinarian-Berse:Celularity, Inc.: Employment. Rousseva:Celularity, Inc.: Employment. Hariri:Celularity Inc: Employment. Zhang:Celularity Inc: Employment.

Abstract: CYNK-101, an allogeneic off-the-shelf human placental CD34+-derived natural killer (NK) cell product, is genetically modified to express a variant of CD16 (FcγRIII) via lentiviral vector transduction. When targeting tumors with monoclonal antibodies, NK cells are key effectors of antibody dependent cellular cytotoxicity (ADCC) following recognition of antibody Fc by CD16. CYNK-101 expresses the CD16 variant (CD16VP) which has a high-affinity due to a Valine at amino acid position 158 along with proteolytic cleavage resistance imparted by Proline at amino acid position 1971,2,3,4. We hypothesize that expressing CD16VP enhances anti-tumor activity of CYNK-101 in combination with monoclonal antibody therapy. Reported here are the in vitro and ex vivo results of evaluating CYNK-101 cytotoxicity against human epidermal growth factor receptor 2 (HER2)+ solid tumors in combination with Trastuzumab, an anti-HER2 monoclonal antibody. Human placental CD34+ cells were transduced with lentivirus expressing CD16VP, and cultured in the presence of cytokines, including TPO, SCF, Flt3L, IL-7, IL-15, and IL-2, to generate CYNK-101 cells. Lentiviral transduction with CD16VP achieved high expression efficiency in multiple placental CD34+ donors. These cells (n=7) expanded at 12041 ± 6394-fold and differentiated into CYNK-101 being & gt;90% CD56+CD3-. CYNK-101 expressed 74.1 ± 5.6% (n=7) of CD16 at the end of cultivation. Proteolytic cleavage resistance conferred by CD16VP in CYNK-101 was evaluated by activating NK cells with PMA/ionomycin (PMAi) to induce CD16 shedding. While 4h PMAi treatment resulted in & gt;89% CD16 cleavage on non-transduced NK cells, & lt;11% cleavage was observed on CYNK-101 cells, demonstrating CD16 shedding resistance. The in vitro anti-tumor activity of CYNK-101 against HER2+ solid tumor cell lines was assessed in combination with Trastuzumab. At effector to target (E:T) ratio of 0.6:1, CYNK-101 (n=7 donors) showed enhanced lysis of NCI-N87 gastric cancer cells in the presence of Trastuzumab compared to that of IgG control, 41.2 ± 11.1% vs. 5.3 ± 4.7% at 4h, 91.3 ± 15.0% vs. 7.5 ± 9.3% at 24h, respectively (p & lt;0.005). Increased production of GM-CSF, IFN-γ, and TNF-α was shown in CYNK-101 plus Trastuzumab against NCI-N87 at 24h compared to that of IgG control. Overall, the enhanced ADCC activity of CYNK-101 in combination with Trastuzumab has been demonstrated against both HER2+ gastric cancer cell lines, NCI-N87 and OE-19; and HER2+ breast cancer cell lines, AU565, BT-474, HCC-1954, SKBR-3, and ZR-75-30. To further evaluate ex vivo ADCC activity of CYNK-101, CYNK-101 cells were intravenously (IV) injected at 2x107 into busulfan-pretreated NOD-scid IL2Rγnull immunodeficient (NSG) mice at Day 0. Recombinant human IL-15 was intraperitoneally injected at Days 0, 2, 4, 6, 8, 10 and 12. At Day 13, CYNK-101 cells were isolated from mouse livers (ex vivo-CYNK-101) and assessed for phenotype and ADCC activity. Ex vivo-CYNK-101 exhibited enhanced cytotoxicity against NCI-N87 in combination with Trastuzumab compared to that of IgG control (30.9% vs. 6.6% at 4h, 90.7% vs. 9.1% at 24h) at the E:T ratio of 0.5:1, as well as increased cytokine productions of GM-CSF, IFN-γ, and TNF-α at 24h. Compared to pre-infusion CYNK-101, ex vivo-CYNK-101 showed not only a higher ADCC activity against NCI-N87, but also a more matured NK cell phenotype with increased expression of CD16, KIR, NKG2D, CD94, and CD11a. Besides, these ex vivo-CYNK-101 cells demonstrated CD16 shedding resistance post PMAi stimulation. In summary, our results demonstrated enhanced in vitro and ex vivo ADCC activities of CYNK-101 in combination with Trastuzumab against HER2+ solid tumors. CYNK-101 exhibited high resistance to CD16 shedding in vitro and ex vivo. Further maturation of CYNK-101 cells post IV infusion was accompanied by ADCC activity enhancement. Evaluation of in vivo ADCC activity of CYNK-101 in combination with Trastuzumab will include both subcutaneous and orthotopic gastric cancer models. Disclosures Kang: Celularity Inc.: Current Employment. Raitman:Celularity Inc.: Current Employment. Rotondo:Celularity Inc.: Current Employment. Gleason:Celularity Inc.: Current Employment, Current equity holder in private company. He:Celularity Inc.: Current Employment, Current equity holder in private company. Somanchi:Celularity Inc.: Current Employment, Current equity holder in private company. Rousseva:Celularity Inc.: Current Employment. Guo:Celularity Inc.: Current Employment. Rana:Celularity Inc.: Current Employment. DiFiglia:Celularity Inc.: Current Employment. Ye:Celularity Inc.: Current Employment, Patents & Royalties. Mahlakõiv:Celularity Inc.: Current Employment. Van Der Touw:Celularity Inc.: Current Employment. Hariri:Celularity Inc.: Current Employment, Current equity holder in private company. Zhang:Celularity Inc.: Current Employment, Current equity holder in private company.

Abstract: Natural Killer (NK) cells are key mediators of antibody dependent cellular cytotoxicity (ADCC) via the CD16 Fc receptor. NK cellular therapies can effectively be targeted to tumor antigens when combined with tumor specific antibodies. Celularity Inc. is developing human placental CD34 +-derived, cryopreserved, off-the-shelf, allogenic NK cells (CYNK-101) with a high IgG binding affinity and proteinase cleavage resistant CD16 variant (CD16VP) for cancer treatment. We hypothesize that expressing CD16VP augments anti-tumor ADCC activity. Reported here are the in vitro and in vivo results of evaluating CYNK-101 cytotoxicity against CD38 expressing multiple myeloma (MM) and lymphoma tumor cell lines when in combination with daratumumab, an anti-CD38 monoclonal antibody. Human placental CD34 + cells were transduced with lentivirus expressing CD16VP and cultured in the presence of cytokines to generate CYNK-101 cells. The in vitro cytotoxic activity of CYNK-101 against CD38 + MM (MOLP-8, LP-1, MM.1S) and lymphoma (Daudi) tumor cell lines, and normal B-cells was assessed in combination with daratumumab via flow cytometry based ADCC assays and cytokine secretion was assessed via multiplex Luminex analysis. In vivo ADCC activity of CYNK-101 was assessed using a disseminated B-cell lymphoma xenograft model in B-NDG-hIL15 mice. B-NDG-hIL15 mice lack T, B, and NK cells and are transgenic for human IL-15 to support CYNK-101 persistence and maturation. Luciferase expressing Daudi cells (3×10 6) were intravenously (IV) injected on Day 0 three days after preconditioning with a myeloablative dose of busulfan to allow for better tumor cell engraftment. CYNK-101 cells (1x10 7) and/or daratumumab (0.05 mg/kg) were IV injected on Days 7, 14 and 21. Tumor burden was assessed weekly by bioluminescence imaging (BLI) and the mice were followed for assessment of their survival (n=5 mice per group). In vitro ADCC studies indicate enhanced cytolysis of CYNK-101 in combination with daratumumab against both MM and lymphoma tumor cells compared to that of IgG control. At 24h at the effector to target (E:T) ratio of 5:1, CYNK-101 (n=5 donors) demonstrated a cytolysis of 87.6 ± 6.3% with daratumumab vs. 37.3 ± 9.5% with IgG control against MOLP-8 (p & lt;0.001), 73.9 ± 2.5% vs. 32.1 ± 7.2% against LP-1 (p & lt;0.001), 77.2 ± 11.5% vs. 67.4 ± 10.7% against MM.1S (p & lt;0.001), and 54.7 ± 24.0% vs. 4.3 ± 2.6% against Daudi (p & lt;0.01) tumor cells. Secretion of GM-CSF, IFN-γ, and TNF-α was increased in CYNK-101 co-cultured with the tumor cell lines in the presence of daratumumab for 24h (n=5 donors, p & lt;0.05). When cocultured with mixed LP-1 and CD38 + normal B-cells, CYNK-101 in combination with daratumumab displayed specific cytotoxicity against LP-1, while sparing CD38 + normal B-cells even at an E:T ratio up to 100:1, demonstrating that CYNK-101 can distinguish CD38 + tumor cells from CD38 + normal cells. Additionally, despite expression of CD38 on CYNK-101 there was no NK fratricide observed when CYNK-101 were in combination with daratumumab. In vivo studies in the lymphoma xenograft model revealed a significant decrease in tumor burden as evidenced from bioluminescence imaging at day 28 (1 week after last CYNK-101 injection) for mice that received CYNK-101 in combination with daratumumab compared to vehicle control (p & lt;0.001), CYNK-101 (p & lt;0.05) and daratumumab (p & lt;0.05). Furthermore, CYNK-101 in combination with daratumumab demonstrated an enhanced survival benefit with a median survival of 35 days versus a median survival of 28 days for the vehicle treated group (p & lt;0.005). In summary, our results demonstrate enhanced in vitro and in vivo ADCC activities of CYNK-101 in combination with daratumumab against CD38 + hematological tumors and warrant further development of this combination therapy for these cancers. Disclosures Raitman: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Gleason: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Rotondo: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. He: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Rousseva: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Guo: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Rana: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. van der Touw: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Ye: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Kang: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Hariri: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Zhang: Celularity Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months.