1483 Activity of IDP-023 allogeneic g-NK cells without antibody targeting in first-in-human phase 1/2 study in patients with advanced multiple myeloma or non-hodgkin lymphoma

<h3>Background</h3> Patients with relapsed or refractory (RR) multiple myeloma (MM) or Non-Hodgkin’s lymphoma (NHL) have poor outcomes, with overall survival generally less than 12 months after best available therapies. More effective and tolerable treatments are needed. IDP-023 is an allogeneic natural killer cell product. By natural epigenetic reprogramming, g-NK cells are FceR1g-negative and exhibit much higher antibody-dependent cytotoxicity (ADCC) following engagement of CD16 than conventional NK cells (cNK). In addition, g-NK cells are negative for the inhibitory checkpoint NKG2A and express high levels of the activating receptor NKG2C, making them uniquely suited to kill HLA-E-expressing target cells. <i>Pre-clinical activity:</i> Robust activity of g-NKs in combination with daratumumab has been demonstrated against MM cell lines, patient-derived primary tumor cells, and in an orthotopic xenograft myeloma model (MM.1S). IDP-023 efficacy was significantly better than expanded cNK cells¹ or competitive NK cell products generated from cord blood or iPSC tested in the same model. <h3>Methods</h3> This is an open label, Phase 1/2, first-in-human, multiple ascending dose escalation, and dose-expansion study of IDP-023 administered as monotherapy +/- interleukin-2 (IL-2), and in combination with daratumumab or rituximab. (NCT06119685). <i>Objectives:</i> The goal of the cohorts without antibody, was to define safety and tolerability. <i>Eligibility:</i> Adults with RR MM who have failed ≥ 3 prior lines of therapy or with RR NHL who have failed ≥ 2 lines of systemic chemotherapy. <i>Treatments:</i> The cohorts described here received a matrix of two regimens (every week x3, or every other day x3) with or without IL-2. Patients received lymphodepleting chemotherapy (LD) followed by subcutaneous IL-2 and intravenous IDP0-023. <h3>Results</h3> As of 9/12/24, 9 patients were treated with IDP-023 without antibody. Eight patients received multiple doses of cells at the lowest dose and 6 also received IL-2. No DLTs were noted. Patients experienced cytopenias consistent with the LD. Two patients experienced serious AEs (febrile neutropenia) that were deemed unrelated to IDP-023. Of the patients who received IDP-023 + IL2, objective antitumor activity was seen in 4 of 5 MM patients who were heavily pretreated (3–7 prior lines of therapy, including 1 patient with prior CAR-T) and one patient with NHL who received prior CAR-T. <h3>Conclusions</h3> IDP-023 was well tolerated in both every week x3 and every other day x3 regimens. Encouraging initial activity was observed with IDP-023 + IL-2 in advanced MM and NHL, even in the absence of combination with ADCC mediating monoclonal antibodies. <h3>Acknowledgements</h3> We would like to thank the patients and their families for contributing in this study. <h3>Trial Registration</h3> NCT06119685. <h3>Reference</h3> Austin B Bigley, Shanae Spade, Nadia H Agha, Sujit Biswas, Suni Tang, Muhammad H Malik, Lu Dai, Shalaleh Masoumi, Bonell Patiño-Escobar, Martina Hale, Guy DiPierro, Ronald Martell, Byron Hann, Nina Shah, Arun P Wiita, Xinli Liu. FcεRIγ-negative NK cells persist in vivo and enhance efficacy of therapeutic monoclonal antibodies in multiple myeloma. <i>Blood Adv</i> 2021;<b>15</b>:3021–3031. <h3>Ethics Approval</h3> Participants have given informed consent before taking part in the study. The study has obtained ethics approval at all active sites and the specific IRB information is below: Site No. | Site Name | IRB Name | IRB Registration No. | IRB Approval Date | 1104 | MDACC | MDACC | IRB00000121 | 7/14/23 1393 | NEXT Virginia | Salus IRB | IRB00006833 | 9/19/23 1409 | Providence Cancer Institute | Advarra | IRB00000971 | 2/14/24 1410 | M Health Fairview - University of Minnesota Masonic Cancer| University of Minnesota| IRB00010642 | 10/4/23 | Center | 1074 | Weill Medical College of Cornell University | Advarra | IRB00000971 | 11/9/23 1425 | SCRI Oncology Partners | Castle IRB | IRB00012054 | 7/24/24 1428 | Valkyrie Clinical Trials | Advarra | IRB00000971 | 7/24/24