Abstract A018: Characterization of the anti-tumor efficacy of memory cytokine enriched NK cells against tumors with neuroendocrine features

Neuroendocrine neoplasms (NEN) consist of slow growing neuroendocrine tumors and highly proliferative neuroendocrine carcinomas. The incidence of NEN continues to rise, yet there remains a lack of effective treatments for this disease. Immune checkpoint blockade (ICB) in combination with chemotherapy is approved in extensive stage small cell lung cancer (SCLC), a very aggressive tumor classically known as NE, but only a subset of patients experiences improved survival. Lack of response to ICB is often attributable to low expression of MHC-class I. Our group recently published that the lack of MHC-class I can instead be utilized to facilitate targeting by NK cells. We found that NK cells stimulated with an IL-15 cytokine superagonist (N-803) were able to effectively target SCLC of all phenotypes. This led us to hypothesize that cytokine stimulated memory-like NK cells may be effective in targeting SCLC and other types of NE tumors. In the present study, the ability of memory cytokine enriched NK cells (M-ceNK) to target human NE cell line models is evaluated. M-ceNK are derived from an apheresis product (from healthy donors or cancer patients) and exposed to a cocktail of cytokines including N-803, IL-12, and IL-18 until a highly purified CD3NEGCD56HIGH cell population results. Characterization across many donors indicates that M-ceNK are highly activated NK cells exhibiting increased natural cytotoxicity receptors (NKp30, NKp44, NKp46), minimal inhibitory markers (KLRG1, TIGIT), elevated IFN-gamma and Granzyme B production, and increased reliance on glycolysis for their metabolic activity compared to healthy donor NK cells. The functional killing capacity of M-ceNK was assessed via in vitro immune cytotoxicity assays; M-ceNK demonstrated a median of 69% lysis (range 35-89%) at an effector to target ratio of 5:1 across 5 SCLC models (DMS79, H69, H446, H1048, H841) as well as 66% and 42% lysis respectively in NE prostate cancer (H660) and lung cancer (H720, H727) models as compared to 6% lysis (range 0-58%) with healthy donor NK cells. Furthermore, M-ceNK provided significant anti-tumor efficacy in two xenograft models of SCLC (H69, DMS79) when administered with N-803 in vivo. To better understand the efficacy of M-ceNK and their role upon encountering tumor cells, we co-cultured M-ceNK and NE tumors together and subsequently performed single cell RNA-sequencing on pairs of matched donor M-ceNK pre- and post- tumor exposure. We observed rapid upregulation of a gene signature indicative of tumor-infiltrating NK cells as well as increases in the expression of chemokines that play a key role within the tumor microenvironment. Further studies will evaluate the functional importance of these changes in gene expression and how they affect the ability of M-ceNK to target tumor cells, secrete cytokines, and proliferate; M-ceNK will also be tested in combinatorial immunotherapy approaches to treat NE and other ICB-refractory tumors. Kristen Fousek, Lucas A. Horn, Haiyan Qin, Nika Rajabian, Miriam Marlene Medina Enriquez, Shantel Angstadt, Manju Saxena, Lennie Sender, Patrick Soon-Shiong, Claudia Palena. Characterization of the anti-tumor efficacy of memory cytokine enriched NK cells against tumors with neuroendocrine features [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A018.