Abstract B007: Developing cytokine-armored CAR-NK cells for the treatment of non-small cell lung cancer

Abstract Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) comprising the majority of cases and exhibiting poor long-term survival despite therapeutic advances. Although adoptive cell therapy (ACT) has demonstrated remarkable efficacy in hematologic malignancies, its translation to solid tumors has been hindered by many factors, including suboptimal immune cell trafficking and profound immunosuppression within the tumor microenvironment, as well as significant manufacturing and logistical constraints associated with personalized autologous cell products. “Off-the-shelf”, allogeneic peripheral blood–derived natural killer (PB-NK) cell platforms offer several advantages, including favorable toxicity profile, lower cost, and simplified production. However, CAR-NK therapies still face critical obstacles, such as limited in vivo persistence and insufficient induction of systemic immune responses. Recent studies indicate that cytokine-armoring strategies using common γ-chain cytokines, IL-15 or IL-21, can enhance NK cell–based ACT by enhancing in vivo persistence and inducing endogenous T-cell responses. Complementing these observations, engineered de novo IL-21 mimetics have demonstrated superior anti-tumor activity compared to native IL-21 when delivered as recombinant cytokine therapies. In parallel, our previous work with in situ dendritic cell vaccines armored with the T-cell–recruiting chemokines CCL21, CXCL9, and CXCL10 has shown that intratumoral delivery of cell products with immune-modulatory capacity can effectively augment T-cell infiltration and potentiate immune checkpoint blockade immunotherapies. Building on these principles, our therapeutic strategy integrates both de novo IL-21 and CXCL9 into allogeneic CAR-NK cells. We hypothesize that this combined approach will induce immediate tumor regression via enhanced CAR-NK cytotoxicity and persistence, as well as durable systemic immune control driven by the synergy between CXCL9-mediated T-cell recruitment and de novo IL-21 signaling. Our findings demonstrate a robust feeder-free expansion workflow for PB-NK cells that supports efficient genetic modification using VSVG-pseudotyped lentivirus to express CAR alongside multiple cytokine cargoes, enabling a versatile platform for next-generation adoptive NK cell therapies. Citation Format: Austin K. Rennels, Ji-Ann Lee, Faith Kim, Ella Yim, Jensen Abascal, Camelia Dumitras, Bitta P. Kahangi, Edgar Perez Reyes, Nalani Coleman, Samantha Chin, Hong Jiang, Michael S. Oh, Michael Palazzolo, Dylan Conklin, Kostyantyn Krysan, Linh M. Tran, Ramin Salehi-Rad, Mohamad H. Abedi, Steven M. Dubinett, Bin Liu. Developing cytokine-armored CAR-NK cells for the treatment of non-small cell lung cancer [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 B007.