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Introduction: AgenT-797 is an allogeneic iNKT cell therapy and represents a novel, scalable, off-the-shelf approach against solid tumors. iNKTs are a unique subset of T cells, that mediate antitumor responses by direct killing, targeting CD1d and other ligands in the tumor microenvironment, and by activating host immune cells. We conducted a clinical trial to investigate agenT-797 activity as single agent and in combination (combo) with PD-1 blockade after prior progression on PD-1 therapy. Methods: Patients (pts) with relapsed or refractory solid tumors were treated with single IV infusion of agenT-797 (no lymphodepletion) at 4.3 × 10^6 or 1.4 × 10^7 cells/kg, as monotherapy or in combo with pembrolizumab (pembro) or nivolumab (nivo). Dose escalation followed 3+3 scheme. Endpoints included safety, persistence of agenT-797, objective responses, duration of response, progression-free survival, and time to response. Adverse events (AEs) were reported per CTCAE v5.0. Dose limiting toxicities (DLTs) were evaluated. AgenT-797 persistence was assessed by assays utilizing SNPs and cfDNA analysis. Serum biomarkers were measured with MSD V-PLEX cytokine assays. On-treatment tumor biopsy was obtained for multiplex immunofluorescence staining and next generation sequencing. Results: As of February 5th, 32 pts (median age 62y, range 30-83) were treated with agenT-797 monotherapy (n=26) or combo (n=6) with pembro or nivo. Pts had median 4 lines of prior therapy (range 1-13). Tumor types included pancreatic (6), NSCLC (4), rectal (4), cholangiocarcinoma/biliary duct (4), and other (14)*. Tolerability was favorable, with no cytokine release syndrome, neurotoxicity, and no DLTs. Treatment-related AEs included 16.7% (5) grade 1, 3.3% (1) grade 2, and 3.3% (1) grade 3 (anemia). At data cutoff, agenT-797 monotherapy and combo revealed early clinical activity. Among 29 evaluable pts, a confirmed partial response in MSI-H gastric cancer refractory to PD-1 treated with agenT-797 + nivo (remains ongoing >6 months) and 8 pts had stable disease (SD). Prolonged SD (>3 months) for 3 monotherapy pts. Overall response rate 20% (1/5) for pts treated with agenT-797 + pembro or nivo. AgenT-797 was detected in peripheral blood up to day 8 post infusion. Preliminary data identified transient increase in serum IFNgamma levels day 2 post infusion. Conclusion: AgenT-797 was well tolerated as monotherapy and in combo with PD-1 (pembro or nivo). Anti-tumor activity in combo with nivo was observed in gastric cancer. Results support the potential of a novel therapeutic strategy employed by agenT-797 to enhance antitumor immunity in PD-1 refractory tumors. Enrollment ongoing and correlative studies will be presented. *PD-1 refractory NSCLC, pancreatic, rectal, cholangiocarcinoma, cervical, gastric, ocular melanoma, renal, and upper tract urothelial Citation Format: Benedito Carneiro, Benjamin Garmezy, John T. Hamm, Rachel E. Sanborn, Trisha Wise-Draper, Anthony El- Khoueiry, Breelyn Wilky, Dave S.B Hoon, Alexa Buffa, Xavier Michelet, Marco Purbhoo, Mark A. Exley, David Einstein. Phase 1 clinical update of allogeneic invariant natural killer T cells (iNKTs), agenT-797, alone or in combination with pembrolizumab or nivolumab in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT275.

Additional file 3: Figure S2. Change in antigen expression at progression. NY-ESO-1 protein expression H-scores as determined by IHC in pre-infusion and post-progression biopsies from all patients whose progression biopsies were evaluable (NÂ =â 15). Paired Mann-Whitney U statistical test was used to evaluate changes between pre-infusion and progression time points.

Additional file 2: Figure S1. Pre-conditioning lymphodepletion regimen influences IL-7 and IL-15 production. Ratio of serum IL-7 (a) and IL-15 (b) plotted pre and post-lymphodepletion. Box plots depict mean, first and third quartiles. p-values between pre- and post-lymphodepletion in paired specimen in each cohort were calculated by the Wilcoxon matched-pairs signed-rank test.

Additional file 1: Table S1. Patient biopsies.