Abstract 892: Afamitresgene autoleucel (afami-cel; formerly ADP-A2M4) demonstrates durable clinical responses by inducing broad immune engagement with anti-tumor activity

Abstract

Afami-cel is a mixed CD4+ CD8+ autologous T-cell therapy engineered to target the cancer testis antigen melanoma-associated antigen A4 in HLA-A*02-positive patients with advanced/metastatic synovial sarcoma or myxoid/round cell liposarcoma (MRCLS). Pooled data from the Phase 1 (NCT03132922) and Phase 2 (SPEARHEAD-1, NCT04044768) trials of afami-cel showed an acceptable benefit to risk profile with an overall response rate of 36.2% and a median duration of response of 52.0 weeks.1 To support the continued investigation of potential mechanisms of durable anti-tumor activity, we previously showed that afami-cel induces broad and enduring peripheral cytokine responses2 and that afami-cel tumoral infiltration is associated with increased presence of activated and proliferative cytotoxic T-cells in the tumor microenvironment.3 Here, we report the results of translational analyses exploring the cooperation between afami-cel-induced innate and adaptive immune responses pooled from the Phase 1 and 2 trials. Methods included measurement of 92 biomarkers related to apoptosis, chemotaxis, metabolism, tumor immunity promotion/suppression, and vascular/tissue remodeling in pre- and post-infusion serum samples from 38 patients. We also conducted multiplex immunofluorescence and gene set variation analysis of Reactome immune system pathway categories and microenvironment cell populations in RNA sequencing data from pre- and post-infusion biopsies from ≥15 patients. Serum analyses showed that patients with a clinical benefit as defined by RECIST v1.1 had significantly greater post-infusion levels of chemotactic markers (Kruskal-Wallis; p<0.05 for partial response [PR] compared to progressive disease, p<0.01 for PR compared to stable disease), indicating higher signaling related to immune-cell recruitment towards lesions. Tumor analyses showed increased expression of genes associated with innate and adaptive immunity, and cytokine signaling, in post-infusion biopsies, including T-cell receptor signaling-related expression, which was consistent with relatively greater spatial protein detection of pro-immune infiltrate. This profile was associated with longer progression-free survival. In conclusion, our data suggest that afami-cel induces peripheral and tumoral innate and adaptive immune responses, a hallmark of durable anti-tumor activity. Updated patient sample data will be presented. 1. D'Angelo SP, et al. J Clin Oncol. 2022;40:16_suppl:11562. 2. D’Angelo SP, et al. Poster 146 presented at: CTOS 2021; Virtual. 3. Van Tine, BA et al. Paper 61 presented at: CTOS 2022; Vancouver, BC, Canada. Citation Format: Cheryl McAlpine, Martin Isabelle, Robyn Broad, Revashnee Naidoo, Ashley Liddle, Elizabeth Duperret, Paul Noto, Ruoxi Wang, Dzmitry Batrakou, Sumit Middha, Chris Evans. Afamitresgene autoleucel (afami-cel; formerly ADP-A2M4) demonstrates durable clinical responses by inducing broad immune engagement with anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 892.