368 Translational analyses reveal mechanisms of afami-cel’s anti-tumor activity in synovial sarcoma

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Background Afamitresgene autoleucel (afami-cel) is an adoptive cell therapy wherein patients are infused with autologous T cells engineered to target tumor cells expressing the cancer/testis antigen melanoma-associated antigen A4 (MAGE-A4). Afami-cel has previously demonstrated clinical benefit in patients with synovial sarcoma.1Herein, we describe translational and biomarker analyses performed to elucidate afami-cel’s mechanisms of action. Methods In SPEARHEAD-1, the open-label Phase 2 trial (NCT04044859), a single infusion of afami-cel was given to eligible patients following lymphodepletion chemotherapy.1 Pharmacokinetic exposure of afami-cel was measured using a quantitative PCR−based assay. Electrochemiluminescence and Proximity Extension Assays were utilized to measure concentrations of cytokines in patient serum for pharmacodynamic assessment. Phenotypic assessment was performed on apheresis material, afami-cel manufactured product, and post-infusion peripheral blood mononuclear cell samples by flow cytometry. Cytotoxicity assays were performed on afami-cel manufactured product and peripheral blood samples isolated from patients post infusion to assess the extent to which functional properties were maintained. Phenotypic analyses of afami-cel and endogenous immune cells in the tumor microenvironment were performed using RNA in situ hybridization and multiplex immunofluorescence imaging at pre-infusion and post-infusion time points. Results Following infusion into patients, detectable afami-cel increased to peak concentrations within 2 weeks, and subsequently persisted and maintained functional cytotoxic ability for extended periods (in some cases >2.5 years). This long-term exposure correlated with clinical benefit and may be attributable to the observed upregulation of phenotypic markers associated with memory formation. Likewise, the persistently low levels of exhaustion markers observed may contribute to afami-cel’s sustained functionality. Correlates between immunophenotypes of circulating transduced cells and clinical benefit will be presented. Treatment induced increases in a range of serum cytokines, most notably interferon gamma. Afami-cel infiltrated the tumor microenvironment and non-transduced T cells were recruited. Phenotypic characterization of infiltrating T cells revealed markers associated with proliferation and cytotoxic ability. Conclusions Cumulatively, these data demonstrate that afami-cel can expand, persist, form memory T cells, and maintain functional activity long term in patients. Furthermore, the induction of interferon gamma production, infiltration of the tumor microenvironment, and recruitment of non-transduced T cells are consistent with afami-cel’s intended mechanism of action. These observations may explain the ability of afami-cel to drive durable clinical responses. Acknowledgements Study sponsored by Adaptimmune (Philadelphia, PA, USA). Writing and editorial support was from Christine Ingleby, DPhil, CMPP, Envision Pharma Inc. (Glasgow, UK) funded by Adaptimmune. Trial Registration ClinicalTrials. gov: NCT04044859. Reference D’Angelo SP, Araujo DM, Abdul Razak AR, et al. Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial. Lancet. 2024;403:1460–71. Ethics Approval The study was approved by local or independent institutional review boards or ethics committees at all participating sites.

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