225 ALK.CAR-T cells as a new potential treatment for ALK + merkel cell carcinoma

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Background Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine skin cancer with limited treatment options. While chemo-immunotherapy remains the standard of care, nearly 50% of patients experience disease progression, with a median overall survival of 10 months. 1Anaplastic lymphoma kinase (ALK) has emerged as a promising therapeutic target in various malignancies,2 including MCC, where it is detected in 40-80% of cases.3 Our group recently developed novel chimeric antigen receptor T-cell against ALK (ALK.CAR-T), demonstrating potent anti-tumor activity against ALK+ neuroblastoma.4 This ALK.CAR-T product is currently under clinical investigation in a Phase I/II clinical trial (NCT06803875).5 In the present study, we evaluated the relevance of ALK.CAR-T immunotherapy in ALK+ MCC tumors.Methods We tested ALK and Merkel cell polyomavirus antigen (MCPyV) expression in a cohort of 178 patients with MCC using immunohistochemistry. In addition, we characterized a panel of MCC human cell lines and two patient-derived xenografts (PDX) to identify potential immunotherapeutic targets (ALK, GD2, and HLA-I – figure 1A-C). ALK.CAR-T cells were co-cultured either in 2D with MCC cell lines or in 3D-microfluidic devices with xenograft-derived organotypic tumor spheroids (xDOTS) to assess their killing efficacy in vitro, either alone or in combination with ALK inhibitors. For in vivo testing, NSG mice were injected intravenously with human MCC cell lines and, after engraftment, treated with ALK.CAR-T cells, either alone or in combination with the ALK inhibitor lorlatinib. Tumor monitoring was performed weekly using IVIS imaging.Results We found ALK expression in approximately 80% of MCC tumors and observed a significant association between ALK expression and poor clinical outcomes. In vitro, ALK.CAR-T treatment effectively killed ALK+ MCC cell lines and xDOTS, associated with an increased production of IFNg and granzyme B. Moreover, the combination with an ALK inhibitor (lorlatinib or nadelalkib) enhanced ALK.CAR-T antitumor activity, even when the ALK inhibitor showed no effect alone (figure 1D-F). In vivo, ALK.CAR-T outperformed GD2.CAR-T, extending the overall survival of mice in two MCC metastatic models. Nonetheless, ALK.CAR-T efficacy was enhanced by lorlatinib, improving tumor control without altering the safety profile (figure 2).Conclusions We identified ALK as a clinically relevant target in MCC and demonstrated that ALK.CAR-T cells, especially when combined with ALK inhibitors, has a potent anti-tumor activity against ALK + MCC. Our study provides a preclinical rationale for expanding the ongoing Phase I/II clinical trial in relapsed/refractory neuroblastoma patients to include patients with MCC, thus broadening the therapeutic indication of ALK.CAR-T.Acknowledgements E.B. was supported by ‘SITC-Bristol Myers Squibb Postdoctoral Cancer Immunotherapy Translational Fellowship’.References Becker JC, et al. Merkel cell carcinoma. Nat Rev Dis Primers Oct. 2017;3(1):17077. doi: 10.1038/nrdp.2017.77Voena C, Ambrogio C, Iannelli F, Chiarle R. ALK in cancer: from function to therapeutic targeting. Nat Rev Cancer May 2025;25(5). doi: 10.1038/S41568-025-00797-9Santoro F, et al. Clinical-pathological evaluation and prognostic analysis of 228 merkel cell carcinomas focusing on tumor-infiltrating lymphocytes, MCPYV infection and ALK expression. Endocr Pathol, Jun 2022;33(2):289–303. doi: 10.1007/s12022-022-09716-2Bergaggio E, et al. ALK inhibitors increase ALK expression and sensitize neuroblastoma cells to ALK.CAR-T cells. Cancer Cell Dec 2023;41(12):2100-2116.e10. doi: 10.1016/j.ccell.2023.11.004‘Study of hALK.CAR T Cells for Patients With Relapsed/Refractory High-risk Neuroblastoma’, NCT06803875. Accessed: Jun. 01, 2025. [Online]. Available: https://clinicaltrials.gov/study/NCT06803875Ethics Approval The patient‘s analysis included in this study was approved by the University of Turin, Department of Medical Sciences, local Ethics Committee (ChBU n. 1–2022). The animal study was approved and conducted at Boston Children’s Hospital Animal Facility (protocol n. 00002434).Abstract 225 Figure 1ALK+ MCC models characterization and ALK.CAR-T efficacy in vitro. (A) Patient samples vs PDXs (ALK and MCPyV IHC). (B) ALK and GD2 expression by FACS (C) MCC cell lines (ALK IHC) (D) Killing assay (E) Killing assay (neladalkib N or lorlatinib L). (F) Co-culture MCC xDOTS in the 3D-systemAbstract 225 Figure 2In vivo efficacy of ALK.CAR-T cells against MCC metastatic models. (A) WAGA tumor progression. (B) Kaplan-Meier survival analysis (relative to A) (C) MKL1 tumor progression. (D) Kaplan-Meier survival analysis (relative to C)

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