Abstract 1544: Generation of ALK CAR-T cells for neuroblastoma therapy

Abstract

Abstract Neuroblastoma (NB) is the most deadly cancer in children with dismal survival in high-risk patients. The majority of NB express the full length anaplastic lymphoma kinase (ALK) receptor, that typically acts as driver oncogene together with MYCN. In contrast to ALK-driven lung cancer or lymphoma, targeted therapies with ALK tyrosine kinase inhibitors (TKIs), despite encouraging, induce only partial responses in NB. Therefore, additional tools to improve NB treatment are strongly needed. To specifically target NB cells, we developed a series of ALK chimeric antigen receptor (CAR) T constructs from antibodies that recognize both human and mouse ALK. Murine ALK CAR-T cells are able to control the growth of ALK+ leukemia and NB in syngeneic tumor models without detectable toxicity. From the leading candidate, we generated fully humanized ALK CAR-T cells that showed potent in vitro killing activity against a large panel of human NB lines, with activity comparable to GD2 CAR-T cells that are currently in clinical trials for NB patients. Remarkably, ALK CAR-T treatment synergized in vivo with the ALK inhibitor lorlatinib. Mechanistically, lorlatinib not only reduced tumor growth, but enhanced ALK expression on the surface of tumor cells, thereby facilitating ALK CAR-T targeting. Combination of ALK CAR-T cells with lorlatinib resulted in enhanced killing of NB cells and cure or markedly increased survival in mouse models of human metastatic NB even with low ALK expression. These findings support the clinical development of ALK CAR-T cells for NB therapy. Citation Format: Elisa Bergaggio, Wei-Tien Tai, Andrea Aroldi, Ineês Mota, Diego Alvarado, Elisa Landoni, Jasna Metovic, Manuel Nüesch, Rafael Blasco-Patiño, Mauro Papotti, Gianpietro Dotti, Roberto Chiarle. Generation of ALK CAR-T cells for neuroblastoma therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1544.