Abstract A075: A Phase I Study of Autologous CAR-T Cells Targeting the B7-H3 Antigen and Containing the Inducible Caspase 9 Safety Switch in Subjects with Refractory Pancreatic Ductal Adenocarcinoma (PDAC)

Abstract Background "In PDAC, overexpression of B7-H3 on tumor cells frequently correlates with fewer tumor-infiltrating lymphocytes, faster cancer progression, and poor clinical outcomes. Treatments targeting B7-H3 correlate with tumor response in preclinical and phase I studies. Specifically, a B7-H3 CAR-T in a PDAC patient derived xenograft (PDX) model yielded some complete responses. This makes B7-H3 CAR-T therapy a promising therapeutic strategy in patients with chemotherapy refractory PDAC; however, CAR-T therapy is associated with life-threatening cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). The use of an inducible caspase 9 “safety switch” can abrogate these toxic effects, if necessary. Methods We are conducting a phase I study of (iC9) -CAR. B7-H3 T cells in subjects with refractory PDAC using a modified 3+3 dose escalation design with doses selected from previous T cell therapy studies in solid tumors. Fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2, administered intravenously (IV), is used as a conditioning regimen, and rimiducid is used to activate the iCas9 safety switch as needed. Disease assessment is performed six weeks after CAR T cell therapy using RECIST criteria. Results We have enrolled a total of five patients with four collected for product manufacturing, and three patients treated at dose level 1 (1×106 transduced cells/kg with a max dose of 1×108 cells). All five patients were Caucasian, non-Hispanic males, aged 63, 66, 68, 72, and 76, all with two prior lines of therapy. No DLTs were observed. Although two patients experienced grade 3 CRS requiring tocilizumab, they did not require treatment with rimiducid. Of the three patients treated, two had progressive disease at the first follow up and one had stable disease. Of the patient with stable disease, one target lesion was noted to have decreased in size by 25%. We have enrolled the next patient at dose level 2 (2. 5×106 transduced cells/kg with a max dose of 2. 5×108 cells), and have a planned dose level 3 (5×106 transduced cells/kg with a max dose of 5×108 cells) if tolerated. Conclusions The use of iC9-CAR. B7-H3 T cells therapy in patients with refractory PDAC is safe at DL1. Continued dose escalation and longitudinal follow-up are ongoing to determine the safety, tolerability, recommended dose and early evidence of efficacy. " Citation Format: Ashwin Somasundaram, Natalie S. Grover, Clarissa A. Urban, Hannah Ratzlaff, Faith B. Buchanan, Catherine J. Cheng, Kaitlin Morrison, Leila V. Kiefer, Allison Camp, Jonathan S. Serody, Barbara Savoldo, Gianpietro Dotti. A Phase I Study of Autologous CAR-T Cells Targeting the B7-H3 Antigen and Containing the Inducible Caspase 9 Safety Switch in Subjects with Refractory Pancreatic Ductal Adenocarcinoma (PDAC) abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr A075.