Abstract CT131: A phase I study of adoptive immunotherapy for advanced ROR1+ malignancies with defined subsets of autologous T cells expressing a ROR1-specific chimeric antigen receptor (ROR1-CAR)
Authors: Specht Jennifer M. , Lee Sylvia , Turtle Cameron J. , Berger Carolina , Baladrishnan Ashwini , Srivastava Shivani , Voillet Valentin , Veatch Josh , Gooley Ted , Mullane Erin , Chaney Colette , Rader Christoph , Pierce Robert H. , Gottardo Raphael , Maloney David G. , Riddell Stanley R. 
Published: August 2018

INTRODUCTION: ROR1 is a type 1 transmembrane tyrosine kinase receptor that plays a critical role in embryonic and fetal development. ROR1 has been described as a possible oncogene and is expressed in numerous malignancies, including a subset of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We are conducting a first-in-human trial targeting ROR1 with CAR-T cells in patients with advanced NSCLC and TNBC. The cellular construct employed targets the Ig/Fz portion of the extracellular domain of ROR1 and contains 4-1BB/CD3ζ intracellular signaling domain. The manufacturing process utilizes autologous peripheral blood lymphocytes, separated into CD4 and CD8 subsets, which are independently cultured with anti-CD3/anti-CD28 beads and IL-2, then transduced with a lentiviral vector encoding the ROR1 CAR. The CAR-T cell product is formulated in a 1:1 ratio of CD4+ and CD8+ CAR-T cells.

STUDY DESIGN: This ongoing phase 1 trial (NCT02706392) is evaluating the safety of administering ROR1 CAR-T cells in escalating doses (3.3x105, 1x106, 3.3x106 and 1x107 cells/kg) following lymphodepletion with cyclophosphamide-containing regimens using a continual reassessment method (CRM) for dose escalation. NSCLC and TNBC patients with adequate organ function and PS, measurable disease, and tumors expressing ROR1 (&gt;20% by IHC) are eligible for enrollment. Persistence of CAR-T cells in blood, cytokine levels, measures of immunogenicity and multi-parametric flow cytometry are being evaluated at multiple time points. Imaging assessments by RECIST 1.1 are performed day 28 - 90, then at 6 and 12 months, and every 6 months as clinically indicated to estimate efficacy.

RESULTS: To date, 6 patients (4-TNBC, 2-NSCLC) have been enrolled and treated. Five patients are evaluable for response. No dose-limiting toxicities, severe neurotoxicity or severe cytokine release syndrome (sCRS) were observed at dose levels 1 and 2. Three patients experienced grade 1 CRS. Three patients had evidence of CAR-T cell expansion between days 14 and 20, with peak CD8+ CAR-T up to 747/uL. Analysis of surface phenotype revealed upregulation of inhibitory receptors on CAR-T cells at the peak of expansion, confirmed by RNA seq. Post-treatment biopsies in 2 patients revealed a low level of CAR-T cell tumor infiltration. Four patients (2-NSCLC; 2-TNBC) demonstrated a mixed response with decreased disease burden at some metastatic sites at first disease assessment. One TNBC patient received 2 CAR-T cell infusions and remains with stable disease 56 days after second infusion with heavy burden of liver metastases.

CONCLUSIONS: ROR1+ CAR-T cells can be safely transferred, expand in vivo in patients with NSCLC and TNBC. Current efforts are directed at understanding and overcoming the mechanisms that limit homing, persistence, and/or function at tumor sites. The trial is continuing enrollment with dose-escalation. Funding provided by 8R01 CA114536-11 and Juno Therapeutics.

Citation Format: Jennifer M. Specht, Sylvia Lee, Cameron J. Turtle, Carolina Berger, Ashwini Baladrishnan, Shivani Srivastava, Valentin Voillet, Josh Veatch, Ted Gooley, Erin Mullane, Colette Chaney, Christoph Rader, Robert H. Pierce, Raphael Gottardo, David G. Maloney, Stanley R. Riddell. A phase I study of adoptive immunotherapy for advanced ROR1+ malignancies with defined subsets of autologous T cells expressing a ROR1-specific chimeric antigen receptor (ROR1-CAR) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT131.