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)

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 (>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