LAUSR

Background: Genetically engineered affinity-enhanced autologous SPEAR T-cells (AFPc332T-cells) directed towards the HLA-A*02-restricted AFP peptide FMNKFIYEI are being tested in an ongoing Phase 1 trial to evaluate safety and antitumor activity in patients with hepatocellular carcinoma (HCC) (NCT03132792). Methods: This is a first-in-human study in HCC patients not amenable to transplant, resection, or loco-regional therapy and failed/intolerant/refused standard of care treatment. Patients must be HLA-A*02:01+ or 02:642+. Patients must have AFP expression by immunohistochemistry at ≥1+ in ≥20% HCC tumor cells or serum AFP ≥400 ng/ml and ≤5% IHC AFP in non-cancerous liver tissue. Up to 24 patients will be enrolled using a modified 3+3 design. Lymphodepletion is with fludarabine 20 mg/m2/day and cyclophosphamide 500 mg/m2/day on days -7 to -5. The initial transduced cell dose is 0.1×109 cells; additional doses are 1×109 and 5×109. Cohort expansion will occur at maximum tolerated dose and may allow doses up to 10×109 transduced cells. Dose-limiting toxicities (DLTs) are adjudicated by a Safety Review Committee. Results: As of 21Sep18, 2 patients were treated with 0.1×109 AFP SPEAR T-cells. Both had cytopenias related to lymphodepleting chemotherapy. Neither experienced cytokine release syndrome or SAEs during initial hospitalization. Liver chemistries show no AFPc332T-related hepatotoxicity. AFPc332T-cells were detected in both patients. One patient had grade 1 cognitive disturbance on day 8. This patient had SAEs of biliary obstruction at week 9 treated with stenting, and abdominal pain at week 12; neither was considered related to AFPc332T. Post-treatment imaging shows stable disease at week 12 by RECIST v1.1. Serum AFP was 12665 ng/ml at baseline, 29616 ng/ml at week 2, and 16,489 at week 12. Week 8 tumor biopsy showed diffuse tissue necrosis with cholestasis suspicious for necrotic tumor cells. No viable tissue was present. Immunostaining for CD3 showed numerous T-cells and T-cell aggregates within the necrotic tissue. The 2nd patient had no SAEs reported; post-treatment imaging is pending. Conclusions: AFP SPEAR T-cells at the 0.1×109 cell dose show no evidence of on target or off target toxicity in the first 2 patients. No protocol defined DLTs were reported. Current data support continued investigation of AFPc332T-cells. Updated data will be presented. Citation Format: Lipika Goyal, Matthew Frigault, Tim Meyer, Lynn G. Feun, Jordi Bruix, Anthony El-Khoueiry, Petr Hausner, Bruno Sangro, Theodore T. Pierce, Elliot Norry, Sulabha Ranganathan, Rafael G. Amado, Richard S. Finn. Initial safety of AFP SPEAR T-cells in patients with advanced hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3183.