Abstract CT109: HITM-SIR: Phase Ib trial of CAR-T hepatic artery infusions and selective internal radiation therapy for liver metastases

Abstract

OBJECTIVES: There are no effective treatment options for patients with unresectable CEA+ liver metastases (LM) from gastrointestinal adenocarcinoma refractory to conventional systemic therapy. In the previous Hepatic Immunotherapy for Metastases (HITM) phase I study we demonstrated the safety and biologic activity of anti-CEA CAR-T cell hepatic artery infusions (HAI). HITM-SIR was a single arm phase Ib trial testing anti-CEA CAR-T HAI followed by selective internal radiation therapy (SIRT) in patients with refractory CEA+ LM. METHODOLOGY: We enrolled 8 patients with unresectable, chemotherapy refractory CEA+ LM and 6/8 completed the study. Two patients were withdrawn for disease progression prior to CAR-T infusion and biliary obstruction due to centrally located disease. Limited extrahepatic disease (EHD) was permitted. Subjects received 3 HAI of anti-CEA CAR-T cells (1e10 cells per dose) along with low dose continuous IL-2 infusions (50,000 IU/kg/day). SIRT was administered in standard fashion 2 weeks following the 3rd CAR-T HAI. Primary objective was to establish safety of the CAR-T/SIRT combination. Secondary objectives included response assessed by modified RECIST (mRECIST), immune-related response criteria (irRC), and tumor marker kinetics. RESULTS: The mean age for enrolled subjects was 54.6 years (39-61) with 3 women and 5 men. Histologies (completed patients): 2 colon, 2 rectal, and 2 pancreas. This heavily pre-treated, advanced disease group of patients received an average of 2.3 lines of prior chemotherapy, 3/6 had >10 LM, and the average largest LM size was 7.3 cm. The average transduction efficiency as measured by CAR expression was 60.4%, with 90.9% viability, and an average production time for >3e10 cells of 13.8 days. There were no grade (G) 4/5 events related to the CAR-T, SIRT, or combination. Toxicities included G 1/2 liver function test elevations (n=5/6), fever (n=5/6), hypereosinophilia (n=2/6), and edema (n=2/6). G3 toxicities included colitis (n=2/6), fever (n=2/6), and edema (n=2/6). One patient experienced a hypertensive crisis during a single CAR-T infusion but tolerated 2 infusions without incident. All colitis episodes resolved with IL-2 dose reductions. Post-SIRT serum CEA decreases were noted in 2/6 patients (-40% and -71%) with CA19-9 decreases in 2/5 detectable patients (-31% and -32%). When considering all on-study time points, 5/6 patients had CEA responses (mean decrease 59.7%) and 4/5 patients expressing CA 19-9 decreases (mean 59.6%). At completion of the study, 3/6 patients had stable disease (SD) in the liver by mRECIST and irRC, and 3/6 SD overall by irRC. Target liver lesion decreases in size among patients with SD ranged from 6-28%. Regression of extrahepatic tumors or abscopal effects were noted in 2/6 at lung and bone sites. One patient remains without evidence of viable liver disease at 10.8 months follow-up. The median overall survival time for all patients is 6.9 months (range 3.8-10.8+). CONCLUSIONS: Following this phase Ib trial, the recommended phase 2 dose for anti-CEA CAR-T HITM infusions is 1010 cells with or without SIRT. The favorable safety profile and evidence of biologic activity indicate that CAR-T HITM infusions should be further studied in a phase 2 trial. Clinical trial information: NCT02416466. Citation Format: Steven C. Katz, Ethan Prince, Marissa Cunetta, Prajna Guha, Ashley Moody, Vincent Armenio, Li J. Wang, N. Joseph Espat, Richard P. Junghans. HITM-SIR: Phase Ib trial of CAR-T hepatic artery infusions and selective internal radiation therapy for liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT109. doi:10.1158/1538-7445.AM2017-CT109

The Role of Immunotherapy in Pancreatic Cancer

“…These results were promising for enhancing the cytotoxic activity of CAR T cells, specifically for tumor cells, while sparing off-tumor normal tissue targets. Early studies have also demonstrated the feasibility of improving local drug delivery to metastases through hepatic artery infusion of targeted CAR T cells [ 116 ]. Improving immunotherapy efficacy by combing T-cell therapies with novel immune-enhancing agents such as ICI, T-reg-depleting therapies, costimulatory molecules like rimiducid, peroxisome proliferator-activated receptor gamma ligands, tyrosine kinase inhibitors, and other drugs that regulate inflammation may also be worth further investigation [ 117 , 118 , 119 , 120 , 121 ].…”

The Landscape of CAR-T Cell Clinical Trials against Solid Tumors—A Comprehensive Overview

“…Sixteen clinical trials target several antigens at the same time [ 35 , 36 ], and two clinical trials do not disclose the targeted antigen ( Table 1 ). The top six targeted antigens that are expressed on solid tumors in many different organs are (1) EGFR [ 37 , 38 , 39 , 40 , 41 ] (14 different organs), (2) NKG2D-ligands [ 42 , 43 ] (11 different organs), (3) HER2 [ 12 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ] (11 different organs), (4) B7-H3 (10 different organs), (5) MUC1 (9 different organs), and (6) CEA [ 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ] (9 different organs) ( Table 1 ).…”

Chimeric Antigen Receptor-T Cells for Targeting Solid Tumors: Current Challenges and Existing Strategies

“…2 patients with no viable liver metastases by PET scan after treatment for up to 12 monthsMedian OS post-treatment was 8.3 months with a mean OS of 9.8 monthsNCT01373047HITMDelivered into the hepatic circulation + systemic IL-2Katz et al [127] n = 9. 1 SD, OS: 4.5 months with 1 patient still alive at 23 monthsNCT 02416466HITM-SIRHepatic artery infusions and yttrium-90 SIR-spheresResults presented at AACR 2017 [128] n = 6. 3 SD, median OS 6.9 months AACR American Association for Cancer Research, AFP α-fetoprotein, ASCO American Association of Clinical Oncology, CAR chimeric antigen receptor, CAR-T chimeric antigen receptor-T cell, CD cluster of differentiation, CEA carcinoembryonic antigen, CEA-CAM5 Carcinoembryonic antigen-related cell adhesion molecule 5, CMV cytomegalovirus, CR complete response, CyFlu non-myeloablative preconditioning chemotherapy composed of cyclophosphamide and fludarabine, EGFR epidermal growth factor receptor, EGFRvIII variant III of the epidermal growth factor receptor, ESMO European Society for Medical Oncology, GD2 disialoganglioside, GPC3 glypican 3, FOLFOX leucovorin [folinic acid], 5-fluorouracil, and oxaliplatin, FU follow-up, HCC hepatocellular carcinoma, HER2 human epidermal growth factor receptor 2, HLA human leukocyte antigen, HITM hepatic immunotherapy for metastases, HITM-SIR HITM with selective internal radiation therapy, HITM-SURE HITM with surefire infusion system, IL interleukin, IL-13Rα2 interleukin-13 receptor α2, IP intraperitoneal, IV intravenous, mCRC metastatic colorectal cancer, MR mixed response, MSKCC Memorial Sloan Kettering Cancer Center, MUC16 mucin 16, MyD88 myeloid differentiation primary response 88, OS overall survival, NKG2D natural killer group 2 member D, NSCLC non-small cell lung cancer, OR objective response, OVA ovarian cancer, PD-1 programmed death 1, PD-L1 programmed death-ligand 1, PET positron emission tomography, PFS progression-free survival, PR partial response, PSCA prostate stem cell antigen, ROR-1 receptor tyrosine kinase-like orphan receptor 1, scFv single-chain variable Fragment, SD stable disease, SITC Society for Immunotherapy of Cancer, Tcm central memory T cells, TCR T cell receptor, TME tumor microenvironment, TNBC triple-negative breast cancer…”