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This phase I study investigated the safety and activity of lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin (CART-meso) in patients with malignant pleural mesothelioma, ovarian carcinoma, and pancreatic ductal adenocarcinoma. Fifteen patients with chemotherapy-refractory cancer (n = 5 per indication) were treated with a single CART-meso cell infusion. CART-meso cells were engineered by lentiviral transduction with a construct composed of the anti-mesothelin single-chain variable fragment derived from the mouse monoclonal antibody SS1 fused to intracellular signaling domains of 4-1BB and CD3zeta. Patients received 1–3 × 10(7) or 1–3 × 10(8) CART-meso cells/m(2) with or without 1.5 g/m(2) cyclophosphamide. Lentiviral-transduced CART-meso cells were well tolerated; one dose-limiting toxicity (grade 4, sepsis) occurred at 1–3 × 10(7)/m(2) CART-meso without cyclophosphamide. The best overall response was stable disease (11/15 patients). CART-meso cells expanded in the blood and reached peak levels by days 6–14 but persisted transiently. Cyclophosphamide pre-treatment enhanced CART-meso expansion but did not improve persistence beyond 28 days. CART-meso DNA was detected in 7/10 tumor biopsies. Human anti-chimeric antibodies (HACA) were detected in the blood of 8/14 patients. CART-meso cells were well tolerated and expanded in the blood of all patients but showed limited clinical activity. Studies evaluating a fully human anti-mesothelin CAR are ongoing.

Pancreatic ductal adenocarcinoma (PDAC) is resistant to T-cell mediated immunotherapy. We engineered T cells to transiently express an mRNA encoding a chimeric antigen receptor (CAR) specific for mesothelin—a protein that is over-expressed by PDAC cells. We performed a phase 1 study to evaluate the safety and efficacy of adoptive cell therapy with autologous mesothelin-specific CAR T cells (CARTmeso cells) in 6 patients with chemotherapy-refractory metastatic PDAC. Patients were given intravenous CARTmeso cells 3 times weekly for 3 weeks. None of the patients developed cytokine release syndrome or neurologic symptoms and there were no dose limiting toxicities. Disease stabilized in 2 patients, with progression-free survival times of 3.8 and 5.4 months. We used FDG-positron emission tomography/computed tomography imaging to monitor the metabolic active volume (MAV) of individual tumor lesions. The total MAV remained stable in 3 patients and decreased by 69.2% in 1 patient with biopsy-proven mesothelin expression; in this patient, all liver lesions had a complete reduction in FDG uptake at 1 month compared to baseline, although there was no effect on the primary PDAC. Transient CAR expression was detected in patients’ blood after infusion and led to expansion of new immunoglobulin G proteins. Our results provide evidence for the potential anti-tumor activity of mRNA CARTmeso cells, as well as PDAC resistance to the immune response. Keywords: immune response heterogeneity, immune therapy, anti-tumor immunity, pancreatic cancer treatment

A phase I study to evaluate the safety and feasibility of an intravenous infusion of autologous T cells transduced to express a chimeric antigen receptor directed against mesothelin (CART-meso) in patients with mesothelin expressing tumors is being conducted at the University of Pennsylvania. Here we report on the first five patients treated with CART-meso T cell infusion. Five patients with recurrent advanced stage cancers (two serous ovarian, two epithelial mesothelioma, and one pancreatic) who had received 4-12 prior regimens, were treated with a single infusion of CART-meso cells. Apheresed autologous T cells were transduced with a lentiviral vector expressing the CAR construct composed of an extracellular anti-mesothelin single chain variable fragment derived from mouse monoclonal antibody (SS1) fused to the intracellular signaling domains of 4-1BB (CD137) and TCRzeta. Each patient received a single dose of 1-3 × 10^7 CART-meso cells/m2. No lymphodepletion with chemotherapy was given prior to infusion. All subjects enrolled were successfully infused and there were no acute adverse events (AE) with infusion. To date, Grade 4 AEs have included sepsis(1), anemia(1), pleural effusions(1), tachypnea(1), dyspnea(1), and aspiration(1) and Grade 3 AEs have included sepsis(1), leukocytosis(2), DIC(1), tachycardia(1), dyspnea(1), hypotension(1), dusky extremities(1), fatigue(1), ascites(1), peritonitis(1), elevated LFTs(1), portal vein hypertension(1), and acute kidney injury(1). After infusion, CART-meso T cells were transiently detectable by PCR in the peripheral blood in all patients up to Day 21-28 after infusion. CART-meso cells were found to traffic to tumor sites within the peritoneum and liver, as well as to off-tumor on-target sites such as pericardial fluid, but without clinical toxicity of pericarditis. Expansion of CART-meso cells was also observed in the pleural fluid of one patient who had a known malignant pleural effusion. Cytokine profiling of the peripheral blood revealed elevations of IL-6 and VEGF with significant elevations seen in the one patient with malignant pleural effusion. No elevations in TNFα or IFNγ were found. Anti-tumor efficacy is suggested by the clearing of malignant cells in the pleural fluid of one patient on Day 21 and Day 26 after infusion, as well as radiological and clinical evidence of stable to decreased burden of disease in one patient. Patient follow-up for 1-3 months post infusion has revealed no evidence of long-term toxicities to date. These interim results suggest that intravenous infusion of CART-meso T cells without lymphodepletion is feasible and safe. In these five patients with metastatic mesothelin expressing cancers, the infusion was well tolerated with no off-tumor on-target toxicities. Laboratory and clinical findings suggest infused T cells are effective and functional. Citation Format: Janos L. Tanyi, Andrew R. Haas, Gregory L. Beatty, Mark A. Morgan, Caitlin J. Stashwick, Mark H. O'Hara, David L. Porter, Marcela V. Maus, Bruce L. Levine, Simon F. Lacey, Anne Marie Nelson, Maureen McGarvey, Naseem DS Kerr, Gabriela Plesa, Carl H. June. Safety and feasibility of chimeric antigen receptor modified T cells directed against mesothelin (CART-meso) in patients with mesothelin expressing cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT105. doi:10.1158/1538-7445.AM2015-CT105