Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is resistant to T-cell-mediated immunotherapy. We engineered T cells to transiently express a messenger RNA encoding a chimeric antigen receptor (CAR) specific for mesothelin, a protein that is overexpressed by PDAC cells. We performed a phase I 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 ¹⁸F-2-fluoro-2-deoxy-D-glucose (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 with 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 antitumor activity of messenger RNA CARTmeso cells, as well as PDAC resistance to the immune response.

Keywords: Antitumor Immunity; Immune Response Heterogeneity; Immune Therapy; Pancreatic Cancer Treatment.

Figure 1. Clinical responses

(A) Baseline patient demographics. (B) Swimmer plot showing patient outcomes. Percent change at 1 month relative to baseline in (C) total MAV and (D) SUV_max for tumor lesions detected using FDG-PET/CT imaging. (E) Sequential coronal maximum intensity projection PET images and (F) sequential unenhanced CT and FDG-PET images for patient 08212-113. In (E), red and yellow arrows indicate liver and primary pancreatic lesions, respectively. In (F), yellow arrows mark a representative liver lesion.

Figure 2. Pharmacodynamic analyses

(A) RT-qPCR analysis to detect CAR expression in whole blood after CARTmeso cell infusion. (B) Longitudinal measurements of serum soluble factors after CARTmeso cell infusion. (C) Differentially recognized proteins detected by self-reactive IgG antibodies in the serum of each patient at 1-2 months after CARTmeso cell infusion compared to baseline. (D) Representative images of H&E staining (40x) and IHC staining to detect CD3 (20x) and mesothelin (40x) expression in metastatic liver lesions analyzed from patient 08212-108 and 08212-113. Red arrowheads indicate malignant cells adjacent to CD3⁺ cells.