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 F-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.

Research progress and design optimization of CAR‐T therapy for pancreatic ductal adenocarcinoma

“…After CAR-T treatment (three times a week for 3 weeks), two patients achieved progression-free survival of 3.8 and 5.4 months. 27 Metabolic activity (MAV) in tumors assessed by metabolic imaging (F18-FDG) remained stable in three patients, while MAV of tumor decreased by 68.3% in another patient whose liver metastases completely disappeared. In addition, no cytokine storm effects or other CAR-T-related side effects were found in any of the patients.…”

“…A phase I clinical trial involving six patients with advanced pancreatic cancer resistant to chemotherapy showed encouraging results. After CAR‐T treatment (three times a week for 3 weeks), two patients achieved progression‐free survival of 3.8 and 5.4 months . Metabolic activity (MAV) in tumors assessed by metabolic imaging (F18‐FDG) remained stable in three patients, while MAV of tumor decreased by 68.3% in another patient whose liver metastases completely disappeared.…”

“…In addition, no cytokine storm effects or other CAR-T-related side effects were found in any of the patients. 27…”

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…Furthermore, high tumor heterogeneity can facilitate antigen escape and in vivo CAR T cells expansion is significantly less pronounced than in patients with hematologic malignancies (103,104). In order to prevent potentially lethal toxicities, safety switch strategies are being tested (98) and the University of Pennsylvania group demonstrated the feasibility, although with limited efficacy, of administering mRNA electroporated mesothelin-specific CAR T cells in pancreatic adenocarcinoma patients (105). Other groups are exploring the possibility of local delivery, to enhance tumor killing and to reduce toxicity.…”

Immunobiology of chimeric antigen receptor T cells and novel designs

“…[18][19][20][21] While not yet as mature, promise has also been seen in the development of CAR T cell therapies for myeloid leukemias, refractory Hodgkin lymphoma, glioblastoma, metastatic pancreatic cancer, and neuroblastoma. [22][23][24][25][26][27][28] Despite the clinical success and promise of CAR T cell therapy in the treatment of refractory malignancies, relapse after CAR T cell therapy has arisen as a major obstacle to the overall effectiveness of CAR T cells as a standalone therapy. As the clinical experience with CAR T cells has matured, it has become apparent that a significant number of patients who initially achieve remission will experience a relapse of their primary cancer after CAR T cell therapy.…”