Development and Preclinical Applications of Pancreatic Adenocarcinoma Models

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

CAPR advanced its collaborative research with Dr. Rosie Kaplan's laboratory at the CCR Pediatric Oncology Branch to investigate genetically modified myeloid (GEMy) and mesenchymal (GEMesy) cell therapies in our KPC mouse models of pancreatic cancer. Both types of cell-based therapeutics have been designed to target PDAC tumor tissues and either facilitate the host immune response against malignant tissue (by functionalizing GEMys cells with an IL12 cytokine-expressing transgene), or alleviate the low patency and drug accessibility in highly desmoplastic stroma-rich pancreatic cancerous tissues (by engineering GEMesys cells to produce a proteolytically active against extracellular matrix hyaluronidase). Several experiments have been completed to initially evaluate the distribution of the engineered cells in vivo, in pancreatic tumor-bearing animals. Homing to the primary tumor has been demonstrated for both types of cells. Follow up experiments will test homing of GEMesys to metastatic sites (such as lung and liver). In parallel, we are currently completing the first-in-class efficacy experiment with therapeutic GEMesy cells in KPC mice with established tumors. In another joint effort with intramural laboratory led by Dr. Ira Pastan, CAPR pancreatic team researchers established a collection of PDAC patient-derived models and evaluated clinical xenograft tissues at various passages in vivo by mesothelin (MSLN)-specific immunostaining. Two models displaying detectable and consistent level of MSLN expression have been employed to demonstrate preclinical potency of novel CAR-T cytotoxic TILs constructed to recognize the per-membrane fragment of MSLN polypeptide that remains tethered to cancer cell membrane upon proteolytic cleavage of MSLN ectodomain. Upon comparison of these novel CAR-T cells with previously characterized CAR-T's recognizing the N-terminal MSLN epitope, a remarkable enhancement of antitumor activity has been demonstrated for the former CAR-T's. The higher anti-cancer potency of CAR-T cells specific for the peri-membrane site correlated with preferential distribution of these cells to the tumor tissue within 4 days post-inoculation, while the cells have been also shown to retain their proliferative capacity in vivo. These experiments unambiguously confirmed differential potency of CAR-T cells specific for one and the same target protein but recognizing two distinct target's epitopes - observations that will be both informative and influential in guiding subsequent clinical trials using CAR-T therapeutics. Studies of CAR-T cell biodistribution, tumor homing and anti-cancer potency have been largely completed and recently submitted for joint publication.