Targeting CA19-9 with High-Specificity CAR-T Cells for Pancreatic Cancer

Chimeric antigen receptor (CAR) T cell therapy targeting CA19-9, an antigen over-expressed in several cancers, including 80-90% of pancreatic cancers.
Problem:
Pancreatic cancer is one of the deadliest common cancers and is now the sixth leading cause of cancer deaths worldwide, underscoring the need for better treatment options. One promising option is CAR-T cell therapy, which has revolutionized the treatment of blood cancers. It utilizes T cells engineered to express CARs that recognize tumor-associated antigens on cancer cells, enabling targeted tumor elimination. However, CAR-T cell therapy’s success in solid tumors like pancreatic cancers remains limited. Key challenges include the uneven expression of most tumor antigens across cancer cells and shared antigen expression with normal tissues, which hinders precise targeting and reduces the effectiveness of tumor elimination by CAR-T cells.
Solution:
CA19-9 is a glycan epitope that potentially drives tumor development in pancreatic cancer. It is over-expressed in 80–90% of pancreatic tumors and in some colorectal, lung, and gallbladder cancers, while being minimally expressed in normal tissues. The inventors developed CA19-9 targeting CAR-T cells that selectively kill CA19-9 positive pancreatic cancer cells with high specificity, offering a promising treatment for CA19-9 expressing tumors.
Technology:
The inventors generated twenty-two CA19-9-targeting CAR-T cell variants, expressing different CAR constructs, that killed CA19 9-positive pancreatic cancer cells with high specificity in vitro. Via in vitro assays and in vivo mouse xenograft models, the inventors determined that CAR-T cells expressing the high-affinity AbLIFT15.28z construct (AbLIFT15.28z-CAR-T cells) displayed the strongest anti-tumor activity. In mice modeling the human pancreatic tumor environment, AbLIFT15.28z-CAR-T cells significantly reduced tumor size and improved survival in both primary and metastatic settings. They also killed six CA19 9-positive gastrointestinal cancer cell lines in vitro and controlled tumor growth across in vivo models of colon, cholangiocarcinoma, gastric, and esophageal cancers.
Advantages:

Complete in vitro killing of CA19-9⁺ tumor cells
High target specificity with minimal/no off-target cytotoxicity
Eliminated CA19-9⁺ pancreatic tumors in xenograft models
2× median survival in orthotopic pancreatic cancer model
>6× median survival in lung metastasis model; 75% survival >250 days
Broad CA19-9⁺ GI cancer activity across pancreatic, colorectal, gastric, cholangiocarcinoma, and esophageal models

Stage of Development:

Preclinical Discovery

Human PDAC cell lines were orthotopically implanted into the pancreas of NSG mice and allowed to grow for 2-3 weeks. Then, the mice were treated with one dose of either non-transduced control or CA19-9 CAR expressing T cells (left panels). In both the SW1990-EV and Capan2-EV models, CAR T cell-treated animals lacked visible tumors at week 2 or week 3 after T cell infusion, whereas mice receiving control T cells all had detectable tumors (middle panels). Accordingly, mice receiving CA19-9 CAR T cells had significantly prolonged survival compared to control T cell-treated mice (right panels). Ctrl T, non-transduced human T cells; CAR T, human CA19-9 CAR T cells.
Intellectual Property: