Pancreatic cancer, the fourth leading cause of cancer mortality in the U.S., is resistant to all standard therapies (overall 5-year survival rate, 5%), highlighting the need for novel treatments. T cells have the capacity to actively infiltrate fibrotic tissue, and adoptively transferred, in v/Y/'o-expanded cytotoxic T lymphocytes (CTLs) targeting tumor-associated antigens can effectively traffic to distant tumor sites, infiltrate even bulky tumor masses and eradicate disseminated tumor cells in a range of malignancies, including Hodgkin lymphoma, nasopharyngeal carcinoma, neuroblastoma and melanoma. Whether this therapy can be successfully extended to the treatment of patients with pancreatic cancer will likely depend on the development of strategies to ensure tumor specificity and circumvention of the adverse effects of the tumor microenvironment, which limits the in vivo persistence and function of the transferred T cells. In this new Project 2 { A. Leen and W. Fisher) will generate cytotoxic T lymphocyte (CTL) lines that target mesothelin (MSLN), a glycoprotein overexpressed in 80-90% of pancreatic carcinomas and containing epitopes recognized by T cells. These cells will then be engineered to express a novel chimeric cytokine receptor (IL4/7R) that should allow them to resist the tumor microenvironment by inverting the function of the immunoinhibitory cytokine IL4 to transmit an immunostimulatory signal that will sustain the expansion and cytolytic function of the infused cells (Aim 1). This strategy, to be tested in a phase I clinical trial in patients with advanced pancreatic cancer (Aims 2 and 3) should safely ensure the sustained function of tumor-targeted T cells in vivo, even in the immunosuppressive tumor microenvironment, and enhance the potency of adoptively transferred T cells. Engineering mesothelin-specific T cells to express a chimeric cytokine receptor that binds the abundant Th2 cytokine IL4, while maintaining a Thi effector phenotype and cytotoxic function, represents a novel achievement in the field, one that may well advance treatment for this devastating tumor. Our project could potentially make use of the icaspQ safety gene developed by Project 1 and the CAR targeting CAF that Project 4 is developing and can provide additional means of enhancing anti-tumor activity to all projects in the program.

Public Health Relevance

Few other solid tumors carry the dire prognosis of pancreatic cancer. To meet the urgent need for useful treatment of this malignancy, investigators in this project have engineered a chimeric cytokine receptor that will both stimulate the expansion and persistence of the modified tumor-directed T cells, as well as protect them from the adverse effects of the surrounding microenvironment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (O1))
Program Officer
Merritt, William D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
United States
Zip Code
Rouce, Rayne H; Heslop, Helen E (2016) Forecasting Cytokine Storms with New Predictive Biomarkers. Cancer Discov 6:579-80
Yagyu, Shigeki; Hoyos, Valentina; Del Bufalo, Francesca et al. (2016) Multiple mechanisms determine the sensitivity of human-induced pluripotent stem cells to the inducible caspase-9 safety switch. Mol Ther Methods Clin Dev 3:16003
Bollard, Catherine M; Heslop, Helen E (2016) T cells for viral infections after allogeneic hematopoietic stem cell transplant. Blood 127:3331-40
Rouce, Rayne H; Sharma, Sandhya; Huynh, Mai et al. (2016) Recent advances in T-cell immunotherapy for haematological malignancies. Br J Haematol :
Ramos, Carlos A; Heslop, Helen E; Brenner, Malcolm K (2016) CAR-T Cell Therapy for Lymphoma. Annu Rev Med 67:165-83
Hegde, Meenakshi; Mukherjee, Malini; Grada, Zakaria et al. (2016) Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J Clin Invest 126:3036-52
DeRenzo, Christopher; Gottschalk, Stephen (2016) Genetically Modified T-cell Therapy for the Treatment of Osteosarcoma: An Update. J Clin Cell Immunol 7:
Zhou, Xiaoou; Naik, Swati; Dakhova, Olga et al. (2016) Serial Activation of the Inducible Caspase 9 Safety Switch After Human Stem Cell Transplantation. Mol Ther 24:823-31
Naik, Swati; Nicholas, Sarah K; Martinez, Caridad A et al. (2016) Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes. J Allergy Clin Immunol 137:1498-1505.e1
Chang, Edmund C; Liu, Hao; West, John A et al. (2016) Clonal Dynamics In Vivo of Virus Integration Sites of T Cells Expressing a Safety Switch. Mol Ther 24:736-45

Showing the most recent 10 out of 189 publications