This project describes a 5 year training program for a career as a Physician-Scientist with the long term goal of establishing a research program within the field of thoracic and pleural oncology. The applicant has finished a fellowship in Pulmonary, Allergy, and Critical Care Medicine at the University of Pennsylvania. He is currently conducting research in adoptive T cell immunotherapy for malignant pleural mesothelioma (MPM), a deadly asbestos-related pleural malignancy for which treatment options remain limited. The research focus of this proposal is to enhance the anti-tumor effect of chimeric antibody receptor (CAR)-based T cell immunotherapy. The central hypothesis of the proposal is that CAR T cell therapy for MPM can be significantly enhanced by improving T cell trafficking, inhibiting tumor microenvironment immunosuppression, and making T cells more resilient to tumor induced functional inhibition.
In Specific Aim 1, CAR T cells will be genetically modified to express chemokine receptors appropriate for the chemokines secreted by MPM tumor in attempt to augment T cell trafficking to tumor.
In Specific Aim 2, T cell signaling molecules/domains known to inhibit T cell activation will be genetically inactivated in order to increase T cell resilience to tumor-induced inactivation.
In Specific Aim 3, using two complementary mouse models of CAR T cell immunotherapy, established inhibitory mediators secreted into the tumor microenvironment that allow evasion of immunity will be inhibited in attempts to augment T cell anti-tumor efficacy. The training component of this proposal includes formal coursework, participation in a rich environment of post-doctoral lectures and seminars in thoracic/pleural oncology, acquisition of advanced laboratory techniques, and individual mentoring. This project will take place under the supervision of Dr. Steven Albelda who is the Director of Lung Research and the Thoracic Oncology Laboratory at the University of Pennsylvania;and Dr. Carl June who is the Director of Translational Research at the Abramson Cancer Center at Penn. Dr. Albelda and Dr. June have mentored over 100 trainees. In addition, an advisory committee of distinguished scientists will provide experimental assistance, intellectual guidance, and career advice throughout the duration of this award.

Public Health Relevance

Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy caused by exposure to asbestos. The incidence worldwide is increasing and will peak within the next decade. Prognosis is dismal (6-18 months of median survival) because current multimodality treatment strategies are minimally effective. The main goal of this study is to investigate ways to engineer a person's own lymphocytes to attack their tumor by genetically inserting an activation receptor targeted to mesothelioma tumor cells (called adoptive T cell therapy using chimeric antibody receptors). This approach has shown dramatic effects in other malignancies. The knowledge derived from this proposal will provide insight into mechanisms of immune evasion and treatment resistance, and hopefully lead to a safe, viable, and effective therapeutic option for MPM and other tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08CA163941-01
Application #
8225814
Study Section
Subcommittee G - Education (NCI)
Program Officer
Perkins, Susan N
Project Start
2012-08-07
Project End
2017-07-31
Budget Start
2012-08-07
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$173,772
Indirect Cost
$12,872
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Moon, Edmund K; Wang, Liang-Chuan; Dolfi, Douglas V et al. (2014) Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin Cancer Res 20:4262-73
Riese, Matthew J; Wang, Liang-Chuan S; Moon, Edmund K et al. (2013) Enhanced effector responses in activated CD8+ T cells deficient in diacylglycerol kinases. Cancer Res 73:3566-77
Predina, Jarrod; Eruslanov, Evgeniy; Judy, Brendan et al. (2013) Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery. Proc Natl Acad Sci U S A 110:E415-24