The outcomes of stage III non-small cell lung cancer seem to reach a plateau following two decades of clinical research by optimally combining cisplatin-based chemotherapy and thoracic radiotherapy. Escalation of radiotherapy dose failed to improve outcome as demonstrated by the recent RTOG 0617 trial. Frequent failures with systemic recurrence following concurrent chemoradiation contribute to disappointing cure rate of locally advanced lung cancer. Encouraging clinical data have come from recent immunotherapeutic trials. Moreover, combining radiotherapy with immunotherapy has yielded potentially synergistic systemic/abscopal (i.e. distant) effects. Molecular studies have pointed to a crucial role for immunomodulating B7-H1 or PDL-1/PD-1 pathway in the control of T cell activation and in maintaining immunotolerance induced by tumor cells. PDL-1, a ligand of PD-1 is over-expressed on human tumors from different tissue origins whereas PD-1 receptor is expressed in T cells to prevent T-cell overactivation in physiological conditions. In certain types of cancer, higher level of PDL-1 has been correlated with poor prognosis. Tumor-induced PDL-1 utilizes multiple mechanisms to evade host immune surveillance, including 1) promoting T cell anergy, exhaustion, unresponsiveness and apoptosis, 2) inducing the expansion of regulatory T cells, and 3) enhancing tumor therapeutic resistance. Four therapeutic biologics targeting the human PD-1 are currently in clinical trials, with promising results [1]. PD-1/PDL-1-blocking mAbs are being evaluated to treat various advanced cancers [2]. Recent reports on clinical trials using BMS-936558 (a PD-1 inhibitor) and BMS-936559 (a PDL-1 inhibitor) showed significant objective responses (18% among patients with non-small-cell lung cancers). The clinical response is also durable, suggesting immune memory. Tumor PDL-1 over-expression correlates with anti-tumor responses in a small patient cohort, suggesting that PDL-1 could be a potential biomarker for PD-1 inhibitors. Integrating PD-1 inhibitors into the standard chemoradiation regimens for locally advanced non-small cell lung cancer potentially breaks immune tolerance against lung cancer cells and synergistically activates T cells as cancer antigens are released following cytotoxic chemoradiation treatment. These immune responses may impact distant microscopic metastases, which are sources for treatment failures in this population of patients. We hypothesize PD-1 and PDL-1 modulate lung carcinogenesis and therapeutic response to chemotherapy and radiotherapy and combining PD-1/PDL-1 inhibitors with chemoradiation regimens improves therapeutic outcomes of lung cancer patients:
Aim 1 : Determine the role of PD-1 and PDL-1 in carcinogenesis and therapeutic response of lung cancer;
Aim 2 : Determine the efficacy and toxicities of combining PD-1 or PDL-1-blocking antibody and thoracic radiotherapy in an orthotopic mouse model of lung cancer. The proposed studies will help us to understand the role of PD-1 and PDL-1 in lung carcinogenesis and therapeutic response of lung cancer.

Public Health Relevance

In this proposal, we will investigate whether PD-1 and PDL-1 modulate lung carcinogenesis and determine how lung cancer responds to chemotherapy and radiotherapy in the presence or absence of PD-1 or PDL-1. The significance of this research is to gain understanding of lung cancer biology and develop novel therapeutic strategies to treat lung cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA178229-02
Application #
8706103
Study Section
Special Emphasis Panel (ZCA1-RTRB-Z (M1))
Program Officer
Bernhard, Eric J
Project Start
2013-08-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
$163,507
Indirect Cost
$58,019
Name
Thomas Jefferson University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Du, Shisuo; Lockamy, Virginia; Zhou, Lin et al. (2016) Stereotactic Body Radiation Therapy Delivery in a Genetically Engineered Mouse Model of Lung Cancer. Int J Radiat Oncol Biol Phys 96:529-37