For this project we propose to assess the utility of cell therapies for delivering the anti-cancer cytokines and chemokines in the context of non-small cell lung cancer models. Lung cancer is the leading cause of cancer related death in the Veteran population and metastasis is a major contributing factor to recurrence and mortality associated with non-small cell lung cancer.
Aim 1 will take advantage TRAIL, a cytokine which induces apoptosis in cancer cells that is currently being evaluated as a therapeutic modality for treating lung cancer in ongoing clinical trials. For this project, antigen specific T cells transposon engineered to express high levels of soluble leucine zipper modified TRAIL will be adoptively transferred using a protocol that facilitates stable long term engraftment. The toxicity and off target effects of TRAIL cell therapy will first be assessed in healthy mice. We will then take advantage syngeneic orthotopic models of non- small cell lung cancer to evaluate the ability of TRAIL cell therapy to block metastasis. Combination cell therapy with acetylsalicylic acid will be assessed as a method of enhancing cancer cell sensitivity to TRAIL induced apoptosis and other candidate molecules that could be used in TRAIL combination therapy will be evaluated using a GFP based apoptosis screen.
Aim 2 will evaluate the hypothesis that a cell therapy delivering the chemokine CCL5 in combination with TRAIL directly to tumors will augment immune-mediated tumor rejection.
In Aim 3 we will determine if CCL5-TRAIL combination therapy blocks cancer progression and enhances survival in a murine orthotopic NSCLC model. This project represents a unique opportunity to examine the utility of delivering anticancer peptides with a cell therapy platform in the context of an immune competent mouse model of NSCLC. These studies will be useful in determining the efficacy of chronic systemic TRAIL therapy and tumor targeted CCL5/TRAIL combination therapy for blocking progression of lung cancer and augmenting tumor rejection.
This project aims to evaluate the utility of a two novel cell therapy platforms for eliminating metastasis and blocking cancer progression in syngeneic models of non-small cell lung cancer. We will take advantage of a transposon based approach to engineer cells for chronic systemic delivery of anti-cancer peptides for blocking metastasis and tumor targeted anti-cancer peptides for augmenting tumor immune rejection.
