Lung cell transplantation for drug induced pulmonary fibrosis in cancer patients

About This Grant

Project Summary/ Abstract Chemotherapy-induced pulmonary fibrosis (PF) represents a major challenge in the treatment of cancer patients. Drugs that are most associated with PF development include bleomycin (BLM), methotrexate and oxaliplatin. Despite the emergence of novel compounds for the symptomatic treatment of PF, lung transplantation remains the only "curative" option, albeit with a low 5-year mean survival rate following transplantation. Furthermore, due to co-morbidities or concern for cancer relapse, many patients do not qualify for lung transplantation, and many that are qualified die while on the waiting list. This highlights the urgent need for novel therapies, with special emphasis on emerging approaches for transplantation of lung stem cells. We propose a simple and robust approach for lung regeneration by lung cell transplantation, based on our extensive proof-of-concept studies in two distinct mouse models of lung fibrosis, including the more relevant BLM mouse model, which demonstrate that a simple i.v infusion of lung single cell suspension, leads to robust engraftment of donor-derived alveolar and endothelial cells, reduces the progression of fibrosis, and improves lung function. Our data have led to the formation of a new company (Lungevia Bio Inc.) which will form a strategic partnership with the PI , aiming at developing the final pre-clinical data required for attaining CMC and an IND from the FDA for a first-in-human clinical trial in cancer patients with chemotherapy-induced lung fibrosis (Aim 1). Considering that this approach is based on transplantation of MHC disparate cadaveric lung cells requiring chronic immune suppression, and based on our Preliminary Results, further experiments in the BLM mouse model will interrogate the possibility that infusion of allogeneic lung cells with bone marrow cells from the same donor could induce immune tolerance towards donor antigens and allow cession of immune suppression (Aim 2). The proposed studies require vertebrate animals because the mechanisms of lung remodeling, pulmonary function, and stem cell engraftment can only be evaluated in the context of an intact living organism. Mice were selected because they are well-characterized vertebrate models that enable precise investigation of gene function and therapeutic interventions. Furthermore, treatment of mice with bleomycin induces pulmonary fibrosis similarly to that found in cancer patients treated with different chemotherapy agents .These studies cannot be adequately performed using in vitro systems, which do not replicate the complex cellular interactions and physiological responses of the whole lung. Once proof-of-concept studies in Aim 2 are completed, the procedure for harvesting a combined cadaveric lung and bone marrow cell product will be optimized and tested in immune deficient mice for toxicity (Aim 3). At project completion, Lungevia Bio, Inc., will support planned subsequent Phase 1 and Phase 2 clinical trials based on the results of the proposed specific aims. If successful, this project may lead to new therapeutic options for cancer patients that develop pulmonary fibrosis as a consequence of chemotherapy.