Targeting Metastatic Lung Tumors with Gene-Edited and Engineered Stem Cells
Abstract
Lung cancers are the second most common form of cancer in the United States with roughly about a 250,000 new cases each year. Non-small cell lung cancer (NSCLC) is an aggressive cancer and the 5-year relative survival rate for NSCLC patients in 25%. Owing to occupational exposure to agent orange, asbestos, diesel exhaust, etc., combined with an increased prevalence of tobacco exposure in active-duty military personnel and veterans, the risk of non-small cell lung cancer (NSCLC) is higher by 50% in these populations as compared to civilians. Despite considerable progress made in the management of advanced NSCLC over the past two decades, improvement in overall survival has been elusive, with brain metastases contributing to half of all NSCLC-related deaths. Brain metastatic-NSCLC (BMLC) tumors in the brain have multiple tumor deposits at the time of diagnosis making surgery an inadequate therapeutic option. In addition, conventional systematic therapies to treat NSCLC brain metastasis are ineffective mainly due to poor delivery of available drugs to the tumor deposits in the brain. Therefore, new therapies are urgently needed for patients with NSCLC brain metastasis. In the ongoing search for therapeutics that can eliminate metastatic tumor deposits, oncolytic viruses have shown great potential in preclinical studies. Among therapeutic viruses, oncolytic Herpes Simplex Virus (oHSV) is one of the most promising candidates for therapy of tumors in the brain as it is an inherently neurotropic virus. oHSV has shown promising efficacy in treating various types of cancers in several animal studies. This has led to the FDA approval for talimogene laherparepvec (T-VEC; recombinant oHSV) which has shown anti-tumor immune response for distant un-injected tumor lesions. Although these studies are promising for primary tumors, there are currently no oHSV based therapeutics/strategies focused on brain metastasis, which is the major cause for NSCLC-related mortality. In our previously published studies, we have shown that mesenchymal stem cell (MSC) mediated delivery of oHSV (MSC-oHSV) extensively targets brain metastasis and single application of MSC-OHSV has therapeutic efficacy in mouse models of brain metastasis. These results although promising, have raised fundamental question for our MSC-oHSV strategy to treat BMLCs: how to boost MSC-oHSV mediated oncolytic virus mediated tumor cell killing and how to boost the immune responses to prevent tumor recurrence? Our ongoing and recent studies on the (1) creation of an in vivo animal model that authentically reproduces tumor growth and tumor progression seen in NSCLC patients and (2) the ability of MSC to track tumors in the brain and to efficiently deliver oHSV and immune system promoting biological agents provide a unique platform to develop and test new therapeutic approaches for advanced melanomas. In this proposal, two underlying principles will be employed to develop therapies that will directly influence the future of advanced NSCLC metastatic tumors in the brain: (1) development of MSC releasing regulatable immunomodulators that selectively target metastatic NSCLC tumors in the brain and (2) testing their ability to only kill tumor cells specifically in the brain in mouse models. The specific aims of the proposed study are to evaluate the fate and therapeutic efficacy of MSC-oHSV and MSC releasing regulatable immunomodulators and immune check point inhibitor in syngeneic and humanized mouse BMLC tumor models. Once validated, these studies can be easily translated into clinics using patients own MSC or reprogrammed cells loaded with oHSV and engineered to release immunomodulators. In next 3-5 years, we envision a therapeutic modality in which at the time of lung metastatic tumor detection in the brain, therapeutic stem cells will be systemically injected into patients to target the metastatic tumor deposits. This will have a major impact in saving the lives of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310550
Entities
People
- Khalid Shah
Organizations
- United States Army