Stem Cell-Mediated Targeted Therapies for Metastatic Melanomas
Abstract
Skin cancers are the most common form of cancer in the United States with roughly about a million new cases each year. Melanoma is an aggressive skin cancer and approximately 87,110 patients have been diagnosed in 2017 with melanoma in the United States, accounting for an estimated 9,730 deaths. Ultraviolet radiation from the sun is the major risk factor for melanoma and hence, individuals with high sun exposure and especially with light skin tones possess a higher risk of melanoma. Despite considerable progress made in the management of advanced melanoma over the past two decades, improvement in overall survival has been elusive, with brain metastases contributing to half of all melanoma-related deaths. Metastatic-melanoma 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 melanoma 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 melanoma 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, especially advanced melanomas in several animal studies. This has led to the U.S. Food and Drug Administration 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 melanomas, there are currently no oHSV based therapeutics/strategies focused on melanoma brain metastasis, which is the major cause for melanoma-related mortality. In our recently published studies (supported by Department of Defense Idea Award), we have shown that mesenchymal stem cell (MSC) mediated delivery of oHSV (MSC-oHSV) via intracarotid artery (ICA) extensively targets BMM and single application of MSC-OHSV has therapeutic efficacy in mouse models of BMM. These results, although promising, have raised fundamental question for our MSC-oHSV strategy to treat BMMs: 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 metastatic progression seen in melanoma patients; and (2) the ability of MSC to home to melanoma 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 melanoma metastatic tumors in the brain: development of MSC releasing regulatable immunomodulators that selectively target metastatic melanoma tumors in the brain; and 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 BMM 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 to 5 years, we envision a therapeutic modality in which, at the time of metastatic tumor detection in the brain, therapeutic stem cells will be systemically injected into patients to target the metastatic t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910517
Entities
People
- Khalid Shah
Organizations
- Brigham and Women's Hospital
- United States Army