Tumor-Specific Th1/Th17 Hybrid Immunotherapy against Established Melanoma
Abstract
Melanoma, skin cancer, is the seventh most common cancer in the United States and approximately 9,940 people will die in 2015 from this cancer as reported by the American Cancer Society. Moreover, new cases in the United States are rising every year, with 73,870 new cases diagnosed in 2015. These numbers urge us to find new effective treatments for this deadly cancer type. The advanced metastatic melanoma is difficult to treat because the malignant cells have metastasized into other organs, and these late stages of the disease often have low survival rates. Chemotherapy, drug, and other immunotherapy are often associated with toxicity and side effects. Thus, adoptive T cell therapy is an alternative approach to treat advanced melanoma and has been demonstrated to have great potential for melanoma treatment. This technology is to exploit patient s existing immune system by isolating specific T cell subset, manipulating cells to target specific tumor as well as expanding these cells ex vivo and later infused back into the patient. Despite the success of adoptive T cell therapy, some patients still fail to respond to the therapy. This could due to the low efficacy and quality of transferred T cells. The ex vivo expanded T cells are often terminally differentiated cells, close to exhaustion, which leads to limited lifespan after adoptive transfer. Current studies are trying to identify more effective T cell subsets or optimize T cell expansion conditions in order to obtain the highest T cell efficacy. In our study, we generated a novel T cell for adoptive therapy so called "hybrid cell (Th1/Th17)." The cells have combined characteristics of T helper-1 or Th1 and Th17, which both are CD4+ T cell subsets. The concept is based on previous studies that demonstrated that Th1 cells possess strong anti-tumor function; however, the cells have limited lifespan due to their terminally differentiated status. On the other hand, Th17 is long-lived and has the ability to better eradicate melanoma tumor than Th1. However, Th17 loses its phenotype in vivo by converting into Th1 cells in order to fight against tumor. We hypothesize that the combine properties of these two subsets may enhance anti-tumor immunity. Thus, we tested our hypothesis in a clinically relevant mouse model bearing melanoma tumor. After adoptive transfer of different T cell subsets (Th1, Th17, and hybrid Th1/Th17), our result has clearly demonstrated that hybrid Th1/Th17 has the highest efficacy in tumor control in which 100% of mice survived from tumor challenge whereas the survival percentage in Th17 group is only accounted for 25%. Moreover, tumor-bearing mice that receive Th1 cells all succumb to tumor relapse as observed in previous studies. The mechanism underlying how hybrid cells augmented stronger tumor immunity than other Th subsets is currently being investigated. Our data suggested that hybrid cells could be a potential candidate for adoptive T cell therapy. In this proposal, we aim to investigate the extensive properties of hybrid cells in regards to their persistency in vivo, memory phenotype, stem cell-like phenotype and their cytotoxic function in tumor eradication. A deeper study into the cellular mechanism will allow us to understand the differences between hybrid cells and well-characterized Th1 and Th17 subsets. Moreover, we aim to test hybrid cells generated from human cells and evaluate them in a xenograft tumor model, which will recapitulate the efficacy of hybrid cells in human system. This study will take approximately 1 year to achieve a clinically relevant outcome in a xenograft tumor model. The validation of hybrid cells will mimic the potential of these cells for treatment of melanoma patients. Moreover, the study may benefit us in applying the hybrid cells against other types of metastatic cancer. The development of hybrid cells into the clinic will benefit greatly patients with advanced metastatic melanoma in wh
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610273
Entities
People
- Anusara Daenthanasanmak
Organizations
- Medical University of South Carolina
- United States Army