Unbiased Microfluidics-Based Isolation of Antigen-Specific T Cells in Non-Small Cell Lung Cancer
Abstract
Immunotherapy has revolutionized the treatment of lung cancer by stimulating immune cells to recognize and destroy tumors, contrary to traditional approaches which seek to directly kill tumors. T cells, the major type of killer immune cell, directly seek out and destroy tumor cells based on antigens displayed at their surface which distinguish them from healthy cells, making the interaction between T cells and tumor antigens the cornerstone of immunotherapy. Despite its importance, our understanding of which T cells recognize and kill tumors remains problematic, limiting our ability to improve upon existing survival rates. Therefore, there is a critical need to better identify the T cells which kill tumors. Although numerous approaches have attempted to elucidate this question, most rely on pre-selection of tumor antigens, which is an imperfect science and results in ~1% success rates. Moreover, these methods rely on numerous challenging, costly and time-consuming steps. Our proposal seeks to develop our novel method, which we have called ATTACH, in order to rapidly, directly, and inexpensively isolate only the T cells which recognize tumor antigens in patients with lung cancer. By developing ATTACH, we seek to identify the best T cells for each patient on a personalized basis in a matter of hours rather than months as is required by competing approaches. Our proposal addresses the following LCRP Areas of Emphasis to identify innovative strategies for the treatment of lung cancer: Identify innovative strategies for the prevention of recurrence or of metastases from lung cancer, (2) develop or optimize prognostic or predictive markers to assist with therapeutic decision-making, and (3) understand mechanisms of resistance to treatment (primary and secondary) by developing a novel streamlined approach for personalized T cell isolation which can directly contribute to each of these areas. Our proposal is initially targeted towards lung cancer patients, considering their high number of potential antigens, high infiltration of irrelevant T cells due to inflammation in the lungs, and urgent need to clearly identify T cell/tumor antigen pairs in this predominant patient population. However, our approach is cancer-type agnostic and could subsequently be applied to patients with other types of cancer or potentially even to other disease contexts including autoimmune disease. By proving the benefits of our approach in the challenging context of non-small cell lung cancer, we will demonstrate our concept and promote its application to other disease settings. Our approach is flexible and could result in numerous applications which would benefit patients with lung cancer, other cancer types and even other diseases. First, by rapidly identifying and enriching the most-relevant T cells in each patient, we could improve upon current therapies by treating patients with a highly personalized and optimized T cell product. Second, our ability to rapidly identify the most important T cells in each patient could allow us to predict clinical outcomes and refine current predictive biomarkers. Third, our approach could allow us to identify novel therapeutic targets, by efficiently identifying only cancer-relevant T cells and characterizing them. Most importantly, our approach will allow scientists and clinicians to save time and money, making these advances accessible to centers and hospitals around the nation and even the world. We anticipate that upon completion of this proposal, we will be in an ideal position to rapidly initiate the development of the clinical and translational applications listed above. Our approach is highly relevant to military members who are exposed to higher levels of carcinogens and mutagens and smoke tobacco at rates 50% higher than the general population. Military members may therefore harbor tumors with higher numbers of mutations and higher levels of inflammation, which significantly complic
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311021
Entities
People
- Alexandre Reuben
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army