In this project, Dr. Reuben and colleagues aim to develop a novel therapeutic strategy harnessing immune response in EGFR-mutant NSCLC. He will use engineered T cells with receptors targeting EGFR antigens to eradicate drug-tolerant persister (DTP) cells, preventing the emergence of resistance following treatment by osimertinib. This work lays the foundation for use of TCR-engineered T cells in treating patients with EGFR mutations.
Research Summary
Although targeted therapies are extremely effective in destroying tumors, they inevitably leave behind a few cancer cells which persist. These are the cells which eventually become resistant to therapy and lead to the death of patients. Although checkpoint blockade immunotherapy has been largely unsuccessful in EGFR-mutant tumors, immunotherapy via cell therapy may offer promise in this setting. EGFR mutations can give rise to short peptides at the surface of tumor cells, called antigens, which allow the immune system to distinguish tumors from their normal counterparts and to specifically destroy them. Importantly, we have identified several antigens that are found solely on or enriched within EGFR-mutant tumors persisting following treatment with EGFR targeted therapies such as osimertinib/Tagrisso. As a result, we have developed a library of receptors which can be engineered into immune cells to allow their direct recognition and destruction of persisting EGFR-mutant cancer cells on the basis of the unique antigens they display. Here, we propose to test a novel approach to eradicate these EGFR-mutant drug persister cells by treating them with engineered immune cells to eliminate the last remaining persister cell and prevent the emergence of resistance following exposure to osimertinib. Our proposal includes two aims: Aim 1 will focus on determining the impact of EGFR-mutant persister cells on the function of immune cells and on their ability to recognize and kill tumor cells. Aim 2 will focus on assessing the ability of receptor- engineered immune cells to eliminate EGFR persister cells when combined with EGFR targeted therapy in vitro and in vivo.
Together, these aims will allow us to determine the therapeutic potential of this novel treatment strategy approach. Our proposal is highly translational, as we have entered into a partnership with Alaunos Therapeutics, a cellular therapy company performing a clinical trial using engineered immune cells at MD Anderson which could facilitate our ability to move these findings into the clinic. Due to the prevalence of the antigens we are targeting (one of which is found in ~90% of lung cancer patients), our approach could extend to almost all patients harboring EGFR mutations.