In this project, Dr. Chiarle and his team will generate T cells that have engineered receptors, called TCR receptors (TCR-T cells), that will selectively target and attack the ALK protein that is expressed by tumor cells. Generation of such cells could be a powerful tool to eradicate ALK+ lung cancer cells and form the basis of a TCR-T cell-based clinical trial for patients with TKI-resistant ALK+ NSCLC.
Research Summary
Patients with an ALK-positive lung cancer are typically young. For these patients several oral ALK inhibitors are available as pills, typically alectinib, lorlatinib, and brigatinib. These ALK inhibitors are very effective and well tolerated and most patients respond for long time. However, tumors may progressively develop resistance and start to grow back. In this setting of relapsing disease, few therapeutic options are left because most patients with ALK-positive lung cancer do not respond to existing immunotherapies.
For several years, we have been working to develop immunotherapy tools specifically for patients with ALK-positive lung cancer. In this proposal, the strategy is to re-engineer patients’ naturally occurring immune cells to target ALK selectively expressed by tumor cells. First, we will discover several receptors (TCRs) that T lymphocytes use to recognize ALK and kill tumor cells. Next, we will re-introduce these TCRs into the T lymphocytes to rapidly generate a large pool of killer cells all directed simultaneous against the tumor. The rapid infusion of a large number of TCR-engineered T lymphocytes, called TCR-T cells, will generate a wave of killing toward which the tumor will not have the time to adapt and escape. While the identification of ALK specific TCR might be difficult and elusive, we already discovered a series of very specific TCRs directed against ALK expressed by ALK-positive tumors in mice. Leveraging the discovery of ALK peptides expressed by human tumor cells, we will now discover specific TCRs that recognize ALK in human lung cancer. We will use these TCR-T cells to cure ALK-positive human tumors in combination with ALK inhibitors. We expect that this combination will be extremely powerful to rapidly eradicate tumor cells in the lung as well as in metastatic sites.
Technical Summary
About 5-7% of non-small cell lung cancers (NSCLCs) have a rearrangement of the anaplastic lymphoma kinase (ALK) gene. ALK-rearranged NSCLC is typically treated with ALK tyrosine kinase inhibitors (TKIs), but no effective immunotherapies are available for refractory or relapsed tumors. In previous work, we have shown that ALK is an immunogenic oncoprotein that induces specific T cell responses with potent killing activity against ALK+ tumor cells in the lung and in distant metastatic sites, such as the brain. Thus, the lack of efficacy of standard immunotherapy in ALK+ NSCLC can be bypassed by the development of tools to induce ALK-specific T cell responses. Our central hypothesis is that the generation of T cells engineered to express TCRs (TCR-T cells) that selectively target ALK+ NSCLC will be a powerful tool to completely eradicate ALK+ lung cancer cells.
In preliminary experiments, we have shown the feasibility of the cloning of ALK-specific TCRs against an ALK peptide expressed by a mouse model of ALK+ lung cancer. In Aim 1, we will test the potency, the safety and the in vivo efficacy of ALK-specific TCR-T cells obtained by T cells engineered to express TCRs against ALK in a mouse model of ALK+ lung cancer. TCR-T cells will be tested alone or in combination with ALK TKI. Their efficacy will be compared to natural anti-ALK T cells induced by vaccination in mice. In Aim 2, we will discover and study the activity of ALK-specific TCRs against human ALK peptides. We will leverage ALK peptides we previously identified to be expressed by human ALK+ NSCLC. The killing activity of these human specific TCR-T cells will be tested against human ALK+ NSCLC in vitro and in vivo, alone or in combination with ALK TKIs. We expect to identify potent and specific TCRs as leading candidates for a TCR-T cell-based clinical trial for patients with TKI-resistant ALK+ NSCLC.