Targeted therapy

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.

Lorlatinib is the only approved ALK-targeted drug for patients with ALK-positive non-small cell lung cancer (ALK NSCLC) who progressed on prior ALK drugs. The average duration of benefit from lorlatinib is seven months before resistance develops. There are currently no approved ALK-directed therapies after lorlatinib.

Our understanding of lorlatinib resistance mechanisms remains limited. However, we know that 1) cancer cells can develop two ALK mutations that block lorlatinib action and 2) cancer cells can activate other pathways so that cancers no longer exclusively rely on ALK.

This proposal addresses ALK resistance directly, with the goal of opening a clinical trial using a novel drug called gilteritinib. Preliminary tests show gilteritinib prevents ALK NSCLC from using alternative pathways to overcome ALK inhibition. First, we propose to obtain tumor-containing samples from patients who are progressing on lorlatinib and perform in-depth sequencing of these cancer cells to thoroughly describe resistance mechanisms in all detectable cancer clones. Next, we will perform drug sensitivity testing on these cancer cells using approved and experimental drugs, including gilteritinib. Finally, we will open a clinical trial using gilteritinib, already approved for treatment of a blood cancer (FLT3+ acute myeloid leukemia). In multiple pre-clinical studies, gilteritinib was able to kill lorlatinib-resistant cells, but this drug has not been given to patients with ALK NSCLC. Our proposal focuses on bringing knowledge obtained from patients’ cancer cells through extensive analysis directly into a clinical trial with a novel drug, maximizing the impact to patients.

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.