Research Funded to Date

Immunotherapy with PD-1 inhibitors can lead to very durable responses in metastatic non-small cell lung cancer, which was previously unheard of. Unfortunately, those who benefit constitute a relatively small subset of patients. Combining PD-1 inhibitors with other drugs to amplify response is an appealing strategy, but our understanding of how to do this rationally is quite limited. In addition, biomarker tests to predict who will benefit most from treatment are not very good at predicting responses. Our study aims to address both of these concerns.

Interferon signaling is a critical part of the body’s immune response to tumors, and can make it better or worse. If one thinks about interferon as a component of inflammation, this makes more sense:  if you get sick, you want an inflammatory response to help get rid of the virus or bacteria making you ill. At the same time, if inflammation persists too long, it can hurt your body (as is seen in autoimmune conditions). Our team recently tried to take advantage of this concept in a mouse disease model, and found a way of combining PD-1 blockade with JAK inhibition (which stops interferon signaling), which led to remarkable anti-tumor responses in mice. We are currently running a study evaluating this same combination and dosing schedule in humans with non-small cell lung cancer.

In parallel with these efforts, we are developing a new biomarker to evaluate patients’ response to immunotherapy. Our group has recently found that we can identify a group of T cells that are “exhausted.” T cells are supposed to identify abnormal cells (like cancer) and get rid of them. Exhausted T cells, just like exhausted people, cannot do their job well. When patients receive a PD-1 inhibitor, their T cells can become “reinvigorated.” As one might imagine, if the T cells do not reinvigorate, they cannot kill the cancer cells.

Small cell lung cancer (SCLC) is an extremely fast-growing type of lung cancer that is most often related to smoking. Patients diagnosed with SCLC that affects more than one area of the body are usually treated with chemotherapy, which travels throughout the body to treat all sites of the cancer. Most patients, up to 70%-80%, tend to have very good responses to chemotherapy at first. Unfortunately, almost all patients eventually stop responding to chemotherapy. Why these small cell lung cancers ultimately stop responding to chemotherapy is not well understood.

Recently, the Charles Rudin laboratory at Memorial Sloan Kettering Cancer Center has created patient-derived xenografts, or patient-derived animal models, to test why some small cell lung cancers stop responding to chemotherapy over time. Using these animal models, we found that a protein called enhancer of Zeste homolog 2 (EZH2), plays an important role in how SCLC develops resistance to chemotherapy. EZH2 does this by decreasing the levels of Schlafen family member 11 (SLFN11), which encourages cells to die after their DNA is damaged. By blocking EZH2 in combination with chemotherapy using irinotecan in mouse models, resistance to chemotherapy was reversed, and the cancer cells began responding to chemotherapy again.

These findings in mouse models from our laboratory provide good evidence that combining a drug that blocks EZH2 with standard chemotherapy might help chemotherapy work more effectively. To answer this question, we will conduct a clinical trial that only has one group of patients, in which all patients receive the same treatment of a drug that blocks EZH2 and standard chemotherapy using irinotecan. We plan to collect blood samples and obtain repeat biopsies on all patients enrolled in this study for additional testing to learn more about the effects of blocking EZH2 on the cancer’s response to chemotherapy. If this experimental drug that blocks EZH2 is shown to be safe and potentially effective when compared with chemotherapy, it would establish a new treatment regimen that can be used not only in patients with SCLC, but potentially in all cancers that grow in response to EZH2.

Lung cancer is the leading cause of cancer-related mortality in the United States, leading to more deaths than the next three cancers combined. Although immunotherapy, a class of therapy aimed at enabling a patient’s own immune system to fight cancer, has revolutionized cancer therapy, the majority of patients with non-small cell lung cancer (NSCLC) still do not derive benefit. As a result, there is an urgent need to identify immunotherapeutic approaches that will benefit a greater number of NSCLC patients.

Proposed is a three-year research career development plan formulated on a clinical trial that is evaluating a novel combination of immunotherapies, genetically modified immune cells plus an immune checkpoint inhibitor, for the treatment of metastatic NSCLC. It is hypothesized that this therapeutic approach will transform a patient’s tumor into a lymph node-like environment, enabling the immune system to identify the tumor as foreign and eradicate it, resulting in an effective immunotherapeutic approach for patients. Samples from patients in the trial will also be evaluated via additional scientific experimental methods to further elucidate alterations in patients' immunologic pathways as a result of therapy.

This novel therapeutic approach has the potential to directly benefit 70% of patients with newly diagnosed metastatic NSCLC or approximately 60,000 people in the United States per year. If proven to be effective, this approach may improve the treatment of other malignancies, which has the potential to benefit an even greater number of patients.