Career Development Award

Despite advancements in lung cancer detection and new therapies, lung cancer remains the most common cause of cancer death in the United States. Over the past decade, the identification of molecular drivers of lung cancer has revolutionized treatment through development of more personalized and effective therapies. Mutations in KRAS, one such driver oncogene, are identified in 25-30% of cases of lung adenocarcinoma. While molecularly targeted therapies have proven effective for other driver oncogenes, such as EGFR and ALK, the clinical activity of molecularly targeted therapy in KRAS mutant lung cancer has been limited as KRAS was long considered an “undruggable” target. Prior efforts focused on targeting downstream signaling pathways were largely ineffective. KRAS G12C mutations are the most common subtype in lung adenocarcinoma and are present in 12% of lung cancer patients overall. In 2013, the identification of the binding pocket of the KRAS G12C protein enabled the development of direct inhibitors, a significant breakthrough for the field. In early phase clinical trials this new class of agents has demonstrated efficacy with 40-50% of patients having substantial tumor shrinkage, representing another major advance for the field. While treatment can lead to tumor regression, nearly all patients have less than maximal responses and are likely to develop acquired resistance. Combinations of molecularly targeted therapy may result in deeper and more durable responses resulting in improved outcomes for patients with KRAS G12C mutant lung cancer.

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.

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.

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.

Lung cancer remains the leading cause of death related to cancer and the majority of lung cancer patients present with advanced disease that is for the most part incurable. Efforts to improve the early detection of lung cancer are crucial to help decrease the number of people who die from lung cancer. It has long been known that genetic information specific to cancer cells can be detected in the blood of cancer patients. Current technologies are enabling us to identify this cancer-specific genetic information directly from blood samples allowing for “liquid biopsies” that offer the potential of making cancer diagnoses directly from blood tests. However, the amount of cancer specific genetic information in the blood of patients with smaller tumors in early stages is often only present in very minute amounts that are difficult to detect. The development of new liquid biopsy technologies that can identify smaller amounts of genetic information more economically could potentially lead to blood tests that are able to detect smaller, more curable tumors and could be used for lung cancer screening. The recent identification of CRISPR-Cas systems, bacterial immune systems adapted to recognize specific genetic sequences, that can accurately detect very small quantities of specific genetic sequences are an attractive platform to develop liquid biopsy tests. The goal of the proposed project is to develop a CRISPR based blood test that can accurately identify genetic sequences specific to lung cancer and can accurately identify patients with early stage lung cancer.

Lung cancer is the leading cause of cancer-related death in both men and women worldwide. The majority of patients initially present with late-stage disease with a 5-year survival rate as low as 5%. Improved understanding of how the immune system interacts with tumor cells has enabled the development of specific drugs that release the brakes off of the immune system allowing these immune cells to attack and kill cancer cells. These immunotherapeutic drugs have shown great promise for the treatment of lung cancer, but in the majority of clinical trials, only about 20-50% of patients respond. To date, measurement of a protein called PDL1 that is expressed on the tumor cell surface has been the most commonly used marker to predict which patients will respond to these therapies. However, even when high expressers of PDL1 are selected to receive immune targeted agents, less than half of patients respond. In addition, these novel drugs have significant economic costs and are associated with drug-related toxicities in 20-30% of patients. Thus, the goal of this proposal is to develop better predictors of response to immunotherapy in patients with lung cancer in order to avoid unnecessary toxicities, reduce costs, and enable a more appropriate therapy to be delivered. We will accomplish this goal in two complimentary specific aims. In Specific Aim 1, we have developed a novel method to quantitate a number of proteins expressed on immune and tumor cells present in the tumor microenvironment from late-stage lung cancer patients using a technique called multi-parametric flow cytometry. We hypothesize that quantifying these proteins will provide a more comprehensive view of the function of these immune cells with the tumor and be able to predict which patients will respond to immunotherapy. In Specific Aim 2, we will focus on a newly developed blood-based biomarker, exosomal PDL1 expression, to predict response to immunotherapy. We will enroll late-stage non-small cell lung cancer patients scheduled to receive an immunotherapeutic agent who will undergo additional tumor biopsies and blood draws for analysis, and patients be followed over time to monitor for response and outcome data.

Lung cancer is the leading cause of cancer death and accounts for more than 160,000 deaths each year. Immunotherapy, aimed at improving the immune system’s response to cancer, has recently emerged as a profound breakthrough for patients with lung cancer. In particular, therapies targeting the programmed death-1 (PD-1) pathway have been successful. PD-1 is a molecule on immune cells, called T cells, that serves as the “brakes” of the immune system, and tumors can exploit this pathway to shut down the potentially effective anti-tumor immune response. PD-1 immunotherapy blocks this cancer-enabling pathway and allows the immune system to reject tumors. Recently, the FDA has approved PD-1 blockade in combination with traditional chemotherapy for the treatment of metastatic non-small cell lung cancer (NSCLC). This combination approach has resulted in significantly longer survival compared to chemotherapy alone. Despite this, many patients still do not achieve clinical benefit or extended survival. Prior studies have shown that tumors with a high number of genetic changes, called “mutations”, respond favorably to PD-1 immunotherapy, possibly because these mutations induce more immune activation that can then be unleashed following blockade of the PD-1 pathway. However, we are unsure how mutations play a role in the response to PD-1 blockade in combination with chemotherapy which, counter to PD-1 blockade, has traditionally been thought to dampen the immune system. It is therefore of immediate urgency that we understand how PD-1 blockade and chemotherapy work together to promote tumor regression and longer survival and to help clinicians better select patients most likely to benefit from these treatments. Here we propose to evaluate the effect of treatment on anti-tumor immune responses in patients receiving anti-PD-1 in combination with chemotherapy versus those receiving anti-PD-1 alone. The findings from this study will significantly advance our knowledge of the immune response to lung cancer and may result in a paradigm shift in how we select patients who are most likely to benefit from PD-1 immunotherapy.

EGFR tyrosine kinase inhibitors (TKIs) have led to dramatic improvements in clinical outcomes among patients with EGFR-mutant lung cancer, but patients typically become resistant after about one year. In 50-60% of cases, resistance is driven by the secondary EGFR T790M resistance mutation. There is now growing evidence that resistant cancers are heterogeneous and that this influences resistance to subsequent therapies. In this proposal, we will take a comprehensive approach to study and characterize the heterogeneity of EGFR-mutant lung cancers and its impact on how cancers respond and become resistant to treatment. We will utilize innovative methods to study heterogeneity on multiple levels, including cell-by-cell variations within individual tumors, variations across different sites of cancer within an individual patient, and fluctuations in heterogeneity over time through “liquid biopsy” analysis. Finally, we will test a new combination treatment strategy designed to delay the emergence of resistance, and use the clinical trial to collect patient samples which will facilitate further studies of how resistance and cancer heterogeneity develops. Ultimately, we aim to identify more effective therapies to decrease heterogeneity, induce more durable responses and improve clinical outcomes.  

Immune targeted therapies, which stimulate the immune system to attack cancer have revolutionized cancer treatment strategies. These successes have offered new therapeutic avenues for cancer patients, especially for those with lung cancer. Despite the impressive clinical efficacy and duration of responses observed, the fraction of lung cancer patients with durable responses remains in the order of 20% and among patients that respond the majority develop acquired resistance. There is therefore an unmet need to maximize efficacy of these treatments by identifying the patients more likely to respond. Our pilot research suggests that response to these therapies is tightly connected to the genetic make-up of tumor cells and acquired resistance may be due to the elimination of certain genetic mutations needed to enable the immune system to recognize and attack malignant cells. In this proposal, we are employing a highly innovative large-scale approach combining genomic and functional immune analyses to understand the mechanisms of response and resistance and develop predictive biomarkers to immune targeted agents. In addition we seek to develop a liquid molecular assay of response to immunotherapy that would more accurately predict outcome compared to conventional radiographic imaging. Our approach, if successful may ultimately inform patient selection for immune checkpoint inhibitors and indicate treatment strategies in patients that demonstrate initial responses but develop acquired resistance. We believe our comprehensive, cutting-edge scientific approach will result in immediate clinical intervention initiatives and is consistent with our mission to deliver improved treatments to patients with lung cancer. 

Identification of key immune escape mechanisms of cancers led to the development of drugs that target these escape mechanisms (immune checkpoints) which have produced durable clinical responses in various malignancies, including lung cancer. Because these drugs (immune checkpoint inhibitors) only benefit a fraction of patients, efforts are now focused on combination treatment strategies to increase responses with the cost of increased toxicities, some of which can be life threatening. Immune checkpoint inhibitors have a unique side effect profile and generally it is due to inflammatory tissue damage, named immune related adverse effects (irAE). Unlike the anticipated side effects of chemotherapies, the onset, duration and severity of side effects of immune checkpoint inhibitors are unpredictable. irAEs share some clinical features with autoimmune conditions. Recent studies suggest 8-9% of the US population carries autoimmune diseases and a quarter of healthy individuals have circulating proteins (auto-reactive antibodies) that are directed against individual's own body. We consider, pre-existing or increasing levels of auto-reactive antibodies and changes in some immune cells caused by immune checkpoint inhibition and radiation therapy, can be predictive markers for toxicity. For this study we plan to use blood samples from patients who are in a clinical trial that combines two immune checkpoint inhibitors with/without radiation therapy. In blood, we plan to measure baseline and subsequent levels of auto-reactive antibodies, and a subgroup of immune cells during therapy. Our goal is to identify a predictive marker set for irAEs and we will also correlate these markers with the response to therapy.