Non-small cell lung cancer (NSCLC)

Background: Provider engagement is key for successful implementation of evidence-based practices. Our prior work reported that providers’ guideline knowledge is strongly correlated to screening practices but other behavioral factors have not yet been measured in lung cancer screening.

Long-term Career Goal: To be a leader in implementation science with expertise in translating evidence-based lung cancer prevention and early detection into clinical practice through mixed-methods research (qualitative and quantitative) and pragmatic trials in the Veterans Affairs (VA). This award will advance the following career goals: To gain experience in: a) measurement science; b) quantitative analysis methods, and to transition to research independence.

Specific Aim: To measure and validate providers’ behavioral factors that influence lung cancer screening implementation.

Methodology: We will adapt the Determinants of Implementation Behavior Questionnaire (DIBQ) for lung cancer screening and leverage ongoing research infrastructure to survey primary care providers at 10 VA medical centers (VAMCs) participating in the Veterans Affairs Partnership to increase Access to Lung Screening (VA-PALS). The adapted questionnaire will be validated using factor analysis and association with prior screening practices. We will assess which behavioral factors are associated with screening using multivariable regression.

Future Directions: The data gathered will be used to design future interventions aimed at increasing provider engagement and measure how provider engagement changes before and after interventions. This proposal will advance the field of implementation science while also leading towards my independence as an implementation researcher.

Immune checkpoint inhibitors have revolutionized the care of patients with metastatic non-small cell lung cancer (NSCLC). Unfortunately, not all patients benefit from this therapy, and rational combinatorial strategies to enhance immune checkpoint inhibitors (ICI) efficacy in therapy non-responders are needed. We and others have shown that patients with liver metastases derive limited clinical benefit from ICI across a wide variety of disease types. In preclinical models, we discovered that liver metastases cause anti-PD-L1 resistance by siphoning tumor-specific T cells from systemic circulation. Within the liver, activated antigen-specific CD8+ T cells undergo apoptosis. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival, and reduces hepatic siphoning of T cells. The central hypothesis of this proposal is that liver SBRT can enhance CPP therapy non-responders in NSCLC patients with liver metastases. In Aim 1, we will conduct a Phase IB clinical trial establishing the feasibility of delivering multi-target liver SBRT following the first cycle of carboplatin, pembrolizumab, and pemetrexed (CPP) in metastatic NSCLC patients with liver metastases. Up to four liver metastases will be targeted. In Aim 2, we will determine whether liver SBRT combined with ipilimumab and nivolumab modulates the hepatic and systemic immune microenvironment in NSCLC patients with liver metastases. The completion of these aims will assess the feasibility of ablating liver metastases with SBRT in combination with chemoimmunotherapy and deepen our understanding of the contribution of hepatic immune tolerance mechanisms in patients. The ultimate goal of this work is to test rationally-developed combinatorial treatment approaches in hopes of improving the care of NSCLC patients.

Activating mutations in KRAS are found in 20 to 40% of lung cancers and not infrequently in combination with additional alterations in genes such as tumor suppressor TP53 or STK11. How activating KRAS mutations and/or co-mutations affect gene expression in both tumor cells and the cells in the surrounding microenvironment is not known. The impact, if any, of these mutations on intra-tumoral heterogeneity in gene expression is not known. Applying single cell RNA sequencing to resected lung adenocarcinoma samples from US Veterans, I will examine and compare the gene expression profiles of tumor cells from lung adenocarcinomas harboring either mutant and wild-type KRAS, and the expression profiles of cells in the surrounding microenvironment, including tumor infiltrating lymphocytes. In addition, I will determine whether KRAS mutational status affects the degree of intra-tumoral heterogeneity in gene expression, a known factor in survival and resistance to treatment. In sum, we hope to identify specific pathways affected by KRAS in both tumor and surrounding non-tumor cells that could be hypothesis-generating and learn use this knowledge to understand how resistance to KRAS specific therapies might be facilitated by pre-existing intra-tumoral heterogeneity.

Lung cancer remains the leading cause of cancer related mortality in the US and globally— responsible for ~1.8 million deaths annually. Randomized trials of low dose CT (LDCT) for lung cancer screening have demonstrated a clear mortality benefit and are recommended by the United States Preventive Services Task Force (USPSTF). However, most individuals currently eligible for screening do not have lung cancer and many at risk populations are not candidates for screening. Additionally, LDCT has a relatively high rate of false positives leading to potentially harmful tests and invasive procedures. Moreover, early experience suggests that LCS outcomes in clinical practice may differ from those observed in randomized trials. Given the concerns with the performance of LDCT, the use of blood and imaging biomarkers to complement the screening process has the potential to enhance its efficacy and effectiveness. Biomarkers could be employed at two different steps of the screening process – as the initial test for cancer screening, to better define the best candidates for screening, or following a positive LDCT scan, to inform lung nodule evaluation and management. While several screening and diagnostic biomarkers have been developed, they have not been formally evaluated in prospective comparative effectiveness trials, nor have they been subjected to cost-effectiveness analyses. More importantly, their impact on lung cancer burden at the population level is still unknown. Our proposed research will inform the following areas of LCS and biomarker discovery: 1) generate a computational framework to estimate and compare the population impact of emerging screening and diagnostic biomarkers, 2) identify the optimal strategy of integrating biomarker tests into LCS, and 3) highlight and identify the characteristics of biomarkers (sensitivity and specificity for histological subtypes, etc.) which are critical for cost-effective biomarker applications.

Lung cancer is the leading cause of cancer-related death in US, and lung adenocarcinoma (LUAD) is the most frequent histology. Early diagnosis is crucial. High-resolution CT has increased the discovery of solitary lung lesions, many of which are benign, whereas some progress to invasive cancer; the identification of novel biomarkers to predict the malignant potential of these lesions is of paramount importance. We found that sodium-dependent glucose transporter 2 (SGLT2) is expressed in human pre-malignant and early-stage LADC, and is required for progression of LUAD. SGLT activity can be measured by PET imaging with methyl-4-[18F] fluorodeoxyglucose (Me4FDG). Importantly, we identified SGLT2 activity in FDG-negative, early-stage lesions in mouse models and in human lung nodules.

Specific aims of the study are: 1. To assess the safety and efficacy of Me4FDG in patients with lung cancer, via a pilot study in 60 patients (30 with pathological diagnosis of LUAD, 30 with a clinical diagnosis of benign nodule); 2. To evaluate the prognostic significance of SGLT2 expression in early lung adenocarcinoma, through SGLT2 staining of 674 samples embedded in tissue microarrays.

The proposed research is likely to introduce a novel diagnostic tool for early diagnosis of lung adenocarcinoma, and further define the prognostic role of SGLT2 in lung cancer. If successful, this pilot trial will open the way for larger clinical studies where we will evaluate the ability of Me4FDG PET to predict the malignant behavior of indeterminate subsolid lung nodules. This will improve the early diagnosis of lung cancer.

Patients with non-small cell lung cancers bearing ALK or ROS1 fusions (FD-NSCLC) often experience an initial, marked response to tyrosine kinase inhibitors (TKI). The eventual emergence of TKI resistance in FD-NSCLC can be partially attributed to cancer-cell intrinsic mechanisms, but these do not fully explain the diversity in patient outcomes. Currently, FD-NSCLC is viewed as a “cold” tumor with only a molecular target, and the role of the tumor microenvironment (TME) in these cancers has not been well studied. As patients have limited options after progression on TKIs, there is an urgent need to identify novel drivers of resistance to develop new, more effective therapies. Based on our preliminary data, we believe innate immune cells, monocytes and macrophages (MoMf), within the FD-NSCLC TME shape tumor response to TKI therapy. Using patient derived cell lines, we found marked TKI resistance in multiple FD-NSCLC cell lines when cultured in media conditioned by MoMf. MoMf-driven TKI resistance was associated sustained pERK activity in the cancer cell. In pre-treatment specimens from patients with FD-NSCLC, multispectral tissue imaging demonstrated a range in number of MoMf within the TME. Our preliminary data suggest the presence of MoMf with the FD-NSCLC TME may alter response to therapy. We propose investigating the mechanisms of MoMf-mediated TKI resistance and potential therapeutic approaches with clinically relevant syngeneic and xenograft animal models and patient-derived FD-NSCLC cell lines. Further, we will examine biopsy specimens from patients
Immunotherapy is a treatment approach that leverages the body’s own immune system to destroy cancer cells. In non-small cell lung cancer (NSCLC), the most common type of lung cancer, immunotherapy has opened the door to durable treatment that approaches cure; unfortunately, this outcome is rare, and many NSCLCs are initially or eventually become unresponsive. It was originally thought that unresponsive malignancies had adapted to prevent immune cells from locating and interacting with the tumor. Our research suggests this is not the case: the tumor can remain inflamed and responsive, but the immune response can become exhausted. Therapies that reinvigorate the immune response (including tumor infiltrating lymphocyte [TIL] therapies) may be particularly effective in this context. In fact, our preliminary studies suggest TIL therapy can work in up to a third of treatment-resistant NSCLCs. Capitalizing on these new insights, our proposal seeks to 1) determine pre-treatment features of sensitivity and resistance to TIL therapy in NSCLC and 2) characterize on-treatment patterns of immune response, focusing on the cells that identify and kill NSCLC cells. Accomplishing these aims will fill critical knowledge gaps, identifying characteristics of tumors likely to respond, or that fail to respond, to TIL treatment. These studies will define a roadmap, guiding application of subsequent TIL research for lung cancer. Taken together, these studies will provide crucial insights into novel treatment approaches for patients with few alternatives and an otherwise grim prognosis.

Lung cancer is the leading cause of cancer-related death in the United States and worldwide. Immune checkpoint inhibitors (ICIs) have shown durable responses and improved survival in some patients with advanced non-small cell lung cancer (NSCLC). However, nearly all patients eventually progress on these therapies, and the median survival for patients with metastatic NSCLC remains around one year. Combining immunotherapy with cytotoxic chemotherapy has shown an incremental benefit but at the cost of increased toxicity. Patients who progress on currently available immunotherapies have few effective treatment options. One significant barrier to ICI therapy efficacy is the tumor microenvironment (TME), which contains immunosuppressive cells including myeloid-derived suppressor cells (MDSCs). MDSCs represent an important tumor immune escape mechanism and play a role in the development and progression of lung cancer. Higher levels of MDSCs in the blood are associated with shorter overall survival in patients with NSCLC, and MDSCs are associated with resistance to immune checkpoint inhibitor (ICI) therapy. However, there is significant variation in methods of measurement of MDSCs including 1) the classification of the most common phenotypes, namely CD15+ polymorphonuclear MDSC (PMN-MDSC) and CD14+ monocytic MDSC (M-MDSC), and 2) the functional assessment of MDSCs. There are also significant differences in MDSC function and phenotype in animal models and in patients with cancer. We propose to investigate the role of MDSCs in tumor immune escape, and to target the immunosuppressive impact of MDSCs to improve outcomes of patients with NSCLC treated with ICI. Utilizing mass cytometry and in vitro co-culture assays, we will evaluate MDSC levels and function as well as immune cell subset changes in patients receiving standard of care immunotherapy to identify the cell populations that drive immune responses and resistance. We will then conduct a phase 1b clinical trial of all-trans retinoic acid (ATRA) combined with atezolizumab to test whether this treatment can improve responses and overcome ICI resistance in patients with NSCLC who have progressed on standard therapies. We hypothesize that a decrease in the frequency and immunosuppressive function of circulating MDSCs will be associated with increased clinical benefit in patients with NSCLC, and that modulation of MDSCs through the use of ATRA given in combination with ICIs will be safe, tolerable, and exhibit preliminary efficacy in overcoming resistance to available ICIs. The proposed studies include the first trial of this novel treatment in patients with lung cancer and will examine the potential for targeting MDSCs to overcome resistance and enhance the efficacy of immunotherapy. If successful, these studies may lead to an increased number of patients with advanced NSCLC experiencing durable responses and improved survival.