Funded Projects

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.

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.

Veterans have significantly greater rates of lung cancer and mortality as compared to civilians. In our prior work, these disparities are partly due to lack of receipt of evidence-based cancer care especially among patients with complex comorbidities, psychosocial concerns, and limited social support, characteristics common among Veteran populations. The overall goal of this research is to overcome structural barriers to ensure delivery of evidence-based lung cancer care among Veterans. In our prior work we identified workforce shortages along with complex psychosocial factors and medical conditions that prevent Veterans from fully engaging in their care. We used community-based participatory research and expert panel methods to develop Engagement of Patients with Advanced Cancer (EPAC) – an intervention that integrates community health workers into care.1 In our randomized trial, EPAC improved evidence-based end-of-life care, Veteran satisfaction and reduced acute care use and total healthcare costs. In this study, with our established Advisory Board comprised of Veterans, caregivers, oncology clinicians, and VA leaders, we will refine EPAC to incorporate evidence-based lung cancer care (Aim 1). We will randomize 60 Veterans newly diagnosed with advanced lung cancer to establish feasibility of the refined EPAC intervention (primary outcome) and secondarily, the effects on evidence-based lung cancer care and Veteran activation (Aim 2). The results will inform a multisite randomized study in the VA.

Lung cancer remains the leading cause of cancer death worldwide and clinical trials show that annual lung cancer screening with low-dose Computed Tomography can reduce lung cancer-related mortality by 20%. Marginalized populations are disproportionately affected by lung cancer and our prior work has shown that these disparities extend to lung cancer screening; in a national cohort of Veterans we found that Black Veterans, those with mental health disorders and lower income were less likely to adhere to lung cancer screening follow-up recommendations. Currently, little is known about how to optimize lung cancer screening in underserved populations and marginalized populations from diverse backgrounds.

This proposed project focuses on identifying barriers and facilitators to lung cancer screening at the patient, provider, facility and community-levels. We plan to use mixed methods to quantitatively explore factors associated with delayed or lack of adherence to lung cancer screening and then perform in-depth qualitative analysis to identify which factors are critical and modifiable. We will use an implementation strategy mapping tool to select evidence-based strategies best suited to address the identified barriers and develop a tailored implementation plan to improve adherence to lung cancer screening, both overall and among underserved populations, at Baystate Health System. This work is critical in achieving equity in lung cancer screening and improving overall lung cancer mortality among patients.

A common source of lung cancer morbidity is presented by incidental pulmonary nodules (IPNs), which can represent missed cancers when incompletely followed. Underrepresented patients are particularly at risk of guidelines discordant care. Our institution cares for a large proportion of these minority communities. We therefore propose to develop a comprehensive program for the identification, risk stratification and management of IPNs identified through imaging in the emergency setting. We first seek to incorporate lung nodule detection and management software into our electronic medical record (EMR). To facilitate recognition of nodules, we will utilize natural language processing to screen and flag imaging. A multidisciplinary ensemble of practitioners will validate findings and participate in management. At the crux of this team will be a patient navigator to communicate with patients and assist in follow-up. We next seek to create an IPN risk prediction algorithm. Clinical and radiographic elements from the EMR will be subjected to artificial intelligence-based review to automatically leverage data towards a machine learning-derived algorithm. The final element of our proposal will investigate a blood-based gene expression assay as a marker for malignancy. Following its evaluation using a cohort of biobanked samples, we will apply this RNA-based detection assay to look for markers of malignancy to facilitate the early detection of lung cancers. We ultimately seek to improve lung cancer care within our largely underserved population through a combination of incorporating patients with IPNs into the health care system and providing appropriate and automated risk stratification to expedite care and diagnosis.

Background: Patients with NSCLC whose tumors harbor a targetable molecular alteration have improved outcomes when they receive targeted therapy. Historically, targetable alterations have been associated with specific patient characteristics such as female gender, young age, non-smokers, and Asians. Given this association, patients with characteristics not commonly associated with targetable mutations do not always receive timely and complete molecular testing. We hypothesize that male gender, age >65, history of smoking, African American race and Hispanic ethnicity will be independently associated with delayed detection and treatment of a targetable alteration. We will evaluate the impact of delayed targeted therapy on overall survival and brain metastasis development.

Methods: We will perform a retrospective cohort study of approximately 2200 patients with EGFR, ALK or ROS1 targetable alterations obtained through multi-institution retrospective chart review. Multivariate logistic regression will be used to evaluate the association of patient characteristics with complete molecular testing prior to first-line therapy, targeted therapy as first-line therapy, and development of brain metastases. Kaplan-Meier methodology will be used to estimate median overall survival. The log rank test will be used to compare median overall survivals. Multivariate Cox Regression will further evaluate interactions between delayed targeted therapy and patient characteristics as well as help control for potential confounders.

Importance: This will be the first study to evaluate the impact of delayed detection and delayed treatment of driver mutations in NSCLC. This information is critical to designing interventions to improve outcomes in patient groups with characteristics not usually associated with driver mutations.

Lung cancer patients and survivors are a growing underserved group, with the lowest quality of life of any cancer survivor group. Lung cancer is also the deadliest form of cancer, with the five year survival rate being 18.6%; survival rates are even lower for intersectional underserved groups. Stigma about having lung cancer, or a feeling of blame and shame for having lung cancer, having caused lung cancer through historical or current smoking, or having others assume one caused their own lung cancer, leads to higher rates of depressive symptoms, lower disclosure of smoking, lower likelihood of engaging with smoking cessation services, and decreased likelihood of following through on treatment recommendations. Thus, lung cancer stigma likely significantly contributes to a lower five-year survival rate for cancer. Importantly, stigmatized intersectional groups experience stark health disparities, with Latinx and Black lung cancer survivors reporting lower quality of life, with Black and LGBTQ lung cancer survivors reporting higher rates of smoking, and with all three groups reporting low access to care and righteous medical mistrust. We have no current interventions to treat this intersectional stigma across the cancer continuum. Promisingly, mindfulness interventions have been shown to decrease stigma in other health contexts and are easily disseminable. In this study, we propose an innovative Multiphase Optimization Strategy (MOST) methodology to build and optimize a brief virtual mindfulness intervention to decrease lung cancer stigma. We will measure behavioral outcomes, too, such as likelihood of accepting a referral to smoking cessation services, in order to detect an effect on the five-year survival rate of lung cancer. We will examine the reach, acceptability, and preliminary efficacy of this intervention in these underserved groups in order to decrease health disparities and extend the five-year survival rate.

Lung cancer is the leading cause of cancer death in the United States, and disproportionate risk is faced in the lesbian, gay, bisexual, trans and queer (LGBTQ) community due to higher smoker rates. Lung cancer screening (LCS) with annual low-dose chest CT has been demonstrated to reduce lung cancer mortality by up to 20% in a subset of high-risk smokers, a benefit that is doubled with sustained smoking cessation. Little is known about LCS in LGBTQ patients; however, in general, this population faces healthcare discrimination and other unique barriers to preventive care. This study will bridge this significant knowledge gap through partnership with an urban LGBTQ community center to tailor and evaluate a smoking cessation and LCS program for the LGBTQ community through a robust mixed-methods approach centered in community-based participatory research. In Aims 1 and 2, we will use a qualitative approach to engage the community and build a tailored cessation and screening navigation program, and in Aim 3 we will pilot the program in single-arm study, evaluating both effectiveness and the implementation outcomes of the program. Results from this study will assist with the development of a sustainable local LGBTQ LCS and smoking cessation program and will be used to inform a larger multicenter trial of the intervention.

KRAS mutations are the most common activating mutation in lung cancer and are identified in 25-30% of cases of lung adenocarcinoma. The clinical activity of molecularly targeted therapy in KRAS mutant lung cancer has been limited, as most prior approaches focused on downstream targets of the MAPK pathway, an approach which was largely ineffective. KRAS G12C is the most common subtype of activating KRAS mutation in NSCLC. Identification of a binding pocket of KRAS G12C enabled the development of covalent inhibitors (Ostrem et al. Nature, 2013), which selectively bind to the mutant cysteine and spare wild type or other mutant KRAS proteins (hereafter referred to as G12Ci). These drugs bind only to GDP-bound (i.e. inactive) KRAS G12C and trap the oncoprotein in its inactive state by preventing nucleotide exchange (Lito et al. Science, 2016). Of this new class of agents, two drugs (MRTX849 and AMG510) have demonstrated efficacy in early phase clinical trials, representing a remarkable breakthrough in the management of KRAS G12C mutant lung cancer. Acknowledging the limited number of patients treated thus far, response rates of 40-50% have been reported, demonstrating clinical activity far superior to prior molecularly targeted approaches for the management of KRAS mutant lung cancer. Despite this major advance it is clear that resistance to therapy, both primary and acquired, will remain a challenge and may in part be due to upstream receptor tyrosine kinase (RTK) signaling. Understanding the mechanisms of resistance to this new class of therapy is of paramount importance to improve the efficacy and durability of response, and for identifying rational combinatorial therapies for future clinical trials.

Small cell lung cancer (SCLC) is an aggressive, neuroendocrine malignancy that accounts for approximately 15% of lung cancers. Despite recent advances, including the approval of immunotherapy combined with chemotherapy for frontline treatment, the median overall survival for patients with extensive-stage SCLC remains approximately one year. These dismal outcomes are attributable, in part, to the lack of approved biomarkers for SCLC, which, in turn, is due to the dearth of available tissue for molecular analysis. Using transcriptomic data, we have developed a gene signature that defines four distinct molecular subtypes of SCLC – each with unique biology and therapeutic vulnerabilities. These subtypes are driven by the presence (or absence) of three transcription factors (ASCL1 – SCLC-A; NEUROD1 – SCLC-N; POU2F3 – SCLC-P; and a fourth triple-negative subtype “Inflamed” – SCLC-I) that are largely mutually exclusive. Our preliminary data suggests that inter- and intra-tumoral heterogeneity among these subtypes drives response and resistance to standard and novel therapies for SCLC, including classes such as PARP inhibitors (PARPi) and immunotherapy. We propose applying bulk and single-cell molecular approaches to assign and longitudinally monitor subtype among our established cohort of patient-derived xenograft models treated with PARPi, as well as patient tumor biopsies from an investigator-initiated trial assessing a PARPi/immunotherapy combination. Based on our preliminary data, we hypothesize that SCLC-P and SCLC-I will preferentially benefit from PARP inhibitors and immunotherapy, respectively, and that subtype shifts detectable at the single-cell level along with accompanying shifts in the composition of the immune microenvironment, will govern response and resistance.

Metastatic non-small cell lung cancer (mNSCLC) is the leading cause of cancer-related death in the United States. Most patients with mNSCLC are treated with systemic agents, which prolong survival and improve symptoms, but are typically not curative. Although recent advancements in immune checkpoint inhibitors have revolutionized the management of mNSCLC lacking targetable driver mutations, only a fraction of mNSCLC patients benefit from immunotherapy. Emerging evidence suggests that ablative radiotherapy can augment immunotherapy responses in metastatic disease; however, strategies to optimize the synergy between local radiation and the immune system are not well defined. We are conducting a randomized phase I/II clinical trial designed to evaluate the safety and efficacy of combination immune checkpoint blockade (ipilimumab + nivolumab) plus multisite ablative radiotherapy as a first-line treatment for patients with mNSCLC. As a secondary analysis of the phase I trial, we propose to investigate biomarkers associated with treatment response. In Aim 1, we propose to compare the diagnostic accuracy of established clinical biomarkers, including PD-L1 immunohistochemistry (IHC), tumor mutational burden, gene expression profiles, and multiplex IHC in predicting response to combination ablative radiotherapy and immunotherapy. In Aim 2, we propose to characterize global transcriptional and genomic changes induced by radiation when given prior to or concurrently with immunotherapy and evaluate whether these changes are associated with treatment response. In addition, in Aim 3, we propose to validate a novel biomarker derived from alternative splicing as a predictor of radio-immunotherapy response. By elucidating the immunomodulatory properties of radiotherapy, we may be able to improve treatment responses and long-term survival in patients with mNSCLC.

With the development of increasingly potent and selective ALK tyrosine kinase inhibitors (TKIs), resistance is commonly mediated by ALK-independent mechanisms, such as bypass pathway activation. As bypass signaling dependencies vary across ALK-rearranged (ALK+) lung cancers, a multipronged approach is needed to broadly suppress potential bypass signals. We have identified MET activation in 20% of ALK+ tumors that are resistant to next-generation ALK TKIs. In preclinical studies, dual ALK/MET blockade re-sensitized MET-amplified ALK+ tumors to lorlatinib. MEK and SHP2 have recently been identified as important effector proteins downstream of several bypass signaling pathways. In ALK+ models harboring diverse bypass signals, pairing an ALK TKI with either a MEK or SHP2 inhibitor demonstrated broad anti-proliferative activity. Based on these findings, we will conduct a clinical trial to evaluate lorlatinib in combination with a MET, MEK, or SHP2 inhibitor for patients with ALK+ lung cancers with ALK-independent resistance. Serial tumor biopsies will be analyzed to characterize molecular determinants of response to combination therapy and identify expression changes induced by treatment. This innovative multi-arm trial will also assess whether dynamics of genetic alterations in plasma can be used to guide intensification of treatment from monotherapy to early combination therapy for patients who have not yet developed resistance to ALK-directed therapy. Collectively, the studies in this grant strive to develop diverse strategies for overcoming ALK-independent resistance, a heterogeneous molecular entity that undermines efficacy of current ALK therapeutics.

The current standard of care for ALK rearranged non-small cell lung cancer (NSCLC) is targeted therapy with ALK tyrosine kinase inhibitors (TKIs) which bind within the kinase domain of ALK. Due to the development of ALK resistance mutations or bypass activation of parallel or downstream signal pathways, patients inevitably relapse. Even with the introduction of second or third generation TKIs, median overall survival has been estimated to be 6.8 years . Recent advances in immunotherapy have demonstrated progress in lung cancer treatment. However, a majority of ALK positive NSCLC patients have yet to realize the benefits from checkpoint inhibitors or CAR-T cell therapies due to primary resistance or toxicity. Therefore, the development of new treatments for ALK-rearranged NSCLC is an area of critical need. We believe that an effective assault on ALK-driven tumors requires the implementation of creative strategies that allow us to expand our arsenal of drugs to target ALK beyond its kinase domain. To meet this challenge, we have developed and employed cysteine druggability mapping (CDM), a method to define the landscape of inhibitor-protein interactions in a cancer cell. CDM identifies cysteines that can bind to covalent drug-like molecules which serve as early prototypes on which to base cancer drug development programs.
Cysteine-reactive covalent inhibitors have already emerged as an effective approach to targeting protein kinases. Osimertinib, a third-generation epidermal growth factor receptor (EGFR) TKI covalent inhibitor, overcomes EGFR T790M resistance mutations following treatment with EGFR TKI, demonstrating significant improvements over standard EGFR TKIs when used as first line therapy. Importantly, targeting cysteines with covalent inhibitors massively expands the number of proteins which are targetable with small molecule inhibitors, including many targets previously considered undruggable.

We will use ALK fusion positive cancer cell lines, together with tumor tissues from patients who developed resistance mechanisms, to generate druggable cysteine profiles by CDM. Druggable proteins specific to ALK fusion positive samples, including EML4-ALK itself, will be prioritized in our screening for protein degraders from a library of over 2,500 advanced cysteine reactive compounds. After screening, we will assess the specificity of the compound hits and validate their anti-tumor activity using ALK fusion positive cell lines and patient derived ALK TKI-resistant cell lines. We consider the use of the novel, cutting-edge cysteine targeting technology to screen for potent therapeutic compounds as a valuable proposition to improve management of patients with ALK positive lung cancer, with the goal of transforming this cancer into a chronic condition.

Several tyrosine kinase inhibitors (TKIs) are available for the treatment of ALK+ NSCLC, but resistance to all ALK TKIs (including alectinib, brigatinib, lorlatinib) has been reported and occurs through a variety of mechanisms. Once patients develop resistance to available ALK inhibitors, they are typically treated with cytotoxic chemotherapy rather than immunotherapy since response rates to PD-1 pathway inhibitors in this population are very low. However, our work in mouse models of ALK+ NSCLC has demonstrated that a vaccine generated against the rearranged portion of ALK can both prevent the development of ALK+ tumors and also more effectively treat them once they arise. We have also recently found evidence for anti-ALK immune responses in patients, as a subset of them generate spontaneous ALK autoantibodies.

We aim to translate our preclinical findings to a first-in-human clinical trial. Aim 1 will test the safety and efficacy of a novel ALK vaccine + an amphiphilic CpG toll-like receptor 9 agonist adjuvant, administered in combination with an ALK TKI or PD-1 inhibitor in patients with TKI-resistant ALK-positive NSCLC. In Aim 2, using liquid chromatography data-independent acquisition mass spectrometry, we will directly identify antigenic ALK peptides presented by MHC molecules on the surface of cancer cells from tumor biopsies obtained on trial participants. In Aim 3, we will study pre- and post-vaccination anti-ALK T-cell responses among trial participants by analyzing peripheral leukocytes and intratumoral immune cells. The overarching goal is to develop a vaccine that stimulates patients’ immune cells to recognize and eliminate ALK+ tumors.

Immunotherapy has transformed treatment for patients with lung cancer, but most patients still do not respond. Interferon signaling has a dichotomous role—without acute signaling, responses cannot occur, whereas persistent signaling can drive adaptive resistance. Our group recently reported in Cell that delayed administration of a JAK inhibitor in combination with immunotherapy can lead to enhanced treatment responses. We have opened a trial to test this approach, but also aim to improve patient selection and monitoring during immunotherapy by studying key parameters of T-cell exhaustion using peripheral blood flow cytometry. Our group recently showed that one could predict which patients would be most likely to respond to PD-1 blockade in this fashion.

Objective/Hypothesis

We hypothesize that in patients with metastatic non-small cell lung cancer (NSCLC) overexpressing PD-L1 (PD-L1=50%), treatment with pembrolizumab followed by delayed administration of itacitinib will improve the objective response rate. We will also measure the impact of this treatment on key parameters of T cell exhaustion and other biomarkers.

Study Design

This is an optimal three-stage trial of pembrolizumab and itacitinib for first-line treatment of PD-L1=50% metastatic NSCLC. Up to 48 evaluable patients with previously untreated metastatic NSCLC with tumor PD-L1=50% will be enrolled. Beginning with cycle 3 of pembrolizumab, the patient will receive itacitinib for 6 weeks. After 6 weeks of treatment with itacitinib, repeat imaging and tumor biopsy will be performed. Objective response by RECIST 1.1 will be determined based on this scan. Pembrolizumab monotherapy will then be resumed in the absence of progression. Serial blood and tumor samples will be used to monitor established biomarkers and markers of T-cell exhaustion using flow cytometry.