We fund translational research to move knowledge as quickly as possible from basic discovery to treatment of patients.
Since 2002, LUNGevity has invested in 212 research projects at 71 institutions in 25 states and the District of Columbia, for a total of $59,886,308.12.
This grant was funded in part by Lung Cancer Initiative
Chromosomal instability (CIN), a phenomenon that occurs when cells acquire chromosomal abnormalities during cell division, is correlated with resistance to immunotherapy, but the underlying mechanisms are poorly understood. Abnormal chromosomal material in the cell triggers a signaling pathway called cGAS-STING that detects the defective genetic material and triggers an immune response. In cancers that are driven by CIN, Dr. Frangieh observed that this pathway does not work as it should, allowing tumors to grow. He and his team have developed a new drug that resets this pathway. Early experiments in lung cancer cells and mice have shown an improvement in immunotherapy efficacy. If successful, this could help patients that do not respond well to immunotherapy.
Lung cancer is one of the deadliest cancers in the world. Immunotherapies help some patients by unleashing their own immune system to attack the tumor, but most lung cancer patients do not benefit, and we do not understand why. Our research focuses on one likely reason: many lung cancers have "chaotic" chromosomes — their genetic material is constantly being shuffled and broken in the wrong places as cancer cells divide. Normally, when broken pieces of DNA leak into the wrong part of a cell, the body has a built-in alarm system — called the cGAS-STING pathway — that detects this damage and calls in immune cells to clear out the threat. This alarm is supposed to be a powerful weapon against cancer.
We discovered something surprising. In lung cancers with chaotic chromosomes, the alarm is going off all the time. This causes the system to get exhausted and stop working — so immune cells are never called in, and the tumor goes unnoticed and untreated.
We have designed a new drug, called C111, that briefly silences the broken alarm so the system can rest and reset. In early experiments in lung cancer cells and in mice, this approach restored the body's natural ability to attack the tumor and made standard immunotherapies work much better in mice. If our work is successful, it could help many patients who do not respond to today's immunotherapies live longer and better lives.
Chromosomal instability (CIN)—the frequent missegregation of chromosomes during mitosis—is a genomic hallmark of solid tumors and correlates with immune evasion and resistance to immunotherapies, but underlying mechanisms are poorly understood. CIN leads to release of DNA into the cytosol where it triggers the cGAS-STING pathway. While activation of this axis usually results in the expression of type I interferons (I-IFNs), potent immune stimulatory cytokines, we find that in CIN-driven cancers the opposite occurs: CIN-mediated tonic cGAS-STING activation suppresses I-IFN production. Understanding and targeting mechanisms underlying this observation may restore immune-mediated elimination of multiple lung cancers.
We generated rigorous preliminary data, including analyses of human genomic data and tissue samples, a series of sufficiency and necessity experiments, and several in vivo studies across multiple lung cancer models, leading us to the following hypothesis: CIN-induced tonic cGAS-STING signaling drives immune escape through STING depletion resulting in interferon tachyphylaxis, and relief of this tonic signal through cGAS inhibition restores immunogenicity and sensitizes various lung cancer types to immunotherapies.
Immunotherapy has improved outcomes for patients with advanced NSCLC. However, many eventually stop responding to treatment. When this happens, doctors must choose among several treatments with limited benefit and no reliable way to predict treatment response which can result in patients experiencing delays in receiving effective treatment options. This project aims to build a blood test to help to help guide treatment selection for patients with advanced NSCLC whose cancer has progressed after immunotherapy. Dr. Singhal will focus on patients enrolled in a previous clinical trial which found that pairing pembrolizumab (an immunotherapy) and ramucirumab (an angiogenesis blocker) improved survival better than standard chemotherapy, but not for all patients. She will examine stored blood samples from trial participants to find patterns linked to response. From these patterns, a new biomarker will be developed to help identify which patients are most likely to benefit from this drug combination. The broader goal is to personalize treatment for patients with advanced NSCLC, improve outcomes, reduce exposure to ineffective therapies and pave the way for future clinical trials.
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Although immunotherapy has improved outcomes for many patients with advanced NSCLC, most patients’ tumors eventually stop responding to treatment. After immunotherapy stops working, doctors must choose among several treatments with limited benefit and no reliable way to predict which patients are most likely to respond. As a result, many patients receive ineffective therapy while experiencing unnecessary side effects and delays in receiving better treatment options.
This project aims to develop a blood-based test to help guide treatment selection for patients with advanced NSCLC whose cancer has progressed after immunotherapy. The study focuses on patients enrolled in a national clinical trial called S1800A, which showed that a combination of pembrolizumab and ramucirumab improved survival for some patients compared with standard chemotherapy. However, only a subset of patients benefited from this treatment.
Using stored blood samples from participants in this trial, we will analyze thousands of proteins circulating in the blood to identify patterns associated with treatment response or resistance. These protein patterns may provide important information about how the cancer and immune system are interacting in real time. We will then develop a new biomarker designed to identify which patients are most likely to benefit from pembrolizumab plus ramucirumab.
Ultimately, this work may help personalize treatment decisions for patients with advanced lung cancer, improve outcomes, reduce exposure to ineffective therapies, and support future biomarker-directed clinical trials.
This proposal seeks to address a major unmet need in non-small cell lung cancer (NSCLC): the absence of predictive biomarkers to guide treatment selection for patients with immune checkpoint inhibitor (ICI)-refractory disease. Although the Lung-MAP S1800A trial demonstrated an overall survival benefit with pembrolizumab plus ramucirumab compared with standard therapy, only a subset of patients derived benefit, underscoring the need to identify biologically defined responders. Existing biomarkers, including PD-L1 and tumor mutational burden, have limited predictive utility in the ICI-refractory setting and fail to capture the immune and angiogenic biology underlying treatment response.
This project will leverage pretreatment plasma specimens from 136 patients enrolled in the randomized S1800A trial to develop a novel plasma proteomic biomarker of ICI sensitivity. Using the SomaScan proteomic platform and the PROphet analytical framework, 7,000 circulating proteins will be quantified to characterize resistance-associated protein patterns associated with response to pembrolizumab plus ramucirumab. The study will: (1) define proteomic signatures underlying sensitivity and resistance to combined ICI and VEGFR-2 inhibition; (2) determine the relationship between these proteomic patterns and established biomarkers; and (3) develop and internally validate a refined proteomic biomarker specific to ICI-refractory NSCLC.
Concurrently, this award will provide structured career development in biomarker-directed clinical trial design, proteomic biomarker development, biostatistical methods, and scientific communication through mentorship from leaders in thoracic oncology, translational proteomics, and biomarker-directed trial design. Successful completion of this work will generate a clinically actionable biomarker and establish the foundation for a future R01 on prospective biomarker-guided treatment selection in ICI-refractory NSCLC.
Dr. Song's team has previously shown that a subset of tumor-associated natural killer (NK) cells can suppress productive responses from T cells in the body that are responsible for killing cancer cells. This may explain why some tumors fail to respond well to immunotherapy. In addition to these findings, Dr. Song also has preliminary data suggesting that suppressive NK cells regulate tumor-associated macrophages, which can either help the immune system attack cancer cells, or support tumor growth, depending on their state. This project will define which types of macrophages take on a tumor-attacking state or a tumor promoting state contributing to immunotherapy resistance. Findings from this study could support future treatment strategies to improve immunotherapy response.
Immunotherapy has changed the treatment of non-small cell lung cancer, but many patients still do not respond, and the reasons for this resistance remain incompletely understood. My previous work identified an unexpected mechanism of resistance: a subset of tumor-associated natural killer, or NK, cells can suppress productive CD8? T-cell responses. Because CD8? T cells are among the main immune cells responsible for killing cancer cells, this finding helped explain why some tumors fail to respond well to PD-1/PD-L1 immune checkpoint blockade.
This project builds directly on that discovery but moves into a new and previously underexplored area. Our new preliminary data suggest that suppressive NK cells do not only affect CD8? T cells. They also appear to regulate tumor-associated macrophages, another major immune cell population in lung tumors. Macrophages can either help the immune system attack cancer or support tumor growth and immune evasion, depending on their state. We found that when NK cells are removed, macrophages shift toward a more inflammatory, antigen-presenting, and potentially tumor-fighting state.
This is a novel finding because NK-cell control of macrophage behavior in lung cancer has not been systematically investigated. By defining this new NK-macrophage axis, this project will reveal an additional layer of immune suppression in lung cancer and identify new strategies to improve immunotherapy. Ultimately, these studies could support future treatment combinations designed to reprogram the tumor immune environment and help more patients benefit from immunotherapy.
Immune checkpoint blockade has improved outcomes in non-small cell lung cancer (NSCLC), yet many patients fail to achieve durable responses, indicating that additional immunosuppressive mechanisms remain undefined. My previous work identified a suppressive tumor-associated NK-cell program that limits productive CD8? T-cell differentiation and contributes to resistance to PD-1/PD-L1 blockade. Building on this finding, the current proposal investigates a distinct and previously underexplored mechanism: regulation of tumor-associated macrophages by suppressive NK cells.
Preliminary data from murine lung tumor models demonstrate that NK-cell depletion induces broad remodeling of the macrophage compartment. In the absence of NK cells, tumor-associated macrophages shift toward a more inflammatory, antigen-presenting, and phagolysosomal activation state, suggesting that suppressive NK cells restrain macrophage programs that could otherwise support antitumor immunity. These findings raise the central hypothesis that suppressive NK cells maintain a macrophage state that limits immune activation and contributes to checkpoint blockade resistance.
This project will define the NK-cell-dependent macrophage programs associated with immunotherapy resistance and determine whether disrupting the NK-macrophage axis enhances response to PD-1/PD-L1 blockade. Using preclinical lung cancer models, single-cell profiling, spatial immune analysis, and functional perturbation approaches, this study will identify macrophage states regulated by NK cells and test their contribution to antitumor immunity.
By extending the established NK-CD8? T-cell mechanism to a novel NK-macrophage regulatory axis, this work will reveal a new layer of immune suppression in NSCLC and provide a mechanistic foundation for macrophage-targeted combination strategies to improve immunotherapy responses.
This grant was funded in part by American Society for Radiation Oncology
Some people with lung cancer have multiple tumors in their lungs, and doctors must determine which ones need treatment right away versus which can simply be monitored over time. In this project, Dr. Adib aims to create a molecular "report card" for each tumor tracking how they evolve from early, precancerous changes into invasive cancer. Rather than labeling tumors as "sick" or "healthy," this approach will measure where each tumor falls on a spectrum of progression, making it possible to catch tumors that current tests might miss. The development of such a “report card” has the potential to personalize care, helping doctors find which tumors should be treated while reducing unnecessary procedures for the ones that can be safely monitored.
Patients with lung cancer can present with multiple separate tumors in their lungs, a condition called multifocal lung adenocarcinoma. For these patients, physicians must determine which tumors require immediate treatment and which can be safely monitored. Current treatment decisions rely primarily on CT scan appearance, but imaging alone cannot by itself distinguish tumors with aggressive molecular features from those with indolent biology.
Our research aims to solve this problem by creating a molecular "report card" for each tumor or set of tumors that can predict future behavior. We will use advanced single-cell technology to analyze tissue from patients with multiple lung tumors, examining tens of thousands of individual cells to understand how tumors progress from early precancerous changes to invasive cancer. Unlike traditional approaches that classify tumors into simple categories, our method captures the continuous spectrum of tumor progression- a way to measure their disease state on a scale rather than simply categorizing them as "sick" or "healthy." This approach can identify tumors in dangerous transitional states that might be missed by conventional testing. We will develop three molecular signatures: one to help predict how advanced a tumor is on the progression spectrum, one to help predict response to radiation therapy, and one characterizing the immune environment. These signatures will be designed for use with standard clinical testing platforms, enabling future validation in stored tissue samples.
This research addresses a growing clinical need as lung cancer screening identifies more patients with multiple suspicious lung nodules. Our goal is to provide physicians with molecular tools to personalize treatment decisions: helping patients receive appropriate intervention when needed while avoiding unnecessary procedures when tumors can be safely monitored.
Multifocal lung adenocarcinoma (MAC) affects up to 20% of lung cancer resection cases, yet no molecular framework exists to distinguish indolent from aggressive lesions or guide treatment decisions between stereotactic body radiation therapy (SBRT), surgery, or surveillance. Current management relies on radiographic features that poorly predict molecular behavior, leading to potential undertreatment of aggressive lesions or overtreatment of indolent disease.
We hypothesize that single-cell transcriptomic profiling can define continuous progression states that, combined with inferred genomic features and immune contexture, will distinguish indolent from aggressive lesions and predict clinical trajectory. We will perform single-nucleus RNA sequencing on surgical specimens from 9 patients with MAC from the MGH Lung Tumor Bank (27 samples: matched normal lung, precursor lesions, and invasive adenocarcinoma) and integrate these data with a published cohort of 25 patients (75 samples, ~800,000 cells) spanning the Normal-AAH-AIS-MIA-LUAD progression spectrum.
In Aim 1, we will apply the Cell-Projected Phenotype (CPP) framework to map progression landscapes across cell types. CPP transforms discrete histopathological labels into continuous scores capturing the spectrum of disease states, amplifying statistical power by treating cells rather than patients as informative observations. Our preliminary data demonstrate CPP scores correlate with histological stage and variant allele frequency from whole-exome sequencing, validating transcriptional-genomic concordance. We will identify populations with intermediate phenotypes representing transitional states, perform trajectory inference, and conduct meta-analysis across cohorts to identify robustly replicated progression signatures. Transcription factor regulon analysis will prioritize master regulators driving stage transitions.
In Aim 2, we will infer copy number variations using CopyKAT and single nucleotide variants using Monopogen from transcriptomic data, correlating genomic evolution with phenotypic states. Phylogenetic reconstruction will distinguish shared truncal drivers (field cancerization) from independent evolutionary trajectories (synchronous primaries). We will characterize immune contexture across progression states, examining HLA expression and antigen presentation machinery. Leveraging these data, we will develop three multivariate signatures using elastic net regularization: (1) CPP-derived progression signature, (2) radiation response signature incorporating DNA damage repair pathways, and (3) immune contexture signature. Signatures will be designed for compatibility with bulk RNA platforms to enable future validation in archival specimens.
This study will establish the first continuous molecular framework for MAC progression, generating candidate signatures for prospective validation in an identified cohort of 120 patients with MAC, with longitudinal outcomes following local therapy.
This grant was funded in part by RETpositive
Patients with RET+ NSCLC respond well to drugs called tyrosine kinase inhibitors (TKIs). However, most patients eventually develop resistance to TKIs over time. This resistance is caused by drug-tolerant persister (DTP) cells that adapt and evolve to evade treatment. In this project Dr. Patil aims to better understand how these DTP cells survive and how to eliminate them before resistance develops by studying special cellular pathways that are thought help DTP cells survive. He will test combinations of RET TKIs with drugs that block these pathways, with the goal of finding drug combinations that delay or even prevent resistance from developing in the first place. Because many of the drugs he will be testing are already used in other cancers, this could lead to new treatments for RET+ lung cancer patients.
Patients with RET fusion-positive non-small cell lung cancer (RET+ NSCLC) often respond very well to targeted drugs called RET tyrosine kinase inhibitors (RET TKIs). These medicines can shrink tumors quickly and improve symptoms. However, most patients eventually develop drug resistance, allowing the cancer to grow again. One important reason for this resistance is that a small group of cancer cells can survive treatment. These “drug-tolerant persister” (DTP) cells are not fully resistant at first, but they adapt to survive under drug pressure and can later evolve into permanently resistant cancer cells.
This project aims to better understand how DTP cells survive and identify new ways to eliminate them before resistance develops. We believe that RET inhibitors place stress on cancer cells as they attempt to divide, forcing DTP cells to rely on special DNA repair and cell-cycle checkpoint pathways to survive. These pathways may represent unique weaknesses that can be targeted with additional drugs.
Using laboratory cell lines, patient-derived tumor models, mouse models, and patient biopsy samples, we will test combinations of RET TKIs with drugs that block DNA damage repair and cell-cycle pathways, including ATR, CHK1, and WEE1 inhibitors. We will also study patient tumor samples collected before treatment, during treatment response, and after resistance develops to understand how these survival pathways change over time. Our goal is to identify treatment combinations that can delay or prevent resistance to RET-targeted therapy. Because many of these drugs already exist and are being tested in other cancers, successful results from this work could rapidly lead to new clinical trials for patients with RET+ lung cancer.
RET fusion-positive non-small cell lung cancer (RET+ NSCLC) demonstrates profound initial sensitivity to selective RET tyrosine kinase inhibitors (TKIs); however, acquired resistance remains inevitable. Emerging evidence suggests that resistance evolution is preceded by the persistence of drug-tolerant persister cells (DTPs), a phenotypically plastic, slow-cycling subpopulation that survives RET inhibition in the absence of new genomic alterations. We hypothesize that RET inhibition induces replication stress and adaptive cell-cycle rewiring in RET+ DTPs, generating synthetic dependencies on ATR/CHK1/WEE1-mediated DNA damage response (DDR) and cell-cycle checkpoint control (CCC) pathways. Because several RET fusion partners, including KIF5B, CCDC6, and TRIM24, regulate mitotic progression, checkpoint signaling, and DNA repair, RET-driven tumors may exhibit unique vulnerabilities during DTP-mediated cell-cycle re-entry.
To interrogate these vulnerabilities, we will evaluate combinations of RET TKIs with DDR/CCC inhibitors using murine RET-driven models (TR.1/TR.2, Trim24-RET), patient-derived RET+ cell lines (CUTO22, CUTO32, CUTO42), and organoid systems. Candidate agents include ceralasertib, prexasertib, olaparib, abemaciclib, adavosertib, and alisertib. Drug sensitivity, proliferation kinetics, apoptosis, and checkpoint activation will be quantified using immunofluorescence-based cell-cycle analyses and IC50 modeling. Lead combinations will subsequently be validated in orthotopic RET-driven lung cancer models, with endpoints including tumor regression, time-to-progression, and tolerability.
Complementary longitudinal spatial single-cell profiling of pretreatment, on-treatment, and resistant RET+ NSCLC patient specimens will define therapy-associated replication stress and proliferative states using multiplex imaging of Ki-67, phospho-Rb, phospho-CHK1, and ?-H2AX. Collectively, these studies aim to establish mechanistically informed combinatorial strategies targeting DTP-specific checkpoint dependencies to delay or prevent acquired resistance to RET-directed therapy.
This grant was funded in part by RETpositive
RET-positive cancers are treated with selective RET inhibitors (SRIs). However, resistance and tumor progression eventually occur. Current approaches to combat this are ineffective due to the ability of resistant tumors to acquire different genetic mutations while increasing in numbers. In this project, Dr. Wu will investigate the use of SRIs in combination with FDA-approved antibody-drug conjugates (ADCs), which kill proliferating tumor cells while sparing healthy cells - to target residual tumors. If successful, this could change treatment strategies for RET-positive cancers. Simultaneously, Dr. Wu will also develop a clinical trial protocol for SRI-ADC combination therapy in people with RET-positive cancers.
RET-positive lung, thyroid, or other cancer types are treated with selective RET inhibitors (SRIs) selpercatinib and pralsetinib. Unfortunately, most patients treated with SRIs have drug-tolerant residual tumors that eventually progress. Current approach is to co-inhibit RET and specific genetic mutations that drive rapid growth of resistant tumors when the disease progresses. However, the effectiveness of this approach is short-lived, because metastatic tumors can acquire many different mutations, which quickly exhaust possible drug combinations. Thus, rather than co-targeting individual genetic mechanisms, we believe that a better strategy is to co-target RET and a converged vulnerability shared by all non-genetic and genetic mechanisms of SRI tolerance before the disease progresses. We identified slow proliferation as a shared vulnerability across different SRI-tolerant residual tumors. Several antibody-drug conjugates (ADCs) that kill proliferating tumor cells while sparing normal cells have been approved by the Food and Drug Administration (FDA) for cancer treatment. In this study, we will evaluate the feasibility and effectiveness of SRI-ADC combination treatment to eliminate SRI-tolerant residual tumors. If it works, our study will reveal a paradigm-shifting approach to 1) increase the depth of tumor response, which in turn will yield a more durable treatment response; and better yet 2) eradicate the residual tumors to achieve a cure. Concurrently, we will develop a clinical trial protocol and seek its approval from the FDA and institutional committees to start a clinical trial of SRI-ADC combination therapy in RET-positive cancer patients.
Most selective RET inhibitor (SRI)-treated cancer patients have SRI-tolerant residual tumors that inevitably progress. Current treatment strategies target genetic mechanisms when the resistance has developed. However, heterogeneity in residual tumors can quickly exhaust the possible drug combinations. Rather than targeting individual genetic mechanisms, a better strategy is to co-target a phenotypical vulnerability shared by non-genetic and genetic mechanisms of SRI tolerance in residual tumors. We identified the slow proliferation activity in SRI-tolerant persisters as a convergent node of their vulnerability, which can be targeted with microtubule (MT) or topoisomerase-I (Topo-I) inhibitors. Recently, MET, TROP2, or ERBB2 antibody-drug conjugates that direct MT or Topo-I inhibitor payloads to carcinoma cells, thus spare normal cells, have been approved for cancer treatment. The goal of this project is to evaluate SRI-ADC combination treatments in RET-altered cancer and to activate a clinical trial of an SRI-ADC combination therapy. The central hypothesis is that an SRI-ADC combination treatment can reduce or eradicate SRI-tolerant residual tumors. Specific Aim 1 will analyze MET, TROP2, ERRB2 expression in a panel of RET-altered cancer cells, and the activity of SRI-ADC (Teliso-V, Dato-DXd, SG,T-DXd) combinations in these cells. Specific Aim 2 will test SRI-ADC combinations selected from Aim 1 in animal models. In Specific Aim 3, we will prepare a proof-of-concept Phase I/II trial of SRI-ADC combination therapy in RET fusion+ cancer patients. Together, the project could lead to a paradigm-shifting combination therapy to improve outcomes of RET-positive cancer treatment.
This grant was funded in part by Rising Tide Foundation for Clinical Cancer Research
Despite the strong initial efficacy of EGFR inhibitors against EGFR-mutated lung cancer, resistance to drugs like osimertinib usually develops. In this clinical trial, Dr. Parang will combine osimertinib with alectinib, a drug previously approved by the FDA to treat ALK-positive NSCLC, to treat patients with stage IV EGFR-mutant NSCLC. Alectinib is also known to inhibit a gene called FER, which has shown to be activated in drug-tolerant persister cells (DTPs). Dr. Parang hypothesizes that inhibiting FER with alectinib will eradicate DTPs and prevent resistance to osimertinib. If successful, this will provide a new and well-tolerated treatment regimen for stage IV EGFR-mutant NSCLC that reduces residual disease.
Despite tremendous therapeutic breakthroughs, patients with Stage 4 EGFR-mutated lung cancer have a poor prognosis. Their overall 5-year survival is less than 50%. This poor prognosis is largely because of one key challenge: the failure of EGFR-inhibitors like osimertinib to eliminate lung cancer completely. Osimertinib works great initially, but there is almost always “residual” cancer that persists. Eventually, the residual disease grows and creates problems for patients. Curing EGFR-mutated lung cancer requires targeting and killing this residual cancer.
We now have exciting data strongly suggesting that residual EGFR-mutant cancer relies on a key gene called FER. And if we target FER we can eradicate and kill the residual cancer that osimertinib can not. There is currently an FDA approved drug that unintentionally happens to be a potent inhibitor of FER. This proposal will test whether inhibiting FER using an FDA-approved drug is safe and effective in patients with EGFR-mutant lung cancer. It will be the first clinical trial that blocks FER in patients with cancer.
Veterans in the US face a higher risk of developing lung cancer due to increased tobacco exposure and occupational exposure to carcinogens. The VA has developed one of the country's largest lung cancer screening programs using yearly low-dose CT scans. While it is known that screening saves lives, it is not known what happens afterward to patients whose cancer is caught via screening. In this project. Dr. Heiden will study the VA records of more than 100,000 Veterans diagnosed with lung cancer over the past ten years, comparing those who had their lung cancer discovered via screening to those whose lung cancer was found in other ways, to see if there are differences in their stage at diagnosis, treatments received, and long-term survival. Findings will help the VA improve its screening program, reduce gaps in who gets screened, and improve care for Veterans. Results from this study may also help shape lung cancer screening in non-VA hospitals across the country.
Lung cancer is the leading cause of cancer death in the United States, and Veterans are at increased risk due to relatively higher smoking rates. To catch lung cancer earlier, when it is more curable, the Department of Veterans Affairs has built one of the largest lung cancer screening programs in the country, using yearly low-dose CT scans for eligible Veterans. While we know from earlier studies that screening saves lives, much less is known about what actually happens to individuals after their cancer is found through screening. For example, do they get diagnosed at earlier stages? Do they need less aggressive treatment? Do they live longer and have fewer cancer recurrences than individuals whose cancer is found in other ways, such as after symptoms develop?
No national study has yet answered these questions in a real-world healthcare setting. This project will use the VA's nationwide medical records to study more than 100,000 Veterans diagnosed with lung cancer over the past decade. We will compare Veterans whose cancer was found through screening with those whose cancer was found another way. We will look at how advanced the cancer was at diagnosis, what treatments they received, and how long they lived afterward. The findings will help the VA improve its screening program, reduce gaps in who gets screened, and guide better cancer care for Veterans. Since the VA's screening program is a national model, these results may also help shape lung cancer screening in non-VA hospitals across the country.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in the United States and disproportionately affects Veterans due to elevated smoking prevalence. The Veterans Health Administration (VHA) has established the nation's most comprehensive lung cancer screening (LCS) infrastructure through the National Center for Lung Cancer Screening and the Lung Precision Oncology Program. Although the National Lung Screening Trial and NELSON trial established the mortality benefit of low-dose CT screening among individuals with high-risk smoking histories, national studies are lacking which characterize the real-world presentation, treatment patterns, and long-term outcomes of screening-detected NSCLC within an integrated healthcare system.
We propose the largest national longitudinal cohort study to our knowledge comparing screening-detected and non-screening-detected NSCLC among Veterans diagnosed between 2013 and 2025, leveraging a highly unique VHA dataset of approximately 100,000 patients with NSCLC. Aim 1 will quantify temporal trends in the proportion of NSCLC cases detected through lung cancer screening from 2013-2025. Aim 2 will compare tumor- and treatment-related difference between screening-detected and non-screening-detected cases of NSCLC. Aim 3 will evaluate long-term outcomes, including overall survival and recurrence, between screening-detected and non-screening-detected NSCLC. This work will represent one of the largest national cohort studies to date characterizing the presentation, treatment, and long-term outcomes of screening-detected NSCLC, providing system-wide evidence to optimize lung cancer screening delivery for Veterans and inform civilian healthcare systems scaling similar programs.
Adoptive cell therapy (ACT) is a form of immunotherapy that uses a patient’s T cells to target and destroy cancer cells. There are two main sources for ACT: 1) white blood cells called tumor-infiltrating lymphocytes (TILs) that are taken directly from tumors, and 2) peripheral blood T cells that are genetically modified to specifically kill tumor cells. TILs are limited in their capacity and function due to challenges in extraction and unpredictability in the number of T cells that can be yielded. In this project, Dr. Delgado Cruz aims to produce a more reliable source of T cells for ACT using genetic engineering to develop tumor-draining lymph nodes (tdLNs) that have increased antitumor activity, with the ultimate goal of enhancing ACT efficacy.
Adoptive cell therapies (ACTs) focus on utilizing patient’s immune cells (T cells) and increasing their capacity to Kill Tumor cells. There are two T-cell sources for ACT: 1) tumor-infiltrating lymphocytes (TILs) extracted directly from tumors, and 2) peripheral blood T cells that are genetically modified to specifically kill tumor cells. TILs are therapeutic in various solid tumors. However, most TILs have limited expansion capacity and function, requiring IL-2 treatment that can be toxic to the patient. It has been shown that naïve-like T cells in the TIL product, correlates with positive therapeutic responses, suggesting that less exhausted T cells are critical for a response.
Research indicates that tumor-draining lymph nodes (Lymph node(s) closest to the tumor) or tdLN may serve as a specialized niche for T cells that recognize tumor neoantigens and possess stem cell-like characteristics suitable for ACT. Our work shows that tdLNs serve as a highly functional third source of tumor-reactive T cells. tdLNs are easily accessible and highly amenable to genetic engineering/expansion. We propose engineering polyclonal tdLNs with 80BB (a co-stimulatory receptor increasing T cell function) may overcome ACT resistance. Resulting in highly effective and more accessible T cell products.
Two primary methodologies for adoptive cell therapy (ACT) utilize distinct cell sources: 1) tumor-infiltrating lymphocytes (TILs) harvested directly from tumors, and 2) peripheral blood T cells genetically modified with either T cell receptor (TCR) or chimeric antigen receptors (CARs) targeting cancer antigens. TIL-ACT relies on autologous T cells capable of recognizing a broad range of tumor neoantigens, making it ideal for therapy of different solid tumors.
However, it faces critical challenges: 1) TIL extraction is complex, time-intensive (5–8 weeks), yields unpredictable lymphocyte numbers; 2) high levels of T cell exhaustion result in limited persistence; and 3) it requires inpatient IL-2, with high risk of severe adverse events.
Despite careful patient selection, ~30% of patients cannot receive treatment post-harvest due to insufficient T cell yield or disease progression. Thus, a more reliable source of less-exhausted, tumor-specific T cells could transform ACT for solid tumors. Our preliminary data on non-small cell lung cancer (NSCLC) shows that tumor-draining lymph nodes (tdLNs) serve as a highly functional third source of tumor-reactive T cells (LNTs). tdLNs offer easy access and are a reliable reservoir of stem-like T cells with broad, tumor-relevant clonal diversity that are highly amenable to genetic engineering. Moreover, engaging both CD28 and 4-1BB co-stimulation in engineered T cells has shown enhanced antitumor activity. We propose engineering polyclonal tdLNs with 80BB (a fusion of CD80 ectodomain to the endodomain of 4-1BB) may overcome ACT resistance. We also propose that tdLN T cells can be easily expanded, resulting in highly effective and more accessible T cell products.
Immune checkpoint inhibitors (ICIs) have improved outcomes for many patients with advanced NSCLC. However, despite biomarkers such as PD-L1 expression and tumor mutational burden (TMB), it is still difficult to predict which patients will benefit from immunotherapy, and for how long. In this study, Dr. Guevara Rodriguez will utilize existing VA genomic and clinical databases to examine genomic and treatment-related factors associated with immunotherapy outcomes in the Veteran population. The overall objective is to develop a VA-based, equity-informed precision oncology framework integrating comprehensive genomic profiling with longitudinal treatment exposure and clinical outcomes to characterize durable immunotherapy benefit in Veterans with stage IV NSCLC.
Immune checkpoint inhibitors (ICIs) have improved outcomes for many patients with advanced non–small cell lung cancer (NSCLC). However, while some patients experience prolonged disease control and survival, others develop early progression despite receiving similar treatments. Current biomarkers such as PD-L1 expression and tumor mutational burden only partially explain these differences, and clinicians still have limited ability to predict which patients will derive durable benefit from immunotherapy.
Veterans with lung cancer represent a particularly important population because they often have substantial tobacco exposure, multiple chronic medical conditions, rural residence, and complex long-term care needs that may influence cancer outcomes and access to precision oncology. The Veterans Health Administration (VHA) and the VA National Precision Oncology Program (NPOP) provide a unique opportunity to study genomic and treatment-related factors associated with immunotherapy outcomes in a large national Veteran population.
This study will evaluate whether specific genomic co-mutation patterns identified through comprehensive genomic profiling (CGP) are associated with durable benefit from ICIs in Veterans with advanced NSCLC. Using existing VA genomic and clinical databases, we will analyze treatment duration, disease progression, and survival outcomes among Veterans treated with immunotherapy. We will also evaluate whether race, rural residence, and comorbidity burden influence access to CGP and immunotherapy outcomes.
The goal of this project is to better understand why some Veterans benefit from immunotherapy longer than others and to support more personalized and equitable approaches to lung cancer treatment.
Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced non–small cell lung cancer (NSCLC), yet substantial heterogeneity in treatment duration and survival remains poorly understood. Although PD-L1 expression and tumor mutational burden (TMB) provide partial predictive value, integrated genomic co-mutation phenotypes associated with durable immunotherapy benefit remain incompletely characterized in real-world populations, particularly among Veterans.
We propose a retrospective multi-site cohort study using Veterans Health Administration (VHA) and VA National Precision Oncology Program (NPOP) data to evaluate associations between comprehensive genomic profiling (CGP)-derived genomic phenotypes and immunotherapy outcomes in Veterans with stage IV NSCLC treated with immune checkpoint inhibitors. Genomic data from Foundation Medicine and Tempus platforms will be integrated with longitudinal treatment exposure and survival outcomes.
The primary outcome will be durable immunotherapy benefit, defined as treatment duration =12 months without radiographic progression or death following ICI initiation. Secondary outcomes will include overall survival, time-to-treatment failure, and longitudinal treatment exposure patterns. Multivariable logistic regression and Cox proportional hazards models will evaluate associations between genomic phenotypes and clinical outcomes while adjusting for demographic, clinical, and treatment-related covariates. Interaction and stratified analyses will evaluate whether race, rural residence, and comorbidity burden influence CGP utilization and modify genomic predictor performance.
This study leverages existing VA precision oncology infrastructure and a large national Veteran cohort to better characterize genomic patterns associated with durable immunotherapy benefit in advanced NSCLC. Findings from this project may inform future biomarker-guided immunotherapy strategies and improve equitable implementation of precision oncology within the VHA.
This grant was funded in part by Rising Tide Foundation for Clinical Cancer Research
Low-density computed tomography can catch lung cancer early, but most lung nodules it detects are benign. Current tools can't reliably tell dangerous nodules from harmless ones. The problem is worst for intermediate-risk nodules, which account for most diagnostic dilemmas. As a result, patients often undergo unnecessary biopsies and surgeries, some cancers are diagnosed late, patients face prolonged anxiety, and healthcare costs rise. This project will validate a diagnostic tool that combines computer analysis of CT images (radiomics) with a blood test for cancer-related DNA changes. If successful, the tool could speed accurate diagnosis, spare patients with benign nodules from invasive procedures, and provide doctors with personalized risk assessment tools to guide treatment decisions.
Lung cancer is the leading cause of cancer-related deaths in both the United States and worldwide. Although screening with low-dose CT scans can detect lung cancer earlier and reduce mortality, many people who develop lung cancer do not meet current screening guidelines. Most lung cancers are still diagnosed at an advanced, incurable stage, including in patients who have never smoked. Lung cancers are often first seen on CT scans as abnormal opacities, called nodules if smaller than 3 cm and masses if larger. However, most lung nodules are not cancerous, making it difficult for doctors to determine who needs additional testing or invasive procedures. As a result, many patients undergo unnecessary biopsies or surgeries. There is a critical need for better, noninvasive tools to accurately identify which nodules are likely to be cancer.
We have developed a novel, noninvasive approach that combines two powerful technologies: advanced imaging features from CT scans (radiomics) and a blood test that analyzes DNA methylation patterns in circulating cell-free DNA (cfDNA), which can reflect early cancer changes. This integrated “multimodal biomarker” uses artificial intelligence to combine these data sources and assess whether a lung nodule is likely to be malignant.
Our preliminary research has shown that this combined method can accurately distinguish cancerous from benign nodules, including at early stages. In this study, we will validate the performance of our biomarker in a prospective, real-world cohort of 500 patients with lung nodules undergoing diagnostic evaluation at UCLA and the VA Greater Los Angeles Healthcare System. We will also evaluate how well the test performs across different patient groups, including smokers, non-smokers, and across various nodule types.
If successful, this biomarker could lead to earlier diagnosis of lung cancer, reduce unnecessary procedures in patients with benign nodules, and support more personalized decision-making. Ultimately, our goal is to bring this tool into clinical practice to help doctors manage lung nodules more effectively using both imaging and a simple blood test.
This grant was funded in part by Rising Tide Foundation for Clinical Cancer Research. Supported in part by Upstage Lung Cancer
Lung cancer is often found too late, and rates are rising even as tobacco use declines, especially among women, which points to other factors such as air pollution and genetics. Current tools for assessing lung nodule risk rely heavily on tobacco exposure history, making them less reliable as more people without tobacco exposure (non-smokers) develop the disease. This leads to unnecessary procedures and surveillance for some patients and dangerous diagnostic delays for others. Sybil, an AI tool, predicts future lung cancer risk from chest CT scans alone, without medical history or doctor annotations. The RESOLVE study will test Sybil's accuracy in patients aged 35 to 75 with lung nodules and evaluate whether its scores improve clinical decisions and follow-up scheduling. If successful, Sybil could enable personalized care, with closer monitoring for high-risk patients and fewer unnecessary procedures for low-risk ones. It could be especially valuable for people who don't qualify for traditional screening but still face elevated risk.
Risk factors for lung cancer are incompletely understood. As tobacco use falls globally, lung cancer rates continue to rise, especially among women, and air pollution, genetics, and other factors are thought to contribute. Powerful and validated tools to risk stratify individuals in terms of their lung cancer risk are lacking. We developed a novel artificial intelligence tool called Sybil that is able to visually examine the total volumetric imaging data contained within a chest CT to assess patterns imperceptible to human clinicians and make predictions about underlying lung cancer risk without the need for demographic or medical information, or clinician annotation of the images. Sybil’s performance has been well validated in a wide variety of patients who qualify for lung cancer screening.
In this project, we will study Sybil among people with pulmonary nodules on their chest CT. Pulmonary nodules are relatively common, and our preliminary work has shown that the lung cancer rate in this population is significantly higher than among those who qualify for lung cancer screening, even though the population with known pulmonary nodules has less tobacco exposure. The best way to risk-stratify and work-up patients with pulmonary nodules remains unclear and hence diagnosis of early-stage cancers can be needlessly delayed and we risk losing track of patients while following nodules. We will perform a prospective multi-site clinical trial to demonstrate that Sybil has high performance in risk stratifying people with pulmonary nodules. Confirming Sybil’s performance in this study is the first step toward incorporating Sybil into clinical decision-making algorithms to improve outcomes for people with pulmonary nodules.
Lung cancer is the leading cause of cancer deaths, with patients with EGFR-mutant NSCLC frequently developing brain metastases that are difficult to treat with existing therapies. Dr. Brea and his team are studying CAR-T cells that target TROP2, a protein commonly found on EGFR-mutant lung cancer cells. Targeting TROP2 can be diffficult because TROP2 is found on healthy cells. To overcome this, Dr. Brea proposes two approaches: (1) delivering CAR-T cells directly into the central nervous system (CNS). The CNS does not express TROP2 but is a site where tumors often reside, and (2) genetically editing the CAR-T cells to prevent them from entering healthy organs like lungs and gut. If successful in preclinical testing, this could provide a new targeted treatment option for patients with EGFR-mutant lung cancer with brain metastases.
Lung cancer is the leading cause of cancer-related deaths, and patients with a specific type called EGFR-mutant non-small cell lung cancer (NSCLC) often develop spread to the central nervous system (CNS). These CNS metastases are difficult to treat and are not well controlled by existing therapies like radiation or even high doses of targeted pills such as Osimertinib. Many clinical trials exclude patients whose cancer has spread to the CNS, leaving few treatment options for this vulnerable group.
We are developing a promising new approach using the patient’s own immune system, called CAR-T cell therapy. We have demonstrated that CAR-T cell that targets a protein called TROP2, which is commonly found on EGFR-mutant lung cancer cells, is effective against EGFR-mutant NSCLC. One barrier to translation to trials is that CAR-T cells can also harm healthy tissues that have TROP2. To overcome this, we propose two key innovations: first, we will deliver the CAR-T cells directly into the CNS in patients with metastatic CNS, where tumors reside but TROP2 is not expressed in normal CNS, avoiding toxicity. Second, we will edit the CAR-T cells to remove a molecule that allows them to enter normal tissues like the lungs and gut, further reducing side effects. Our research will test this strategy in patient derived preclinical models to show that it is both safe and effective. If successful, this could lead to a new, highly targeted treatment for patients with EGFR-mutant lung cancer with CNS metastases.
EGFR-mutant non-small cell lung cancer (NSCLC) frequently metastasizes to the central nervous system (CNS). While EGFR inhibitors such as Osimertinib or radiation can be effective initially, patients often develop further CNS progression with limited durable options. Moreover, patients with active CNS disease are often excluded from clinical trials, leaving a critical unmet need for more effective and CNS-active therapies. We have developed a novel TROP2-directed chimeric antigen receptor (CAR)-T cell therapy for EGFR-mutant NSCLC. TROP2 is a clinically validated target in this setting, with high expression in EGFR-mutant tumors and preserved expression in CNS metastases.
Our preclinical studies show that TROP2 CAR-T cells display potent cytotoxicity, superior to TROP2-directed antibody-drug conjugates. However, systemic delivery of CAR-T cells targeting epithelial antigens carries substantial risk of on-target/off-tumor toxicity. To address this, we propose a combinatorial strategy: (1) localized intraventricular delivery of TROP2 CAR-T cells to the CNS, and (2) CRISPR/Cas9-mediated knockout of the integrin aEß7, a homing molecule that mediates T cell trafficking to epithelial tissues. This approach is designed to retain efficacy while reducing systemic toxicity. We will evaluate TROP2 and aEß7 expression in patient CNS metastases, optimize TROP2 CAR-T designs using patient derived ex vivo and vascularized tissue platforms, and test safety and efficacy in EGFR-mutant CNS xenograft models and humanized TROP2 transgenic mice. This proposal advances a rationally engineered CAR-T strategy for a patient population with few options and lays the groundwork for a CNS-directed clinical trial.
EGFR gene alterations are found in 15%-30% of lung adenocarcinomas (LUADs). While EGFR-targeted therapies are initially effective, most patients eventually relapse due to treatment resistance. Recent research has identified "persister cells" - tumor cells that survive throughout targeted treatment and are believed to be a primary cause of cancer recurrence in EGFR-mutant LUAD. This project aims to understand how these persister cells survive despite targeted therapy and identify ways to eliminate them. The ultimate goal is to identify resistance factors, develop therapeutic strategies to eradicate persister cells, and provide the scientific foundation for clinical trials to improve outcomes for patients with EGFR-mutant LUAD.
Alterations in the EGFR gene are present in ~15-30% of all lung adenocarcinomas (LUADs). EGFR targeted therapies are initially effective, but most LUADs eventually relapse. Recent studies suggest some tumor cells survive throughout targeted treatment. These cells, called “persister cells”, are thought to be a primary mechanism of relapse in some patients with EGFR-mutant LUAD. In this project, we aim to study how these persister cells remain healthy despite treatment with targeted therapy and to identify targets to eliminate them. We will use cutting-edge technologies to study the biology of persister cells in clinical samples and mouse models. We will identify and validate factors causing resistance to therapy, propose therapeutic strategies for the eradication of persister cells, and provide the preclinical rationale for the initiation of clinical trials to improve outcomes for patients with EGFR-mutant LUAD.
Up to 40% of resistance mechanisms to EGFR targeted therapies in lung adenocarcinoma (LUAD) are unknown. Drug tolerant persister cells (DTPs) constitute a reservoir of therapy resistant cells that can be found even in never-treated LUAD tumors and survive during the minimal residual disease (MRD) stage despite the ongoing pressure of targeted therapy, leading to lung cancer relapse. These cells do not harbor classical genetic alterations such as secondary mutations in EGFR. Importantly, several preclinical studies have shown that this drug tolerance state is reversible after drug removal, supporting the involvement of epigenetic rather than genetic resistance mechanisms. However, the biology of DTPs, and in particular their epigenetic landscape, is largely unknown. The eradication of DTPs is crucial for improving outcomes for patients with EGFR-mutant LUAD. In this proposal we will integrate single-cell transcriptome and epigenome analyses to nominate drivers of drug tolerance.
We will (1) characterize MRD biospecimens at single-cell level to investigate the distinct transcriptomic MRD subclusters and determine the molecular and cellular dynamics of MRD samples. Collecting MRD clinical samples is highly challenging since re-biopsies are not standard practice. Therefore, insights gained from this analysis will be very valuable in understanding the mechanisms underlying drug tolerance in EGFR-mutant LUAD.
We will (2) leverage our unique set of patient-derived xenografts (PDXs) to mimic MRD in vivo and characterize the dynamics of resistance to osimertinib (3rd generation EGFR targeted therapy) in these models. We will perform a comprehensive transcriptomic and epigenetic characterization by single-cell RNAseq, chromatin immunoprecipitation sequencing, ATACseq and methylation analysis to decipher the epigenetic reprogramming that occurs over time. The integration of our transcriptomic and epigenomic data from these models will nominate molecular pathways and targets associated with drug tolerance and resistance.
Finally, (3) we have identified EP300 in an in vivo CRISPR screen as a druggable epigenetic vulnerability in osimertinib-treated DTPs. EP300 along with other candidates previously identified in clinical samples and PDXs, will be extensively validated in vitro and in vivo. This proposal will provide knowledge of the mechanisms underlying drug tolerance and resistance in patients with EGFR-mutant LUAD and may gather robust preclinical data to propose novel therapeutic strategies to be evaluated in clinical trials.
Lung cancer is the leading cause of cancer deaths globally. While immunotherapy has improved survival rates, many tumors don't respond due to mutations that can lead to poor treatment outcomes. In this project, Dr. Woodard will investigate how T cells are prevented from entering tumors with specific mutations and explore ways to enhance T cell migration to improve immunotherapy response. She will focus on PLA2G10, a protein that blocks T cell entry into lung tumors, examining how it prevents CD4+ and CD8+ T cell migration and its relationship with common lung cancer mutations. The goal is to understand and improve T cell exclusion mechanisms to make immunotherapy more effective.
Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. Immunotherapy has led to dramatic improvements in survival, but not all tumors respond with certain mutations predicting a poor immunotherapy response. This award will test a hypothesis of how T cells are excluded from tumors with certain mutations and study how to improve T cell migration into tumors as a way to improve tumor response to immunotherapy. PLA2G10 is a protein that mediates T cell exclusion from lung tumors, we will study how this protein prevents migration of CD4+ and CD8+ T cells and we will study its association with common lung cancer mutations.
NSCLC is the leading cause of cancer related mortality in the United States and worldwide. Immune checkpoint inhibitors that target the programmed cell death-ligand 1 (PD-L1) pathway have revolutionized the outcomes of NSCLC; however, only a minority of patients obtain clinical benefit from immunotherapy. PLA2G10 is a protein that mediates T-cell exclusion by inhibiting migration of CD4+ and CD8+ T-cells and its association with common lung cancer mutations is unknown. Lung cancer mutations such as tumor suppressor gene Serine/threonine kinase 11 (STK11), are associated with decreased immune cell infiltration into the tumor and associated with immunotherapy resistance.
The proposed project will utilize the resources of the Yale Lung SPORE BioRepository of treatment naïve and immunotherapy treated surgically resected, stage I-III NSCLC tumor samples. We will then study the immune tumor immune microenvironment in relation to PLA2G10 overexpression in tumors with and without STK11 mutations (Aim 1). The impact of STK11 mutations and PLA2G10 will then be studied on T-cell migration in lung cancer cell lines (Aim 2). Our hypothesis is that PLA2G10 expression is a driving mechanism for T cell exclusion observed in STK11mut tumors. We propose to demonstrate that inhibition of PLA2G10 in STK11mut cell lines will improve T-cell migration and sensitize tumors to immunotherapy. Thus, we will explore PLA2G10 as a novel therapeutic target in immunologically cold tumors and future applications of this research would be to study drug combinations that overcome T-cell exclusion as an immunotherapy resistance mechanism.
