Research Database

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.   

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.

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.

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.

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.

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. 

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 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.

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.

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.

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 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.

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.

Black Veterans face disproportionately higher rates of lung cancer diagnosis and death compared to other groups. Despite lung cancer screening (LCS) being life-saving through early detection, many Black Veterans remain unscreened due to low awareness, distrust of the VA system, and negative beliefs about lung cancer outcomes. This research aims to address these barriers by partnering with the National Association for Black Veterans (NABVETS) to co-design and test a community-based LCS awareness toolkit that can be distributed through trusted community organizations. 

Dr. Ogidigo will investigate how obesity affects lung cancer progression using a diet-induced obesity mouse model. She will focus on understanding how obesity-driven metabolic and chromatin changes influence lung tumor biology, and test incretin mimetics (metabolism-targeting drugs such as GLP1 agonists) as potential treatments to slow tumor growth in obesity models of lung cancer. By identifying obesity-specific molecular mechanisms and therapeutic targets, she aims to develop more effective, personalized treatment strategies for lung cancer patients with obesity or metabolic dysfunction.

While immunotherapy has significantly improved outcomes for non-small cell lung cancer (NSCLC), many patients still don't benefit from current treatments. Dr. Oh has developed a CCL21-DC vaccine that uses engineered dendritic cells (DCs) to display tumor mutations and train the immune system while producing CCL21 protein to attract more tumor-killing T cells. He has completed a clinical trial combining this vaccine with pembrolizumab immunotherapy in patients with NSCLC, and collected tumor biopsies and blood samples before and after treatment. Using advanced sequencing techniques on these samples, he aims to understand how the vaccine affects tumor-targeting T cells and their interactions within tumors. These studies will guide future improvements in DC vaccines and other immunotherapies for lung cancer patients.

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. 

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. 

Dr. Grippin will investigate how mRNA vaccines can be combined with radiation therapy to improve lung cancer treatment outcomes. Preliminary data shows that NSCLC patients who received mRNA vaccines alongside radiation and immune checkpoint inhibitors had better survival rates. The study aims to optimize this combination therapy to overcome resistance in immune-refractory lung cancer as well as develop enhanced mRNA vaccine formulations. The findings will provide additional data for clinical trials integrating mRNA vaccines into standard lung cancer care, potentially making immunotherapy more effective.

Dr. Deutsch’s proposal centers around finding better pathologic predictors of response to neoadjuvant IO in early stage NSCLC.  She will utilize machine learning/artificial intelligence to test an algorithm that she and her team have developed that assesses percent residual viable tumor (%RVT), which is the amount of tumor left at the time of surgery.  Dr. Deutsch will also characterize tissue specimens using a novel immunofluorescence platform to identify cell types and spatial relationships that are associated with patient benefit to immunotherapy+chemotherapy.  This approach can help inform which patients should receive a given therapy, how they will respond, and additional possible targets for the development of new therapies.