We fund translational research to move knowledge as quickly as possible from basic discovery to treatment of patients.
Since 2002, LUNGevity has invested in 200 research projects at 69 institutions in 24 states and the District of Columbia, for a total of $55,743,471.02.
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.
This grant was funded in part by American Society for Radiation Oncology
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.
Immune checkpoint inhibitors (ICIs) help the immune system fight cancer, but many tumors still resist these therapies. mRNA vaccines, like those originally developed for COVID-19, may help boost the immune system’s response to cancer, but scientists don’t fully understand how to use them effectively. We have spent a decade studying mRNA vaccines, and recently discovered a new way that they generate immune responses against tumors. On a high level, we found that mRNA vaccines, even when they are directed against infectious diseases like COVID, activate the immune system to be on high alert for cancer. Since radiation acts in a similar way, we hypothesize that both of those therapies will synergize to help each other work more effectively.
Our early research in both patients and mice supports this hypothesis, demonstrating that patients who received radiation prior to mRNA vaccines had improved survival relative to their peers. To confirm this hypothesis further, we will study how the timing of radiation therapy affects the ability of mRNA vaccines to shrink tumors. We will also experiment with different mRNA vaccine formulations that we think will make them stronger immune stimulants. By combining mRNA vaccines and radiation, we hope to create more effective, accessible, and long-lasting cancer immunotherapies for patients who need them most.
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet many tumors remain resistant. mRNA vaccines have emerged as a promising strategy to enhance antitumor immunity, but their optimal integration with radiation therapy is not well understood. Our recent clinical findings suggest that mRNA vaccines potentiate ICI responses through mechanisms linked to Type I interferon (IFN), a key mediator of radiation-induced immune activation. Notably, we found that patients with non-small cell lung cancer (NSCLC) and metastatic melanoma who received an mRNA vaccine within 100 days of ICI initiation had nearly double the median overall survival (OS), with the most pronounced benefit observed in those receiving pre-vaccine radiation therapy (Grippin, Nature, In Revision). Based on this data, we hypothesize that methods to increase Type I IFN signaling including pre-vaccine radiation will augment responses to mRNA vaccines. To investigate this hypothesis, we propose the following Specific Aims:
1. Interrogate the interactions of radiation and mRNA vaccines. Mice will receive mRNA vaccines, ICIs and radiation therapy before, concurrently, or after vaccination. Tumor growth and immune responses will be analyzed to assess whether pre-vaccine radiation enhances mRNA vaccine efficacy via Type I IFN signaling.
2. Engineer next-generation mRNA cancer vaccines that maximize Type I IFN production. This aim will test the hypothesis that modifications to mRNA vaccines that enhance Type I IFN stimulation will enhance their antitumor effects.
This work will provide critical mechanistic insights into how radiation therapy synergizes with mRNA vaccines and guide the development of more effective cancer immunotherapy strategies. These findings will lay the foundation for clinical trials integrating mRNA vaccines into radiation regimens, with the potential to overcome resistance and improve patient outcomes in immune-refractory cancers.
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.
Lung cancer is the leading cause of cancer-related death in the United States. Black Veterans are especially affected, facing higher rates of both lung cancer diagnosis and death compared to other groups. Although lung cancer screening (LCS) can save lives by finding lung cancer early, many Black Veterans have not been screened. This is often due to low awareness, lack of trust in the VA, and negative beliefs—such as thinking that lung cancer always leads to death or that it cannot be effectively treated.
My research aims to reduce these barriers and improve LCS uptake among Black Veterans by developing community-based interventions in close partnership with the community. Our study builds on our previous community-based intervention to develop a feasible and scalable solution to increase awareness and uptake of LCS. Partnering with National Association for Black Veterans (NABVETS), a national community-based organization (CBO) that supports Veterans through education, healthcare access, and social connection - we will co-design and test a LCS awareness toolkit that can be shared through trusted CBOs like NABVETS. This work is the first step toward a larger, randomized trial that will test the effectiveness of a culturally relevant and tailored intervention, developed in partnership with Black Veterans, to improve awareness of and uptake of LCS.
Lung cancer is the leading cause of cancer-related death in the United States, with Black Veterans facing disproportionately high rates of both lung cancer incidence and mortality. Despite the potential of lung cancer screening (LCS) to reduce lung-cancer mortality, barriers such as low awareness of LCS, mistrust of the VA, stigma and fatalism about lung cancer have resulted in low uptake, particularly among Black Veterans. There is an urgent need for culturally relevant, community-driven interventions that can increase LCS awareness and uptake among Black Veterans.
My research portfolio seeks to address health disparities in lung cancer and to engage the community in research to develop acceptable and culturally relevant interventions to improve health outcomes. My LUNGevity proposal will expand my team’s prior work by co-designing a scalable LCS awareness toolkit with National Association for Black Veterans (NABVETS), a national community-based organization (CBO) that supports Black Veterans (Aim 1) and conducting a feasibility pilot of this intervention (Aim 2). The hypothesis driving this research is that leveraging the expertise and infrastructure of CBOs to disseminate a culturally relevant, scalable LCS awareness toolkit can increase both awareness and uptake of LCS among Black Veterans. This project serves as a foundational step that will guide future research to evaluate the effectiveness of this intervention on a wider scale, ultimately leading to a more sustainable model for improving LCS in Black Veterans through CBOs.
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.
The development of immunotherapy has significantly improved patient outcomes for non-small cell lung cancer (NSCLC). Unfortunately, many patients with NSCLC nevertheless do not benefit from current immunotherapies, and new strategies are required to move the field forward. Our lab has previously developed a cancer therapy called the CCL21-DC vaccine with the goal of overcoming immunotherapy resistance. This treatment involves the injection of dendritic cells (DCs), which are cells specialized in displaying tumor mutations and training the immune system to target those mutations. We have further engineered these DCs to produce CCL21, which is a protein that attracts more tumor-killing T cells. We recently performed a clinical trial studying the combination of the CCL21-DC vaccine and the immunotherapy drug pembrolizumab in patients with NSCLC. This study obtained tumor biopsies and blood samples from patients both before and after DC vaccine injections, and we plan to use these samples to better understand the impact of this therapy on the immune system.
We propose using cutting-edge sequencing techniques to assess whether the CCL21-DC vaccine leads to more tumor-targeting T cells both within the tumor and in the blood. We will also analyze the interactions between these T cells and other types of cells in the tumor. The results of our project will provide a more complete understanding of how DC vaccines impact the immune system and how tumors develop resistance. This project can therefore guide future efforts at improving DC vaccines and other immunotherapies for patients with lung cancer.
The treatment of non-small cell lung cancer (NSCLC) has been transformed by the use of immune checkpoint inhibitors (ICIs), but many patients still do not respond to ICIs or subsequently develop resistance. The efficacy of ICIs is dependent on the recognition of tumor-specific neoantigens by T cells, a process that is supported by dendritic cells (DCs) that present antigens and activate T cells. Abetting the function of DCs thus represents a therapeutic avenue that can help overcome immunotherapy resistance. This goal can potentially be accomplished via direct injection of DCs as a cellular vaccine. DCs can further be engineered to express chemokines, such as CCL21, that promote T cell infiltration into the tumor. The Dubinett Laboratory has previously developed a CCL21-gene modified dendritic cell (CCL21-DC) vaccine, and we have conducted a phase I clinical trial studying the combination of the vaccine with the ICI pembrolizumab.
We plan to study the immunologic effects of the CCL21-DC vaccine using longitudinal patient biospecimens from this trial, including tumor biopsies and peripheral blood samples. The aims of this proposal are to 1) determine post-treatment changes in T cell clonal evolution and immune cell phenotypes; and 2) evaluate spatial relationships between T cells and the tumor microenvironment after treatment. Our objective is to characterize the impact of the CCL21-DC vaccine on antitumor T cell activity and identify cell-cell interactions that influence therapeutic efficacy. The results of these studies will inform future generations of DC vaccines and improve our understanding of immune resistance mechanisms in NSCLC.
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.
This project investigates how obesity and overweight influences lung cancer progression by using a diet-induced obesity (DIO) mouse model. I will assess tumor growth through imaging and analyze transcriptomic, metabolomic, and epigenetic changes linked to overnutrition or obesity. A key focus is understanding how obesity-driven metabolic and chromatin alterations affect lung tumor biology. The study also tests incretin mimetics—metabolism-targeting drugs—for their potential to slow tumor growth in obese or overweight models. By uncovering obesity-specific molecular mechanisms and therapeutic vulnerabilities, this work aims to inform more effective, personalized treatment strategies for lung cancer patients with obesity and associated metabolic dysfunctions.
The overall goal of this project is to improve the quality of life for lung cancer patients. Lung cancer is lethal and accounts for ~20% of all cancer-related mortality in the United States. Lung cancer, a leading cause of cancer-related mortality worldwide, poses significant challenges due to limited therapeutic options and poor survival rates, particularly in the context of obesity.
To address these complexities, this study will utilize a diet-induced obesity (DIO) mouse model along with dietary interventions to investigate the impact of obesity and overnutrition on lung tumorigenesis. We will monitor tumor growth using imaging techniques and conduct transcriptomic and metabolomic profiling to characterize the functional consequences of the obese phenotype at various stages of tumor progression. Furthermore, we will explore the epigenetic landscape of overnutrition and obesity-associated lung cancer by generating a comprehensive genome-wide map of histone modifications and chromatin accessibility. In addition, we will evaluate the therapeutic role of metabolism-related agents in obesity-related lung cancer. Using the DIO mouse model, we will assess the efficacy of monotherapy therapy with incretin mimetic or combination therapy with immune inhibitor in attenuating overnutrition lung cancer progression.
This research will provide unprecedented insights into the molecular mechanisms underlying obesity-associated lung cancer and identify novel therapeutic strategies to improve patient outcomes. The successful completion of this project will offer valuable insights into the interplay between obesity, metabolism, and epigenetics in lung cancer progression. By targeting metabolic and epigenetic vulnerabilities, this research has the potential to advance our understanding of lung cancer biology and pave the way for the development of more effective and improved therapeutic interventions. Ultimately, this work aims to address the unmet need for targeted therapeutic strategies to combat lung cancer and enhance patient outcomes.
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.
Immunotherapy revolutionized the treatment of lung cancer, and is now being extended so patients can receive therapy before surgery. This was supported by a large clinical trial, CheckMate 816 (CM816), where patients with lung cancer showed improved survival when treated with immunotherapy+chemotherapy before surgery, compared to chemotherapy alone followed by surgery. However, there is an unmet need to identify who is most likely to benefit from such an approach. To address this gap, we will apply novel, next-generation pathology biomarkers utilizing machine learning/artificial intelligence and multispectral imaging. Specifically, we have shown that the amount of tumor left at the time of surgery, termed percent residual viable tumor (%RVT), predicts survival. To date, %RVT assessment is primarily performed visually on glass slides using a light microscope. We developed a machine learning-based algorithm for assessing %RVT on digitized glass slides using a small cohort of patients at Johns Hopkins to improve standardization and throughput in preparation for broad usage. Here, we will test the algorithm’s performance in a larger cohort of patients (the CM816 patients). Additionally, we will characterize tissue specimens using the novel multiplex immunofluorescence AstroPath platform, which uses algorithms first developed in astronomy, to identify cell types and spatial relationships that are associated with patient benefit to immunotherapy+chemotherapy. Our goal is to use cutting-edge technologies to improve the care of lung cancer patients by informing which patients should receive a given therapy, how well patients will do after receiving therapy, and possible additional targets for the development of new therapies.
As seen in the phase III trial CheckMate 816 (CM816), neoadjuvant anti-PD-1+chemotherapy improves survival for patients with resectable non-small cell lung cancer (NSCLC), with pathologic response as a major trial endpoint. Our team led the Central Pathology Review for CM816, and we showed the first prospective evidence that the full spectrum of % residual viable tumor (%RVT) associates with event free survival. Given the data supporting pathologic response as a survival surrogate, %RVT will likely be incorporated into the next generation of clinical trials and may ultimately guide clinical decision-making. %RVT is primarily evaluated using visual assessment of routine hematoxylin and eosin-stained slides. We developed a machine learning-based approach to score %RVT, which allows for a standardized approach that can be completed rapidly for a large volume of patients, and we propose to test this algorithm in resection specimens from CM816. Additionally, we will use multiplex immunofluorescence (mIF) to quantify individual features of pathologic response, locate them within the larger tumor bed, and determine the relative contribution in predicting patient outcomes. Furthermore, we will use the novel AstroPath platform, a mIF whole-slide imaging platform that uses algorithms first developed in astronomy to generate tumor-immune maps, to identify additional pre- and on-treatment biomarkers of response. Our goal is to leverage emerging technologies (i.e, machine learning and mIF) to develop the next generation of pathology biomarkers, including pathologic response assessment, and to identify additional features that can potentially be targeted in combination with anti-PD-(L)1+chemotherapy to improve clinical benefit in patients with NSCLC.
The introduction of targeted therapies and immunotherapy for early-stage lung cancer is associated with improved survival, but patients can only benefit if they partake in adjuvant and neoadjuvant therapies. Data has shown that inequalities exist for patients with lower socioeconomic status as well as non-White patients when it comes to being referred for and receiving treatment after surgery. These inequalities are likely to increase as new drugs are developed in clinical trials comprised of predominantly white patients. In this project, Dr. Nobel will study the impact of disparities on uptake of adjuvant therapy for NSCLC in a largely minority patient population at Montefiore Medical Center in Bronx, NY. She will provide social support and health literacy to engage patients in their care and collect genetic data about their tumors, which will contribute to future clinical trials that are more inclusive.
Systemic therapy after surgery to remove lung cancer has been demonstrated to improve survival. However, data has shown that there are inequalities in which patients are referred for and receive treatment after surgery, specifically for lower socioeconomic status and non-White patients. As new treatments have been developed, these inequalities are likely to increase as these drugs have been developed in clinical trials predominantly composed of White patients and the benefits in other populations are not known. We have previously demonstrated that using nursing and peer navigators to help guide patients in their cancer care improves treatment adherence in our predominantly Black and Hispanic low socioeconomic status population in the Bronx. The BRONx-TEAM project aims to improve patient outcomes by using a navigation pathway focused on increasing patient adherence to systemic therapy after surgery for non-small cell lung cancer resection. We believe that by providing social support and improving health literacy we can get patients to be more informed and engaged in their cancer care. Furthermore, we will gather genetic data about the patients tumors. Given our patient population, we have a unique opportunity to contribute to the literature to understand the relationships between tumor genetics, treatment types and outcomes in non-White patients. Furthermore, we will investigate the use of a commercial genetic panel to assess risk for recurrence. Given the lack of this type of data in low income non-White patients, we believe that this exploratory portion of our study will serve as an important foundation for future clinical trials that are more inclusive than the currently available literature.
As seen in the phase III trial CheckMate 816 (CM816), neoadjuvant anti-PD-1+chemotherapy improves survival for patients with resectable non-small cell lung cancer (NSCLC), with pathologic response as a major trial endpoint. Our team led the Central Pathology Review for CM816, and we showed the first prospective evidence that the full spectrum of % residual viable tumor (%RVT) associates with event free survival. Given the data supporting pathologic response as a survival surrogate, %RVT will likely be incorporated into the next generation of clinical trials and may ultimately guide clinical decision-making. %RVT is primarily evaluated using visual assessment of routine hematoxylin and eosin-stained slides. We developed a machine learning-based approach to score %RVT, which allows for a standardized approach that can be completed rapidly for a large volume of patients, and we propose to test this algorithm in resection specimens from CM816. Additionally, we will use multiplex immunofluorescence (mIF) to quantify individual features of pathologic response, locate them within the larger tumor bed, and determine the relative contribution in predicting patient outcomes. Furthermore, we will use the novel AstroPath platform, a mIF whole-slide imaging platform that uses algorithms first developed in astronomy to generate tumor-immune maps, to identify additional pre- and on-treatment biomarkers of response. Our goal is to leverage emerging technologies (i.e, machine learning and mIF) to develop the next generation of pathology biomarkers, including pathologic response assessment, and to identify additional features that can potentially be targeted in combination with anti-PD-(L)1+chemotherapy to improve clinical benefit in patients with NSCLC.
In patients with EGFR-mutant NSCLC, tyrosine kinase inhibitors (TKIs) have been an effective treatment, but over time these patients develop resistance to TKIs, leading to tumor relapse. Dr. Yang’s project focuses on cancer cells called drug-tolerant persisters (DTPs), which are implicated in TKI resistance. A gene called HER3 is expressed in DTPs, and Dr. Yang will use specially engineered immune cells, called CAR-T cells, to target both HER3 and EGFR simultaneously. If successful, this approach would result in a bi-specific CAR-T cell that can be further evaluated in clinical trials.
In lung cancer patients with a specific genetic mutation in EGFR, certain drugs can be helpful, but over time, the cancer can learn to resist these drugs, making them less effective. We're focusing on a small group of tough cancer cells, called DTPCs, that survive the initial treatment because they might be the key to curing the cancer for good. We've noticed that a gene called HER3 is expressed more in these cells. We also have promising results from CAR-T cell therapy. It is a treatment using T cells, a type of immune cells, engineered with the chimeric antigen receptor (CAR) so they can find and destroy cancer cells. We've found that CAR-T cells targeting EGFR can kill DTPCs. We believe if we use these T cells to attack both HER3 and EGFR at the same time, we might have a better chance of killing off these stubborn cancer cells. To make sure this idea works, we'll first check if HER3 is indeed more expressed in these DTPCs in the lab and samples from patients. Then, we'll test our HER3-targeting CAR-T cells to see if they can kill these DTPCs. If that looks promising, we'll tweak the T cells to target both HER3 and EGFR and see if they work even better. If all goes well, we'll be able to make one of the first effective CAR-T cells to target both HER3 and EGFR and try them out in clinical trials.
In NSCLC patients harboring mutant EGFR, treatment with tyrosine kinase inhibitors (TKIs) has demonstrated efficacy. However, the emergence of resistance to EGFR TKIs remains a significant challenge, leading to disease progression. Targeting drug-tolerant persister cells (DTPCs), a rare subpopulation surviving initial treatment, emerges as a more effective strategy than awaiting the development of complete drug resistance, holding potential for curative cancer therapy. Based on our preliminary data on the upregulation of HER3 in DTPCs resistant to EGFR TKIs and the potent antitumor activity of EGFR-targeting chimeric antigen receptor (CAR)-T cells against DTPCs. We propose that HER3 is a promising target expressed on EGFR-TKI DTPCs and that CAR-T cells simultaneously targeting both EGFR and HER3 are an effective approach for targeting DTPCs with improved overall efficacy. In this proposal, we will evaluate HER3 as a therapeutic target for CAR-T cell therapy against EGFR-TKI DTPCs by validating its expression in DTPCs using in vitro cell models, in vivo xenograft and PDX models, and patient tissues. Additionally, we will evaluate the anti-tumor activity of HER3-targeting CAR-T cells against DTPCs. Subsequently, we will develop and characterize EGFRxHER3 bispecific CAR-T cells, evaluating their CAR expression, antigen binding affinity, and anti-tumor activity. We next will assess their anti-tumor efficacy in xenograft and PDX models to guide the selection of the most promising bispecific CAR-T cells for further development. If completed successfully, we will have EGFRxHER3 bispecific CAR-T cells ready for GMP-compliant clinical-grade CAR manufacturing, in preparation for clinical trial evaluation.
This grant was co-funded by Rising Tide Foundation for Clinical Cancer Research
The objective of this project is to develop a blood test that can improve upon current limitations in lung cancer screening. Dr. Patel and his team have developed a method to accurately measure alterations in DNA that are cancer-specific by looking at levels of methylation of circulating tumor DNA (ctDNA) in the bloodstream. Using this method, Dr. Patel will develop a predictive model to identify patients with lung cancer based on these DNA alterations at a single time point, as well as an algorithm that can track these changes in a patient’s DNA over time. If successful, this could help detect lung cancer earlier in its development, thereby leading to better outcomes for patients.
Lung cancer is by far the most deadly cancer in the U.S., with total lung cancer deaths exceeding those of the next three major cancers combined. Such dismal statistics are largely attributable to the insidious nature of the disease; by the time symptoms appear, the cancer has often spread to an extent that makes cure unlikely or impossible. In contrast, patients who are diagnosed at earlier stages have much better outcomes, as their tumors can be entirely removed or eradicated prior to distant spread. Thus, annual chest CT scans for lung cancer screening have proven to be effective at reducing lung cancer deaths, and are currently recommended for patients with a heavy smoking history. However, CT-based screening programs have been practically challenging to implement, and uptake has been slow. An alternative screening approach that has been garnering much enthusiasm is based on development of a simple blood test that detects DNA fragments shed from tumor cells into the bloodstream. Several commercial and academic groups have been racing to develop blood tests for cancer screening based on this concept, and the field has made impressive progress. However, detection of early-stage lung cancers has remained particularly challenging, with sensitivities reaching only ~20-40% for Stage I disease. A key limitation for detection of small, early-stage tumors has been the extremely low abundance of DNA fragments bearing cancer-specific features (such as mutations) in the circulation. To overcome this limitation, our group has developed a technology that can accurately measure cancer-specific alterations in DNA which are more highly abundant (known as “hypermethylation”). In the current project, we propose to develop a predictive model to identify patients with lung cancer based on probabilities inferred from measurement of these DNA alterations. We will then further improve the sensitivity for detecting the earliest stages of lung cancer by developing an algorithm that tracks longitudinal changes in a patient’s DNA signal over time rather than relying on just a single time-point.
Early detection of cancer has long been one of the grand challenges of medicine. It is widely acknowledged that better methods for detection of small, asymptomatic tumors are likely to translate to substantial improvements in cancer survival rates. This is an especially important priority for lung cancer because of its high incidence, high rate of late-stage diagnosis, and high mortality. Over the past decade, liquid biopsy approaches based on detection of cancer-specific mutations or epigenetic changes in cell-free DNA (cfDNA) have made significant inroads towards this goal. However, detection of early-stage lung cancer has been particularly challenging because of the minute amounts of tumor DNA shed into blood. Methylation of cfDNA has emerged as a biomarker of choice for many early detection efforts, but existing technologies are designed to probe for cancer-specific methylation patterns either at pre-specified target sites or across broad genomic regions. The former approach prioritizes a limited subset of cancer-relevant signals, whereas the latter approach yields sparse cancer signals from extensive sequence data. Our group has developed a liquid biopsy technology that comprehensively profiles hypermethylated promoter sequences in cfDNA arising from anywhere in the genome. Using a high-stringency capture strategy based on methylation density rather than sequence, our method is able to globally profile hypermethylated promoters without pre-specifying targets. Gene silencing via promoter hypermethylation is a fundamental mechanism of carcinogenesis, and this aberrant signal can be detected at very low levels in plasma because background methylation patterns in healthy plasma are remarkably consistent. To optimize sensitivity for detection of early-stage lung cancer, we will develop a scoring scheme based on probabilistic machine learning to predict the likelihood of lung cancer by integrating hypermethylation signals across thousands of cell-free DNA fragments. Unlike most current liquid biopsy-based early detection efforts which are focused on identifying individuals with cancer based on a single time-point measurement, here we propose to develop a longitudinal early detection algorithm based on measurement of serial increases in cancer-specific epigenetic signals over time due to tumor growth and accumulating changes in the epigenome.
This project will investigate the role of cells called macrophages, key components of the immune system that have multiple functions, including immune surveillance within a unique communication pathway called hedgehog (Hh). The hedgehog signaling pathway is involved in cell growth and differentiation, as well as maintenance of stem cells and tissue repair. Disruption or inhibition of Hh can create an environment that is less favorable for survival of cancer cells, allowing a patient’s immune system to combat it more effectively. This research has the potential to benefit patients who have been diagnosed with NSCLC, who have not responded to current treatments including immunotherapy by boosting the body’s own defense mechanisms.
Lung cancer remains one of the most lethal types of cancer worldwide, with non-small cell lung cancer (NSCLC) accounting for a majority of cases. The goal of our research is to better understand the relationship between certain immune cells called macrophages and NSCLC, and how this interaction contributes to the cancer's survival and resistance to treatment. The scientific premise of our project lies in investigating a unique communication pathway known as hedgehog signaling within these macrophages and determining how it impacts the immune system's ability to fight lung cancer. If successful, our research has the potential to benefit patients who have been diagnosed with NSCLC, particularly those who have not responded to current treatments including treatment with immune therapies. By disrupting the hedgehog signaling pathway in macrophages, we hope to create a tumor immune environment that is less favorable for cancer cell survival, allowing patients' immune systems to effectively combat the disease. This research can pave the way for innovative therapeutic approaches that boost the body's own defense mechanisms.
The prognosis for patients with metastatic non-small cell lung cancer (NSCLC) remains poor despite recent progress in immune checkpoint blockade (ICB) therapy. Thus, there is an urgent need to understand mechanisms for lung cancer immune evasion within the tumor microenvironment (TME) in order to develop more effective and durable strategies for treating lung cancer. Tumor associated macrophages (TAMs), a major component of the tumor stromal mass, generally display an anti-inflammatory phenotype and can facilitate tumor growth by promoting angiogenesis, invasion, and metastasis, as well as immune evasion. However, it remains largely undefined exactly how these TAMs regulate anti-tumor immune responses within the TME. Will test the hypothesis that hedgehog signaling in TAMs interferes with recruitment of CD8+ T cells to the TME through the following specific aims: 1) Investigate the role of Hh inhibition with anti-PD-L1 therapy in non-small cell lung cancer; 2) Study the impact of Hh inhibition on TAMs and changes within the TME. The objective of this project is to understand signals required for functional polarization of TAMs within the TME and its contributions to immune cell dysregulation and cancer progression, and whether combined Hh inhibition and ICB can overcome resistance to immunotherapy.
This project will investigate novel protein degraders (called PROTACs) as a treatment for RET-positive cancers, and will evaluate their efficacy in vitro and in vivo in prostate and lung cancer. PROTACs are highly specific molecules that degrade unwanted or harmful proteins in cells (in this case, RET tyrosine kinase). This research aims to provide a novel therapeutic approach targeting RET signaling, which could overcome resistance to existing RET inhibitors. If successful, it would be a first-in-class compound for further clinical development.
RET receptor tyrosine kinase is a proto-oncogene that requires a co-receptor and secreted ligand for activation. Activating RET mutations are oncogenic targets in non-small cell lung cancer, medullary thyroid cancer and neuroendocrine type cancers. Two RET-specific kinase inhibitors (BLU-667 and LOXO-292) have been FDA approved for treating RET fusion positive cancers. This has led to a tremendous advance in lung cancer therapy and objective response rates in patients naïve to RET inhibitors or who have received other RET inhibitors such as cabozantinib or vandetanib. It is also apparent that RET therapy-driven resistance is common and new alternatives are needed to drug this pathway. Our hypothesis is that targeting RET with novel, first-in-class RET degraders will result in cell death that is more durable than existing inhibitors of RET kinase activity. We will test these novel degraders on several models of prostate and lung cancer to assess on target RET degradation and efficacy in cell line and mouse models. Once novel RET protein degraders are developed and tested in prostate and lung cancer models in vitro and in vivo, we plan to perform pre-clinical optimization studies of compounds and work towards clinical implementation in late stage prostate, lung, and other cancers that rely on RET signaling for survival.
Two RET-specific kinase inhibitors (BLU-667 and LOXO-292) have been FDA approved for treating RET fusion positive cancers. This has led to a tremendous advance in lung cancer therapy and objective response rates in patients naïve to RET inhibitors or who have received other RET inhibitors such as cabozantinib or vandetanib. It is also apparent that RET therapy-driven resistance is common and new alternatives are needed to drug this pathway. Our hypothesis is that targeting RET with novel, first-in-class RET degraders will result in cell death that is more durable than existing inhibitors of RET kinase activity. We will test hypothesis via the following specific aims: Aim 1. Development and characterization of RET degraders for treating RET positive cancers and Aim 2. Evaluate efficacy of RET degraders in in vitro and in vivo NEPC models. In aim 1, we propose to develop RET degraders based on a new RET inhibitor, vepafestinib, and assess RET degrader specificity and activity using a panel of prostate and lung cancer cell line models that overexpress RET or contain RET fusions. We will then evaluate the efficacy of our RET degrader in in vitro and in vivo models of lung and prostate cancer. Once these novel RET protein degraders are developed and tested, we plan to perform pre-clinical optimization studies of compounds and work to identify a suitable pharma partner to develop for clinical implementation in late stage prostate, lung, and other cancers that rely on RET signaling for survival.
This project will explore the use of neoantigens to evaluate immunogenic priming of dendritic cells (DC) in RET+ NSCLC. Neoantigens are short protein fragments present only in cancer cells that bind to genetically encoded proteins known as human leukocyte antigens (HLA). Dr. Cummings will use features of HLA to predict which cancer-specific protein fragments best match an individual’s immune system, utilizing a biobank of RET-rearranged NSCLC biospecimens. This approach could help identify optimal immunogenic targets, that could be translated into a pathway for clinical use of personalized DC vaccines.
RET-rearranged non-small cell lung cancer (NSCLC) is a rare subtype of lung cancer that is driven by growth signals triggered by RET activation. RET-specific inhibitors are effective initially, but most benefit from this treatment for only 1-2 years before additional treatment is needed. Chemotherapy is a widely-available option but typically provides less than six months of benefit, and it is unclear whether immunotherapy alone or in combination with chemotherapy is a better option. Findings from other gene-rearranged NSCLC studies, particularly those on ALK-rearranged NSCLC, suggest that immunotherapy works better when the immune system is better exposed to abnormalities created by the gene-rearrangement. These are neoantigens, or short protein fragments present only in cancer cells that bind to human leukocyte antigen (HLA), a scaffold that displays these protein fragments to the immune system. One issue with this approach is that these fragments have to be specifically matched to the immune system of an individual, and even the most common forms of HLA are only found in 20% of people. This means that these types of approaches would be applicable to at most 1 out of 5 people with RET-rearranged NSCLC. Our techniques broaden this approach by using features of HLA to predict which cancer-specific protein fragments best match an individual’s immune system (motif neoepitopes), including neoantigens from RET rearrangements and those predicted from the individual’s tumor. We propose to use our biobank of RET-rearranged NSCLC biospecimens, which have not been previously analyzed, to determine whether we can detect and elicit enhanced immune responses with motif neoepitopes, neoantigens related to RET-rearrangements, or other predicted neoantigens. We can then offer this approach in a currently open clinical trial investigating immune system optimization through an application to the FDA.
RET-rearranged non-small cell lung cancer (NSCLC) presents challenges in management following progression on selective tyrosine kinase inhibitors (TKIs). Platinum-based chemotherapy and docetaxel are available options but are without durable benefit. Real world data with single-agent and combination chemo-immunotherapy suggests modest benefit and possible efficacy if immunotherapy-based approaches are appropriately optimized. For the past decade, our group has meticulously curated hundreds of NSCLC biospecimens including matched tissue and blood from multiple timepoints, including 7 RET-rearranged NSCLC cases that have not previously been analyzed. We have extensive expertise in neoepitope prediction and personalized immunotherapy through dendritic cell (DC)-based vaccination. Our most recent collaboration enabled functional assessments of T-cells through nanovial-based affinity repertoires, further enhancing our ability to predict and translate immunogenic peptides through a personalized vaccine-based program. We propose to use our RET-rearranged NSCLC biospecimens to systematically study T-cell-specific responses to identify optimal immunogenic peptide targets, an approach that could be translated in our currently open and approved DC vaccination trial (NCT03546361) through single patient exemptions.
This project aims to develop new therapeutic approaches for RET-positive cancers, focusing on overcoming resistance to currently available RET inhibitors. Dr. Somwar and colleagues will investigate ways to block the growth of lung cancers with altered RET in a pathway called MAPK (mitogen activated kinase), which is involved in many biological processes involving cell growth and survival. MAPK is implicated in developing resistance to RET inhibitors and finding strategies to target this pathway in combination with RET could benefit many patients who have no approved therapy options after tumor reoccurence.
Lung cancers are one of the leading causes of death in the US. Significant progress has been made over the past three decades to understand the biology of lung cancers and to stratify these diseases into subsets of patients who will get the maximum benefit of a given form of therapy. New technologies now allow for each patient to have their tumor DNA sequenced to find genetic causes of their cancer. Many genes that regulate cell growth are altered by mutations that cause the unrestricted growth that lead to cancer. Scientists have developed strategies to take advantage of these aberrant genes by finding chemicals or biological agents that will antagonize the protein products of these genes. One gene that is altered in 2% of lung cancers is called RET and there are two drugs that block the tumorigenic function of this cancer-causing gene (oncogene). Although patients respond very well to these two anti-RET drugs at first, they soon become resistant to the therapeutic effects. Additional genetic changes in RET or other genes in the cancer cells that regulate growth are responsible for the drug resistance. Our goal in this grant proposal is to find ways to block the growth of lung cancers with altered RET that stopped responding to anti-RET inhibitors. The strategy that we will test involves the simultaneous inhibition of RET and other proteins in another growth promoting pathway called the MAPK (mitogen activated kinase) pathway. We believe that this therapeutic strategy can benefit more than 30% of patients who stop responding to current drugs that target lung cancers with RET genetic alterations.
RET fusions result from abnormal rearrangements of the kinase domain of RET with other non-essential genes and drive tumorigenesis. These oncogenic chimeric tyrosine kinases are found in approximately 2% of non-small cell lung cancer (NSCLC).Two FDA-approved selective RET inhibitors (selpercatinib and pralsetinib) have shown great response rates in lung cancer patients. However, resistance to RET inhibitors inevitably occurs, limiting therapeutic benefit. Multiple mechanisms of resistance to RET inhibitors have been described, including acquired RET solvent front mutations (G810R/S/C/V), and RET-independent mechanisms of resistance due to amplifications of other receptor tyrosine kinases (RTK) including MET, FGFR1 and ERBB2, and alterations in the RAS-MAPK pathway. Some second-generation RET inhibitors that target secondary RET mutations have been recently developed including vepafestinib (TAS0953/HM06) which is currently being tested in phase I/II clinical trials in the US and Japan for RET fusion positive lung cancer. There is a clinical need to identify mechanisms of resistance to vepafestinib and develop strategies to overcome them.
RET with solvent front mutations, amplification of MET/FGFR1/ERBB2 and RAS-MAPK pathway mutations account for >30% of all resistance mechanisms to first-generation RET drugs, and importantly, all of these alterations are expected to activate the RASMAPK pathway. Therefore, a therapeutic strategy that tackles RAS-MAPK pathway activation is expected to benefit >30% of patients who acquire resistance to first-generation RET drugs. Moreover, given that RET fusions, like all tumors arising from activated RTKs engage the RAS-MPAK pathway for oncogenesis, we believe that many treatment-naïve patients may also benefit from a therapeutic strategy that targets RET and the RAS-MAPK pathway.
Our first goal in this proposal is to simultaneously address resistance due to RAS-MAPK pathway alterations and extending the benefit of first-generation RET drugs by developing a combination therapy strategy involving RET and pan-RAS, MEK1/2 or ERK1/2 inhibitors. Our second goal is to decipher mechanisms by which the transcription factor capicua (CIC) regulate RET-driven tumorigenesis and resistance to RET inhibitors. We will perform transcriptomic, epigenic and proteomic profiling to gain insights into RET-ERK-CIC interaction. Our third goal is to identify and target resistance mechanisms to vepafestinib, so that a therapeutic strategy will be in place for when patients being treated with this drug develop resistance.
Our team includes leaders in the field of lung cancer clinical and translation research who have been at the forefront of lung cancer genomics and therapy, developing state of the art therapeutic strategies. We are well positioned to translate the findings from this study to the clinic within two years. These studies have the potential to benefit more than 30% of lung cancer patients with RET fusions.
