Recurrent

Cancer that has come back after cessation of treatment

TROP2 Directed CAR T in NSCLC as a Strategy for Eradicating Persister MRD

2023

Health Equity and Inclusiveness Research Fellow Award

Elliott Brea, MD, PhD

Dana-Farber Cancer Institute

Boston

This project proposes to develop novel therapeutic approaches to treat advanced EGFR-mutant NSCLC. CAR-T cell therapy is a type of immunotherapy treatment that uses genetically altered T cells to find and destroy cancer cells more effectively. TROP2 is a protein that is over expressed on the surface of NSCLC and is a target of the antibody-drug conjugate (ADC), sacitizumab-govitecan, which is FDA-approved to treat other solid tumors. Dr. Brea hypothesizes that TROP2-directed CAR-T targeting of EGFR-mutant NSCLC will be superior to standard Osimertinib treatment.

Research Summary

While advances have been made in treating advanced or metastatic cases of Non-small cell lung cancer (NSCLC) with either targeted therapy or immunotherapy, most patients will progress after these first line therapies and require subsequent treatments which are limited in efficacy. EGFR mutant (EGFRm) lung adenocarcinoma is the most common type of NSCLC in patients without a history of tobacco use. They often respond to first line treatments called EGFR inhibitors (EGFRi) that target or block EGFR but unfortunately this is usually not curative in patients with advanced or metastatic EGFR mutant lung cancer. Chimeric antigen receptor T-cell therapy (CAR-T) works by engineering a patient’s immune fighting cells called T-cells to fight the cancer utilizing a receptor, which is matched to proteins expressed on the cell surface of cancer cells. When the receptor recognizes the cancer- associated proteins, T cells bring their powerful anti-cancer attack directly to the malignant cells. CAR-T has shown significant promise in blood cancers with durable responses observed. TROP2 is a protein present in NSCLC and is the target of FDA approved antibody-drug conjugate (ADC) sacitizumab-govitecan for breast and bladder cancer and is in clinical trials for lung cancer. Our goal is to demonstrate that TROP2 directed CAR-T cell therapy is effective in NSCLC, and can eradicate disease in a more durable fashion when compared to standard therapy with EGFRi. We plan to use the results of this work to translate this to clinical trials evaluating this promising strategy for treating lung cancer.

Technical Abstract

While immunotherapies in cancer have allowed for major advances in the field, most patients with advanced or metastatic solid tumors do not achieve durable responses. While CAR-T cell therapy and bispecific antibody therapies which utilize T-cells as their effector have shown promise and durable responses in hematologic malignancies such as DLBCL and multiple myeloma, the promise of similar responses in solid tumors remains an unmet goal. TROP2, a cell surface protein normally expressed during fetal development and at low levels in some normal adult tissue, is over expressed on a variety of solid tumors including NSCLC, and has emerged as an ideal target. TROP2 is the target of the recently FDA approved ADC sacitizumab-govitecan for breast cancer as well as for patients with locally advanced or metastatic urothelial cancer and is currently being tested in phase II/III trials in NSCLC. However, response in patients and in animal models are not durable, even when targeting minimal residual disease (MRD; defined as the residual disease after effective genotype directed systemic treatment). We propose utilizing TROP2 directed CAR-T to target EGFRm NSCLC at MRD, which we hypothesize when compared to TROP2 directed ADC will demonstrate a more durable response. Our preliminary data support the high activity of TROP2 directed CAR-T against EGFRm NSCLC including in the MRD state after osimertinib treatment. We expect these findings to translate to approaches utilizing CAR-T cellular therapy to target the MRD state after targeted therapy.

Key words

Acquired resistance

Adenocarcinoma

Epidermal growth factor receptor (EGFR)

Metastatic

Non-small cell lung cancer (NSCLC)

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Tumor draining lymph node immunomodulation to decrease recurrence in NSCLC

2022

Health Equity and Inclusiveness Junior Investigator Award

Jonathan Villena-Vargas, MD

Weill Medical College of Cornell University

New York

Lymph nodes are small structures that work as filters for foreign substances, such as cancer cells and infections. These nodes contain infection-fighting immune cells that are carried in through the lymph fluid. This project will study the lymph node draining basin, which is involved in the spread of a tumor from the original location site to distant sites, and whether activating cancer-fighting T-cells can decrease recurrence in NSCLC. Dr. Villena-Vargas will use animal models to investigate whether immune checkpoint inhibitors enhance lymph node T-cells memory, which increases their ability to recognize cancer cells in the bod and can prevent metastatic recurrence.

Research Summary

Approximately 25% of the patients diagnosed with non-small cell lung cancer (NSCLC) exhibit early-stage disease. Patients with early-stage (I/II) NSCLC are routinely treated by surgery, which results in local control. However, systemic relapse (metastasis) occurs in 50% patients within 5 years of surgical intervention even with additional therapy such as chemotherapy and/or radiation. Immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 axis have revolutionized the treatment landscape, generating therapeutic efficacy in approximately 25% of patients in early and advanced stages of lung cancer. However, there are currently inconclusive studies as to 1) timing of treatment 2) optimal combination therapy 3) prediction of patient response. In order, to recapitulate early-stage lung cancer treatment and metastatic recurrence, we have established a murine model of resection and recurrence. Our preliminary data has revealed a major immune response at the level of the tumor draining lymph node (TDLN) with PD-1 checkpoint blockade. In addition, this response is primarily responsible for T-cell memory differentiation, proliferation, and survival with subsequent decrease in metastatic recurrence in responding mice. Given these results, we hypothesize that optimal therapy against metastatic recurrence will be dependent on establishment of appropriate T-cell memory “immunosurveillance”. In addition, we have shown that the memory nodal response can be augmented by utilizing a cytokine immunomodulatory combination strategy with cure in over 70% of mice. Importantly, we have characterized that these specific T-cell memory population are uniquely found in the TDLN of early-stage patients (i.e. not in the primary tumor or peripheral blood that is commonly interrogated). In this proposal we will utilize a combination of both novel preclinical mouse models and patient-derived tumor draining lymph node T cells, to dissect molecular and cellular mechanisms of “immune-memory” response or resistance to immunotherapy, the key steps in establishing immunosurveillance for freedom from metastatic recurrence.

Technical Abstract

Anti–PD-1 therapy has transformed the management of NSCLC, but only a subset of patients respond to anti–PD-1 therapy, and responses are rarely curative. Understanding the effects of anti–PD-1 therapy on the composition and functional state of tumor-associated immune subsets can identify mechanisms of response and resistance to anti–PD-1 therapy and provide insights into rational combination strategies to improve upon response rates. Although the effects of anti–PD-1 therapy within the tumor immune microenvironment in preclinical and human subjects have been previously reported, we propose to broadly characterize the effects of anti–PD-1 therapy on the tumor draining lymph nodes (TDLN). Studying the TDLN is particularly valuable because it is the primary sites at which the tumor antigen exposure and the main site of immune T-cell differentiation. To determine the effect of ICI response in the lymph node, we have created an immunocompetent murine model that recapitulates early-stage treatment and outcomes in patients. Additionally, we have characterized TDLN T cells from early-stage cancer patients and have been able to recapitulate our preclinical findings of unique memory T-cell subsets. Our preliminary results of the immune cell type composition, checkpoint expression, and cytokine expression within TDLNs suggest that there are major remodeling events within the TDLN mediated by anti–PD-1 therapy that are critical for conferring effective antitumor long-term immune responses. We demonstrate that unique memory T cell subsets undergo significant activation, expansion, and maturation in response to anti–PD-1 therapy, to shape antitumor programming in TDLNs. Importantly, our proposed study will provide a methodological demonstration in both a murine model and human TDLN that simultaneous uses Flowcytometry, functional immune assays and single cell sequencing that will enable deep interrogation of the immune profile to PD-1 inhibition resistant and responsive patients.

Key words

Adenocarcinoma

Immune checkpoint inhibitors

Immunotherapy

Metastatic

Non-small cell lung cancer (NSCLC)

Recurrent

Squamous cell lung cancer

Stage III

Stage IV

Tumor microenvironment

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Integrated Blood-Based and Radiographic Interception of Lung Cancer

2017

SU2C-LUNGevity-ALA LC Interception Award

Grant title (if any)

SU2C-LUNGevity Foundation-American Lung Association Lung Cancer Interception Translational Research Team

This grant was co-funded by Stand Up to Cancer, LUNGevity, and the American Lung Association

Lecia Sequist, MD

Massachusetts General Hospital

Boston

Max Diehn, MD

Stanford University

Palo Alto

Tilak Sundaresan, MD

Kaiser Permanente San Francisco

San Francisco

Gad Getz, PhD

Broad Institute

Cambridge

The SU2C-LUNGevity Foundation-American Lung Association Lung Cancer Interception Translational Research Team, headed by LUNGevity Scientific Advisory Board (SAB) member Dr. Lecia Sequist, is developing a lung cancer interception assay (LCIA) that can be used in conjunction with low-dose CT scans. This assay will be based on an integration of several blood-based assays that examine circulating tumor cells and circulating tumor DNA.

Technical Abstract

Statement of the Problem: Currently, low dose CT (LDCT) screening for lung cancer is recommended for high-risk individuals, defined as current or former smokers (quit within the past 15 years) with a 30-or-more pack-year smoking history, 55 to 74 years of age, and with no evidence of lung cancer. However, uptake of LDCT screening has been impeded by high rates of false-positive results, which in turn add significant physical and emotional stress to patients as well as additional healthcare costs. Since LDCT is now commonly available, lung nodules detected in LDCT scans are plentiful, but imprecise guidelines for care make it a challenge to ensure quality follow-up and expedited diagnoses for those with lung cancer. Furthermore, screening is not available for those who don’t meet the screening criteria (younger age or low smoking history) when they are the exact population among whom lung cancer rates are rising.

Proposed Solution: Leveraging expertise of academic research centers (Massachusetts General Hospital, Broad Institute, and Stanford University) and a non-profit managed-care consortium (Kaiser Permanente), the Dream Team will develop a test called the Lung Cancer Interception Assay (LCIA) to complement LDCT screening.

The proposal is novel in that it will develop complex computational algorithms to combine high-sensitivity/high-accuracy blood-based molecular biomarkers with image-based biomarkers to create the LCIA assay. At the end of the award period, a streamlined product, the LCIA, will be ready to use in population-level definitive trials for the early detection of lung cancer.

Key words

Adenocarcinoma

Circulating tumor cells

Circulating tumor DNA

Non-small cell lung cancer (NSCLC)

Recurrent

Screening

Squamous cell lung cancer

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Molecular mechanisms of acquired drug resistance in small cell lung cancer

2014

Career Development Award

This grant was funded in part by the American Lung Association

John Poirier, PhD

Memorial Sloan Kettering Cancer Center

New York

Small cell lung cancer is an exceptionally aggressive type of lung cancer. While these tumors are initially responsive to a combination of chemotherapy drugs, tumor recurrence is near universal. Dr. Poirier will develop and study models of drug resistance to identify new strategies to overcome chemotherapy resistance.

Research Summary

Small cell lung cancer (SCLC) is a common, aggressive, and exceptionally lethal type of lung cancer that is not typically discovered or diagnosed until it has already spread throughout the body. Newly diagnosed SCLC is remarkably sensitive to combination therapy with a combination of two drugs, cisplatin and etoposide, even in patients with extensive-stage disease. While many tumors respond to therapy, shrinking significantly in bulk, this treatment is never curative – when these tumors return, they are generally quite resistant to further therapy. Extensive-stage SCLC is uniformly fatal; less than 1% of patients will be alive five years after diagnosis. Remarkably little is known about how or why these tumors become resistant to this therapy. Defining the basis of acquired chemotherapy resistance in SCLC could have clear and important ramifications for clinical management of this disease. Targeting the key determinants of acquired chemoresistance could be integrated into first-line treatment, and/or could drive rational targeted therapeutic studies for recurrent disease. There are now multiple technical approaches that could comprehensively define the genomic and epigenetic changes that drive acquired resistance in SCLC. This research will use two parallel approaches to analyzing acquired resistance in SCLC: studying resistance in patient samples and studying resistance in patient tumors grown in mice.

Technical Abstract

Small cell lung cancer (SCLC) is a common, aggressive, and exceptionally lethal malignancy that is usually metastatic at the time of diagnosis. Newly diagnosed SCLC is remarkably sensitive to chemotherapy, with response rates of over 60% to cisplatin and etoposide even in patients with extensive-stage disease. These chemotherapy responses are often both rapid and deep, but are never curative: extensive-stage disease recurs universally, in most cases within a few months after completion of first-line therapy. Recurrent SCLC is remarkably refractory to treatment. The median overall survival of patients with extensive-stage SCLC is about nine months from the time of initial diagnosis, and the 5-year survival is less than 1%. Defining the basis of acquired chemotherapy resistance in SCLC could have clear and important ramifications for clinical management of this disease. Targeting the key determinants of acquired chemoresistance could be integrated into first-line treatment, and/or could drive rational targeted therapeutic studies for recurrent disease. We now have in hand multiple technical approaches that could comprehensively define the genomic and epigenetic changes that drive acquired resistance in SCLC. In this award application, we propose two parallel approaches to analyzing acquired resistance in SCLC: analysis of primary samples and patient-derived xenografts before and after acquired resistance.

Key words

Acquired resistance

Chemotherapy

Recurrent

Small cell lung cancer (SCLC)

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Molecular predictors of outcome in non-small cell lung cancer

2012

Career Development Award

Christopher A. Maher, PhD

Washington University in St. Louis

St. Louis

Dr. Maher is working to improve on the accuracy and usability of tests that identify lung cancer patients who are likely to relapse. He is using next-generation sequencing techniques to develop a signature set of key genetic changes and convert it to a clinical test that will be able to predict who is at high risk for relapse.

Research Summary

Currently, approximately 30% of non-small cell lung cancer (NSCLC) patients will die from recurrent disease despite undergoing surgery. Therefore, there is a critical need to develop accurate markers to distinguish high-risk patients who are more likely to have recurrent disease from patients who are at a lower risk for recurrent disease. To date several groups have applied high-throughput methods to identify a set of genes, or a “signature,” that will classify patients as high-risk or low-risk. However, there are two limitations to existing approaches. First, technological advances in sequencing technology offer an opportunity to identify additional markers, which would have eluded previous approaches, and therefore could result in a more accurate signature. Second, previous methods for developing a signature were developed on tumor material that is not routinely collected in clinics. This presents a critical need to develop an assay that can effectively apply a predictive signature on samples collected in the clinic. Therefore, our proposal focuses on using newer sequencing technologies to generate a refined signature for predicting which patients have more aggressive disease. We then proposed two goals for adapting this signature into a clinically useful assay. First, we intend to confirm that the predictive signature works on the same sample material collected in a clinic. Second, we intend to test our predictive signature on a completely independent cohort of patients to ensure it accurately stratifies patients with more aggressive disease. Overall, if the proposed aims are met, this research could lead to an improved assay that could be widely adopted in the clinic to stratify high-risk patients for more aggressive therapies and assign less aggressive treatments to patients at low risk for recurrence.

Technical Abstract

Approximately 30% of patients with stage 1 non-small cell lung cancer (NSCLC) will die from recurrent disease despite surgical resection . Currently, there is a lack of reliable molecular predictors being routinely used in the clinic for identifying patients at high risk for developing recurrent disease and therefore may benefit from more aggressive therapies. To date several groups have applied microarray-based methods for global gene expression profiling of frozen tumor tissues in an attempt to identify prognostic ‘signatures’ in patients with early stage NSCLC. Building upon this, through a meta-analysis of seven independent microarray studies Govindan et al. were able to identify a 64-gene signature that is highly predictive of survival in patients with stage I NSCLC. However, recent advances in high-throughput sequencing have enabled an unbiased view of the transcriptome including novel transcriptional events such as gene fusions, splicing variants, and novel transcripts. This offers an opportunity to incorporate additional markers, which may have eluded previous technologies, but could serve for improving a predictive signature of survival in non-small cell lung cancer (NSCLC). However, despite the potential of RNA-Seq to improve existing predictive signatures, we are still faced with the challenge of translating these findings into a platform where they can be reliably applied to formalin fixed paraffin embedded (FFPE) clinical tissue specimens routinely collected in tertiary referral centers. Therefore, this proposal focuses on refining the 64-gene predictive signature using transcriptome sequencing and developing a NanoString nCounter assay to reliably predict survival of patients with resected stage I NSCLC, using RNA derived from FFPE tumor blocks. To accomplish this we have proposed the following specific aims: (1) use transcriptome sequencing to detect molecular predictors of outcome in patients with stage I NSCLC, (2) validate the technical performance of the NanoString nCounter using an RNA-Seq predictive signature across FFPE tumor blocks of resected stage I NSCLC, and (3) clinically validate the prognostic power of the predictive signature across an independent sample set. Overall, if the proposed aims are met, this research could lead to an improved assay that could be translated into future prospective studies for risk-stratifying stage I NSCLC patients.

Key words

Anaplastic lymphoma kinase (ALK)

Biomarker or biomarker testing

KRAS

Molecular profile or molecular testing

Mutation profile

Non-small cell lung cancer (NSCLC)

Recurrent

Stage I