Career Development Award

Role of KIRs in Regulating Anti-tumor Immunity and Autoimmunity

2023

Diane Tseng, MD, PhD

University of Washington and Fred Hutchinson Cancer Center

Seattle

Checkpoint immunotherapy has advanced treatment of NSCLC, but the majority of patients do not experience long-term disease control and are at risk for autoimmune-related side effects. In this study, Dr. Tseng will examine specialized cells called CD8+ T that express receptors (KIR+) that suppress autoimmunity to understand how these cells regulate the immune system’s cancer-fighting ability during checkpoint immunotherapy treatment. Insights gained from this study could result in better strategies for improving efficacy while decreasing immune-related side effects.

Research Summary

Checkpoint immunotherapy has greatly advanced the treatment of non-small cell lung cancer, but only a minority of patients experience long-term disease control and all patients are at risk for side effects related to inflammation in normal organs (known as autoimmunity). Notably, patients developing mild autoimmune side effects are reported to have improved response rates to checkpoint immunotherapy compared to patients that do not develop side effects. However, the scientific basis of this relationship between treatment efficacy and toxicity is not well understood. There has been a recent scientific breakthrough shedding light on a novel role of an immune cell subset involved in controlling autoimmunity. These specialized immune cells are CD8 T cells that express killer cell immunoglobulin-like receptors (KIR+ CD8+ T cells) and function to eliminate other immune cells that drive autoimmune disease. This study is examining the idea that KIR+ CD8+ T cells play an important role in controlling autoimmune side effects from checkpoint immunotherapy, but may also impact how well the immune system fights the cancer. The first goal of this study is to understand how the normal functions of KIR+ CD8+ T cells break down when patients develop autoimmune side effects from checkpoint immunotherapy. The second goal of this study is to understand the extent to which KIR+ CD8+ T cells regulates the immune system’s cancer-fighting capabilities. Better understanding the relationship between desirable immune responses against tumor and undesirable autoimmune toxicities can lead to better strategies for improving the effectiveness of immunotherapy and minimizing side effects.

Technical Abstract

Checkpoint immunotherapy has advanced the treatment paradigm for non-small cell lung cancer (NSCLC), but only some patients respond to treatment and many patients experience immune related adverse events (irAE). Understanding the distinct and overlapping mechanisms regulating anti-tumor immunity and autoimmunity due to checkpoint immunotherapy is critical for developing more effective and less toxic therapies. A subset of CD8+ T cells expressing killer cell immunoglobulin-like receptors (KIR) have recently been shown to suppress autoimmunity without impairing anti-viral immunity by eliminating autoreactive T cells. We reason that KIR+ CD8+ T cells may also play an important role in regulating autoimmunity arising from checkpoint immunotherapy. Furthermore, we reason that KIR+ CD8+ T cells may also regulate the activity of tumor-reactive T cells to varying degrees, since tumor-reactive T cells are a specialized type of autoreactive T cells. This study examines the hypothesis that KIR+ CD8+ T cells dampen autoimmunity and anti-tumor immunity during checkpoint immunotherapy treatment. To test this hypothesis, we will first interrogate the activity of KIR+ CD8+ T cells during the development of irAE after immune checkpoint blockade (specific aim 1). Next, we will evaluate the impact of KIR+ CD8+ T cells on anti-tumor immunity in NSCLC (specific aim 2). This study may shed light on the biological mechanisms regulating autoimmunity and anti-tumor immunity in lung cancer patients undergoing checkpoint immunotherapy. Insights gained from this study may pave the way toward clinical strategies for improving immunotherapy efficacy while minimizing irAEs.

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The Germline-Somatic Interaction in Young-Onset Lung Cancer

2023

Career Development Award

This grant was funded in part by Lung Cancer Initiative

Jaclyn LoPiccolo, MD, PhD

Dana-Farber Cancer Institute

Boston

Although the average age at diagnosis is 70, thousands of new patients under 45 are diagnosed with lung cancer every year, most of whom have never smoked. Dr. LoPiccolo hypothesizes that these patients may share inherited genetic changes that predispose them to developing lung cancer at a younger age. In a preliminary analysis of young-onset lung cancer patients, Dr. LoPiccolo has found that approximately 30% of these patients carry rare mutations in known cancer-associated genes. In this study, Dr. LoPiccolo will investigate whether these mutations affect response to targeted or immune-based therapies. This insight is likely to identify risk factors among young lung cancer patients, which could lead to improved screening and treatment options for this population.

Research Summary

Lung cancer is the most common cause of cancer death in both men and women. Although the average age at lung cancer diagnosis is 70, thousands of new lung cancers occur in patients under 45 years old, most of whom have never smoked. There have been few efforts to analyze potential causes of young-onset lung cancer, particularly looking for inherited genetic changes, which are present in all cells in the body, that are shared among these patients and might predispose to developing lung cancer at a young age. To investigate whether inherited genes cause lung cancer in young patients, we collected blood samples from more than 350 lung cancer patients aged 45 and under at diagnosis and sequenced their genomes. In a preliminary analysis of 243 patients, we found that roughly 30% of young lung cancer patients carry rare, harmful inherited mutations in known cancer-associated genes, higher than many cancers known to have a strong genetic component. In addition to predicting cancer risk, inherited mutations that are present in every cell may influence how a tumor behaves and responds to treatment. We hypothesize that understanding the inherited contribution to tumor development may affect the response of cancer to targeted or immune-based therapies. Additionally, finding genetic risk factors could identify a group of people eligible for yearly CT screening and early detection of lung cancer (currently only used only for patients over 50 years old with heavy smoking histories), and/or guide therapies for lung cancer patients in the future.

Technical Abstract

Lung cancer is the most common cause of cancer-related mortality in North America. Although the average age at diagnosis is 70, thousands of new lung cancers are diagnosed each year in patients under 45 years over 45 years old (median age of diagnosis = 67). The work proposed here will further define this difference in a larger cohort, and address whether the identified variants or genes affect tumor evolution and treatment outcomes. The aims of our study are to identify a population of young lung cancer patients with elevated germline risk, and to investigate the mechanism of the germline-somatic interaction in young lung cancer. The young lung cancer population also provides a lens through which to better understand oncogene-driven lung cancer that occurs in non-smokers – increasingly important as global smoking rates decline.old, most of whom have never smoked. Given that younger patients develop lung cancer decades earlier and without known environmental insults, we hypothesized that underlying germline genetic variation predisposes to developing lung cancer at a young age. Here, we assembled a cohort of over 350 patients diagnosed with lung cancer at age 45 or younger and performed germline whole-genome sequencing (WGS). Preliminary data from 243 patients with median diagnosis age of 37 showed at least 30% of patients carry clinically actionable pathogenic germline alterations in cancer-associated genes, at rates exceeding those seen in many other cancer types – with key age-specific differences when compared to ancestry-matched lung cancer patients from The Cancer Genome Atlas diagnosed over 45 years old (median age of diagnosis = 67). The work proposed here will further define this difference in a larger cohort, and address whether the identified variants or genes affect tumor evolution and treatment outcomes. The aims of our study are to identify a population of young lung cancer patients with elevated germline risk, and to investigate the mechanism of the germline-somatic interaction in young lung cancer. The young lung cancer population also provides a lens through which to better understand oncogene-driven lung cancer that occurs in non-smokers – increasingly important as global smoking rates decline.

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Randomized Phase II Trial of Iadademstat with ICI Maintenance in SCLC

2023

Career Development Award

Noura Choudhury, MD

Memorial Sloan Kettering Cancer Center

New York

Small cell lung cancer (SCLC) is difficult to treat, and most patients diagnosed have a poor prognosis. Most patients with SCLC treated with first line chemoimmunotherapy progress within months of immune checkpoint inhibitor (ICI) maintenance therapy. Previous studies in mice have revealed that SCLC treated with iadademstat and maintenance ICI shows enhanced tumor response compared to ICI alone. Dr. Choudhury will conduct a phase II randomized trial investigating this combination in patients with SCLC versus standard of care ICI alone to evaluate progression free survival.

Research Summary

We will conduct a phase II randomized clinical trial investigating the efficacy of combining iadademstat with maintenance ICI versus standard of care ICI maintenance alone for patients with SCLC. We will analyze cell-free DNA in the blood to identify whether treatment with iadademstat and ICI drives conversion to neuroendocrine-low SCLC subtype, which has not been previously demonstrated in a prospective clinical trial. From on-treatment biopsies, we will perform transcriptomic and immunohistochemical analysis to determine whether treatment with iadademstat and ICI induces immunogenicity in SCLC with increased expression of genes in the antigen presentation pathway.

Technical Abstract

Extensive-stage small cell lung cancer (ES-SCLC) has exceptionally poor prognosis, with median survival of one year from diagnosis. Despite neoantigen abundance, SCLC is poorly immunogenic with low expression of major histocompatibility complex class I (MHC-I). As a result, most patients with SCLC treated with first line chemoimmunotherapy progress within months of immune checkpoint inhibitor (ICI) maintenance therapy. Characterization of SCLC by subtypes defined by expression of master transcription factors (TFs) have suggested that ICI-responsive SCLC tumors are composed of neuroendocrine-low (NE-low) subtype with relatively high expression of MHC-I without POU2F3 and with downregulation of ASCL1 and NEUROD1. The hypothesized transcriptional plasticity of SCLC, or subtype switching in response to therapeutic pressures, suggests that leveraging conversion to NE-low subtype with increased immunogenicity may enhance response to ICI. We have shown that inhibition of lysine-specific demethylase 1 (LSD1) with ICI therapy augments tumor regression in ICI-resistant genetically engineered SCLC mouse models, with subsequent upregulation of MHCI and the antigen presentation pathway and suppression of NE gene signatures. With these data supporting its clinical investigation, we propose a phase 2 randomized trial of iadademstat, an oral LSD1 inhibitor, with ICI maintenance in patients with ES-SCLC who have completed initial chemoimmunotherapy. We hypothesize that combination iadademstat and ICI maintenance therapy will improve progression-free survival and promote conversion to NE-low, immunogenic SCLC. We will trace key SCLC TF activity throughout treatment using a novel cell-free DNA (cfDNA) nucleosome profiling assay and utilize optional on-treatment biopsies to characterize differential gene expression with treatment.

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Combination checkpoint blockade plus VEGF inhibitor in EGFR-mutated NSCLC

2022

Career Development Award

This grant was funded in part by The Huff Project

Joshua Reuss, MD

Georgetown University

Washington

Osimertinib is the standard of care for treating non-small cell lung cancer with EGFR mutations. Unfortunately, the tumors inevitably develop resistance to osimertinib. Currently, very few treatment options exist for patients whose cancers have become resistant to osimertinib. Dr. Reuss is conducting a phase 2 clinical trial to test whether two immunotherapy drugs, atezolizumab and tiragolumab, given with a VEGF inhibitor, bevacizumab, are effective in controlling EGFR-positive NSCLC that has become resistant to osimertinib.

Research Summary

The targeted-therapy (TT) osimertinib has become the frontline standard-of-care for patients with advanced non-small cell lung cancer (NSCLC) who have a mutation in the epidermal growth factor receptor (EGFR) gene, which causes the cancer to grow. Despite this, most people experience progression of the cancer, at which point effective treatments are limited. Immunotherapy targeting the programmed death-1 (PD-1) pathway, while revolutionary for patients without such a mutation, has shown limited benefit in patients with EGFR-mutated NSCLC. Therapies targeting additional immune barriers, as well as a molecule called vascular endothelial growth factor (VEGF), may change this. VEGF suppresses important immune cells and pathways that help make immunotherapy work, and high levels have been found in EGFR-mutated NSCLC. Crucially, several clinical studies have shown promise by combining therapies targeting VEGF with immunotherapy and chemotherapy in EGFR-mutated NSCLC. This suggests that treatments targeting VEGF may help immunotherapy work better in these patients, but how that happens is unclear. It is also unknown if these therapies can be combined without chemotherapy, or if additional immunotherapies can magnify this benefit. To address these questions, we are conducting a phase 2 clinical trial evaluating a novel immunotherapy drug tiragolumab (targeting a molecule called TIGIT) together with the PD-L1-targeting antibody atezolizumab and VEGF-targeting antibody bevacizumab in advanced TT-refractory EGFR-mutated NSCLC. Critically, tumor biopsies and blood samples will be obtained from patients pre- and on-treatment to examine what properties in EGFR-mutated NSCLC make it resistant to immunotherapy, and determine how the tumor and immune system change during treatment. By doing this, we aim to show how therapy targeting VEGF works together with immunotherapy to provide benefit. Knowledge gained from this could help unlock the power of immunotherapy for EGFR-mutant NSCLC, and provide a novel treatment for patients afflicted with this sub-type of NSCLC.

Technical Abstract

The targeted-therapy (TT) osimertinib is frontline standard-of-care for patients with advanced non-small cell lung cancer (NSCLC) harboring mutations in the epidermal growth factor receptor (EGFR) gene. However, nearly all patients develop resistance, at which point treatments are limited. While revolutionary for many cancers, anti-PD-(L)1 immune checkpoint blockade (ICB) has been ineffective in EGFR-mutated(m) NSCLC. Targeting angiogenesis, and specifically vascular endothelial growth factor (VEGF), may be key to changing this. VEGF promotes immunosuppression through multiple mechanisms including inhibition of cytotoxic T-cell trafficking and promotion of regulatory T-cell proliferation. Pre-clinical and clinical evidence has revealed activated EGFR to be a dominant regulator of angiogenesis in EGFRm NSCLC, with increased expression of VEGF and hypoxia inducible factor-1α observed in EGFRm compared to wild-type NSCLC. Clinically, combination chemotherapy with anti-PD-L1 and VEGF blockade has shown efficacy signals in EGFRm NSCLC. However, whether upregulated VEGF potentiates the uninflamed tumor immune microenvironment (TIME), and underlies the observed synergy of these therapies in EGFRm NSCLC, remains unexplored. It is further unknown if VEGF inhibition can be combined with PD-1 blockade to promote benefit in the absence of chemotherapy, or whether blockade of additional checkpoints can further expand anti-tumor immune populations, specifically NK cells, which appear to be upregulated in EGFRm NSCLC responsive to ICB. To address these impactful questions, we have designed a single-arm translationally-focused phase 2 clinical trial assessing the efficacy of tiragolumab (anti-TIGIT) plus atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF) in advanced TT-refractory, ICB-naïve, EGFRm NSCLC. Critically, the proposed analyses detailed herein of tumor and blood samples obtained pre- and on-treatment will focus on (1) immunopathologic features of ICB resistance in EGFRm-NSCLC and (2) TIME infiltration and immunologic reprogramming imparted by these therapies. The findings from this study will help to define the innate barriers preventing induction of durable anti-tumor immunity by ICB in EGFRm NSCLC, and identify strategies to overcome them.

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Therapeutic targeting of BRAF fusion altered lung cancer

2022

Career Development Award

Michael Offin, MD

Memorial Sloan Kettering Cancer Center

New York

Alterations in the BRAF gene can lead to the development of non-small cell lung cancer. BRAF fusions are a type of BRAF gene alterations. These fusions are powerful growth stimulators of lung cancer. Currently, no treatment exists for cancers that harbor these BRAF fusions. Dr. Offin will be testing a series of new drugs in preclinical cell line and animal models of lung cancer. The ultimate goal of his project is to identify new drugs that can be tested in clinical trials.

Research Summary

With the growing adoption of next-generation sequencing (NGS) as a standard of care diagnostic test for patients with lung cancers we have an increased understanding of the genetic landscape of these tumors and strive to derive novel targeted treatment options. BRAF is a protein member of the RAF family kinases and is part of a signaling cascade that, when activated, can lead to cell growth. Under normal physiological conditions the activity of RAF kinases is tightly controlled by negative regulators and down-regulation of growth factor action to prevent uncontrolled cell growth and tumor formation. In cancers, BRAF can be permanently activated by genetic events when alterations occur in the active part (kinase domain) of the enzyme or when the kinase domain is fused with parts of other proteins leading to uncontrolled activation of BRAF. There is currently no approved or recommended therapy for cancers that arise from BRAF fusions. Our goal in this proposal is to test three small molecule inhibitors that target BRAF fusions in disease models derived from patient tissue (patient-derived xenografts [PDX]) to determine the most effective drug that can move forward to a phase 1 clinical trial. We also aim to generate additional tractable patient-derived models that will aid in exploring and developing new therapy for people with cancers driven by BRAF fusions. Finally, in order to develop combinatorial therapy, we aim to identify the signaling pathways active in patient-derived and isogenic cell lines engineered to express BRAF fusions. The applicant is ideally situated to translate these findings to the clinic.

Technical Abstract

Rearrangement of the BRAF gene results in a potent oncogene that is a driver in 2.8% of NSCLC with BRAF alterations. To date there is no approve targeted therapy for any cancer type with BRAF fusions. Studies by our group and others have shown that mutant-specific BRAF kinase inhibitors do no inhibit BRAF fusion kinases. Instead, pan-RAF inhibitors seem more effective as therapy for cancer cells harboring these fusions. We therefore hypothesize that targeting BRAF fusions with pan-RAF inhibitors are likely to be effective therapy for this molecularly defined subset of NSCLC. Our goal in this proposal is to generate the preclinical data necessary to propel a phase 1 clinical trial of a pan-RAF inhibitor specific to patients with NSCLC harboring a BRAF fusion. We have generated seven preclinical disease models with BRAF rearrangement, including two NSLC patient-derived xenograft models with matching cell lines that will allow this project to go forward immediately. In Aim 1 we propose to generate additional NSCLC PDX, organoid and cell line models that will expand the platforms available to examine the efficacy of these BRAF inhibitors. We will test the efficacy of three pan-RAF inhibitors (LY3009120, belvarafenib, KIN-2787) in vitro and in vivo in Aim 2. We believe that combination therapy may eventually be necessary to extend the duration of response to BRAF targeted therapy. To find candidates that can be exploited for combination therapy, in Aim 3 we will map the signaling pathways that are activated by BRAF fusions in isogenic cell lines and inhibited specifically by BRAF inhibitors in cells with BRAF fusions. Given that resistance to therapy is inevitable, we will seek to generate resistance to the three pan-RAF inhibitors in vitro and in vivo and then identify and validate potential mechanisms of resistance. To be able to bring the goals of this proposal to fruition, I have assembled a team with clinical, translational and basic research expertise to help guide me. As a thoracic oncologist with clinical trial expertise, I am ideally situated to translate the findings of this study to the clinic.

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Phase 2 trial of neoadjuvant KRAS G12C directed therapy in resectable NSCLC

2022

Career Development Award

Kristen Marrone, MD

Johns Hopkins School of Medicine

Baltimore

Around one in three patients with non-small cell lung cancer are diagnosed with early-stage disease, where surgery is offered as curative therapy. Unfortunately, the cancer can recur in 50%-60% of patients. The rate of recurrence is higher in patients whose tumors have certain mutations, such as mutations in the KRAS gene. Dr. Marrone and her team will be conducting a phase 2 trial to test whether treatment with a KRAS G12C blocking drug, adagrasib, given as a single drug or in combination with an immunotherapy drug, nivolumab, before a patient undergoes surgery can delay or prevent recurrence in patients whose tumors have a KRAS G12C mutation.

Research Summary

Although one in three patients diagnosed with non- small cell lung cancer (NSCLC) are found to have potentially curable earlier stage disease, for many the cancer will return. Rates of cancer returning are higher in patients whose tumors have certain mutations, such as KRAS. Immunotherapy with immune checkpoint inhibitors has improved survival for patients with later stages of NSCLC and around the time of surgery. Targeted therapies for KRAS are also improving outcomes for patients with advanced NSCLC. The goal of this study is to evaluate if immunotherapy alone or in combination with a targeted pill for a specific KRAS mutation called G12C is safe and can eliminate cancer cells when given prior to surgery for earlier stage NSCLC. Using immunotherapy and targeted therapies in early stage NSCLC may increase rates of cure compared to surgery and chemotherapy alone.

It is important to understand how and why this therapy may improve cure rates in early stage KRAS mutated NSCLC. Therefore, we will also evaluate the quantity and quality of the immune response with this clinical trial therapy. By evaluating the T cells in the tumors after these treatments, we will better understand how to create a deeper and stronger immune response in KRAS-mutated NSCLC. This is essential because we know that a patient’s own immune system can help increase cure rates and control cancer for longer than other therapies alone. Overall, our trial seeks to create new treatment opportunities for surgical lung cancer while improving outcomes across all stages of KRAS-mutated NSCLC.

Technical Abstract

Although about a third of patients with non-small cell lung cancer (NSCLC) present with resectable disease, a majority will experience death and relapse from their cancer. Exciting recent advances in the use of immune checkpoint inhibition in this early stage space presents a promising way forward for our patients. As the most commonly mutated oncogene, activating KRAS mutations are found in 30% of lung adenocarcinomas; G12C mutations have been associated with higher risk of recurrence following resection. Adagrasib (MRTX849), a potent, highly selective novel small molecule inhibitor of KRAS G12C, has shown promise in previously treated advanced NSCLC. Our study represents a novel application of precision oncology in the resectable NSCLC disease setting with the neoadjuvant use of adagrasib monotherapy or in combination with immune checkpoint inhibition. We will identify safety and clinical efficacy signals of both of these therapeutic approaches. Leveraging our institutional expertise of using single- cell transcriptomics of tumor- infiltrating lymphocytes (TIL), we will evaluate neoantigen-specific transcriptional programs with a focus on KRAS-specific changes, and correlate with clinical outcomes. Overall, our study aims to ultimately improve cure rates of resectable KRAS G12C-mutated NSCLC.

Key words

Biomarker or biomarker testing

KRAS

Non-small cell lung cancer (NSCLC)

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Innate immunity as a mechanism of TKI resistance in fusion-driven NSCLC

2021

Career Development Award

This grant was funded in part by The Huff Project

Erin Schenk, MD, PhD

University of Colorado

Boulder

Fusion-driven NSCLC is a group of lung cancers that are driven by specific changes in oncogenes. These lung cancers tend to be addicted to these oncogenes. Such fusion-driven NSCLCs are treated with targeted therapies that block the effect of the oncogenes. However, the cancer inevitably comes back because the tumors become resistant. Traditionally, fusion-driven NSCLCs have not been successfully treated with immunotherapy. Dr. Schenk is testing how these cancers can be treated with immunotherapy through another immune pathway—the innate immunity pathway.

Research Summary

In patients with non-small cell lung cancer, a subset of tumors carry a genetic alteration resulting in the expression of ALK or ROS1 fusions (FD-NSCLC). These tumors frequently respond to and are controlled by tyrosine kinase inhibitor (TKI) therapy for several years. Eventually, these tumors develop TKI resistance and some of the resistance mechanisms are readily identified in the cancer cells. In a similar portion of patients, the reason for TKI resistance development is unknown. Based on our preliminary data, we propose that the tumor microenvironment (TME), specifically the monocytes and macrophages (MoMf) surrounding the cancer cells, contributes to the development of TKI resistance. However, the potential role of the TME as a mediator of TKI resistance has not been well studied in patients with FD-NSCLC. Using cell lines derived from patients, we observed FD-NSCLC cell lines were more resistant to TKI when grown in MoMf conditioned media. This resistance was associated with increased activation of a key cancer cell signaling pathway that drove the decreased sensitivity to TKI. In pre-treatment biopsy specimens, we found that the TME of patients with FD-NSCLC contained variable levels of MoMf. We believe our preliminary data suggests MoMf within the TME influence patient outcome to TKI therapy. We will test our hypothesis in clinically relevant animal models, patient derived FD-NSCLC cell lines, and patient biopsy specimens. Ultimately, we hope to identify novel MoMf-mediated mechanisms of TKI resistance as there is an urgent need to develop new, more effective therapies for these patients.

Technical Abstract

Patients with non-small cell lung cancers bearing ALK or ROS1 fusions (FD-NSCLC) often experience an initial, marked response to tyrosine kinase inhibitors (TKI). The eventual emergence of TKI resistance in FD-NSCLC can be partially attributed to cancer-cell intrinsic mechanisms, but these do not fully explain the diversity in patient outcomes. Currently, FD-NSCLC is viewed as a “cold” tumor with only a molecular target, and the role of the tumor microenvironment (TME) in these cancers has not been well studied. As patients have limited options after progression on TKIs, there is an urgent need to identify novel drivers of resistance to develop new, more effective therapies. Based on our preliminary data, we believe innate immune cells, monocytes and macrophages (MoMf), within the FD-NSCLC TME shape tumor response to TKI therapy. Using patient derived cell lines, we found marked TKI resistance in multiple FD-NSCLC cell lines when cultured in media conditioned by MoMf. MoMf-driven TKI resistance was associated sustained pERK activity in the cancer cell. In pre-treatment specimens from patients with FD-NSCLC, multispectral tissue imaging demonstrated a range in number of MoMf within the TME. Our preliminary data suggest the presence of MoMf with the FD-NSCLC TME may alter response to therapy. We propose investigating the mechanisms of MoMf-mediated TKI resistance and potential therapeutic approaches with clinically relevant syngeneic and xenograft animal models and patient-derived FD-NSCLC cell lines. Further, we will examine biopsy specimens from patients
Immunotherapy is a treatment approach that leverages the body’s own immune system to destroy cancer cells. In non-small cell lung cancer (NSCLC), the most common type of lung cancer, immunotherapy has opened the door to durable treatment that approaches cure; unfortunately, this outcome is rare, and many NSCLCs are initially or eventually become unresponsive. It was originally thought that unresponsive malignancies had adapted to prevent immune cells from locating and interacting with the tumor. Our research suggests this is not the case: the tumor can remain inflamed and responsive, but the immune response can become exhausted. Therapies that reinvigorate the immune response (including tumor infiltrating lymphocyte [TIL] therapies) may be particularly effective in this context. In fact, our preliminary studies suggest TIL therapy can work in up to a third of treatment-resistant NSCLCs. Capitalizing on these new insights, our proposal seeks to 1) determine pre-treatment features of sensitivity and resistance to TIL therapy in NSCLC and 2) characterize on-treatment patterns of immune response, focusing on the cells that identify and kill NSCLC cells. Accomplishing these aims will fill critical knowledge gaps, identifying characteristics of tumors likely to respond, or that fail to respond, to TIL treatment. These studies will define a roadmap, guiding application of subsequent TIL research for lung cancer. Taken together, these studies will provide crucial insights into novel treatment approaches for patients with few alternatives and an otherwise grim prognosis.

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Targeting myeloid-derived suppressor cells in lung cancer

2021

Career Development Award

Dwight Owen, MD

The Ohio State University Comprehensive Cancer Center

Columbus

Immunotherapy has become a standard treatment regimen for advanced-stage non-small cell lung cancer. However, most patients do not respond. One significant barrier to immunotherapy efficacy is the tumor microenvironment (TME), which contains immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs). MDSCs represent an important tumor immune escape mechanism and play a role in the development and progression of lung cancer. Dr. Owen will be studying how this group of cells can be targeted to improve the effect of immunotherapy.

Research Summary

Lung cancer is the leading cause of cancer-related death in the United States and worldwide, and the typical survival for patients with advanced lung cancer is approximately one year. Treatments that specifically target the immune system have been shown to improve survival in some patients, yet most patients eventually need supplementary treatments to manage their disease. Even with advances in treatment, the optimal treatment for patients after other therapies fail is still unknown. We need to understand why current treatment options either do not work from the beginning, or stop working over time, in order to develop new strategies to improve outcomes for patients with lung cancer. In this study, we will study the combination of an approved immune targeting treatment (atezolizumab) with a vitamin A derivative called all-trans retinoic acid (ATRA). ATRA, an oral, non-chemotherapy medication commonly used to treat a form of leukemia, may be help to in promote an immune response when taken along with immunotherapy. Our studies focus on a specific cell of the immune system that can interfere with available immune treatments, myeloid-derived suppressor cells (MDSCs). We will study changes in MDSCs in the blood during treatment to see if these changes can predict whether the treatment is working, or if it is likely to stop working soon. We hope that our immune cell studies will lead to improved treatment options for patients with lung cancer, and that the new drug combination described in this proposal will lead to better outcomes in patients with lung cancer when current treatment options fail to control the cancer.

Technical Abstract

Lung cancer is the leading cause of cancer-related death in the United States and worldwide. Immune checkpoint inhibitors (ICIs) have shown durable responses and improved survival in some patients with advanced non-small cell lung cancer (NSCLC). However, nearly all patients eventually progress on these therapies, and the median survival for patients with metastatic NSCLC remains around one year. Combining immunotherapy with cytotoxic chemotherapy has shown an incremental benefit but at the cost of increased toxicity. Patients who progress on currently available immunotherapies have few effective treatment options. One significant barrier to ICI therapy efficacy is the tumor microenvironment (TME), which contains immunosuppressive cells including myeloid-derived suppressor cells (MDSCs). MDSCs represent an important tumor immune escape mechanism and play a role in the development and progression of lung cancer. Higher levels of MDSCs in the blood are associated with shorter overall survival in patients with NSCLC, and MDSCs are associated with resistance to immune checkpoint inhibitor (ICI) therapy. However, there is significant variation in methods of measurement of MDSCs including 1) the classification of the most common phenotypes, namely CD15+ polymorphonuclear MDSC (PMN-MDSC) and CD14+ monocytic MDSC (M-MDSC), and 2) the functional assessment of MDSCs. There are also significant differences in MDSC function and phenotype in animal models and in patients with cancer. We propose to investigate the role of MDSCs in tumor immune escape, and to target the immunosuppressive impact of MDSCs to improve outcomes of patients with NSCLC treated with ICI. Utilizing mass cytometry and in vitro co-culture assays, we will evaluate MDSC levels and function as well as immune cell subset changes in patients receiving standard of care immunotherapy to identify the cell populations that drive immune responses and resistance. We will then conduct a phase 1b clinical trial of all-trans retinoic acid (ATRA) combined with atezolizumab to test whether this treatment can improve responses and overcome ICI resistance in patients with NSCLC who have progressed on standard therapies. We hypothesize that a decrease in the frequency and immunosuppressive function of circulating MDSCs will be associated with increased clinical benefit in patients with NSCLC, and that modulation of MDSCs through the use of ATRA given in combination with ICIs will be safe, tolerable, and exhibit preliminary efficacy in overcoming resistance to available ICIs. The proposed studies include the first trial of this novel treatment in patients with lung cancer and will examine the potential for targeting MDSCs to overcome resistance and enhance the efficacy of immunotherapy. If successful, these studies may lead to an increased number of patients with advanced NSCLC experiencing durable responses and improved survival.

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Predictive biomarkers of radio-immunotherapeutic response in NSCLC

2020

Career Development Award

Sean Pitroda, MD

The University of Chicago

Chicago

Dr. Pitroda and his team will develop a biomarker signature that can predict which patients are the most likely to benefit from an immunotherapy-radiation therapy combination. The ultimate goal is to determine which patients are likely to benefit from this combination treatment.

Research Summary

Lung cancer is the leading cause of cancer-related death in the United States. Metastasis, or the spread of cancer from its original site, occurs in most patients with lung cancer and is typically incurable. Recently, immunotherapy drugs, which reactivate one’s own immune system to fight off cancer, have revolutionized the treatment of metastatic lung cancer. Unfortunately, less than half of patients respond to immunotherapy. In an effort to improve the outcomes for patients with metastatic non-small cell lung cancer (mNSCLC), the most common type of lung cancer, we combined immunotherapy with high-dose radiation therapy in the largest clinical trial of its kind to-date. We found that the combination treatment was not only safe, but highly effective resulting in treatment responses and excellent survival for the majority of patients. Here, we propose to utilize cutting-edge genetic technologies to investigate the synergy between radiation therapy and immunotherapy. Importantly, we propose to validate a completely novel biomarker as a predictor of treatment response. By understanding how radiation therapy improves the response to immunotherapy, we may be able to fulfil an unmet clinical need by improving the long-term survival of patients with mNSCLC.

Technical Abstract

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

Key words

Chemotherapy

Circulating tumor DNA

Molecular profile or molecular testing

Mutation profile

Non-small cell lung cancer (NSCLC)

Radiotherapy

Stage - all

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SCLC molecular subtypes to predict targeted and immune therapy response

2020

Career Development Award

Carl Gay, MD, PhD

The University of Texas MD Anderson Cancer Center

Houston

Dr. Gay and his team will test an immunotherapy-DNA damage response (DDR) inhibitor combination therapy in SCLC patients and validate a biomarker profile. Dr. Gay’s research aims to develop a new drug therapy combination and determine which patients are likely to benefit from it.

Research Summary

Small cell lung cancer (SCLC) is among the most aggressive malignancies. While this disease responds initially to standard of care therapy, the tumors rapidly develop resistance to these and other available treatments, leading to limited patient survival. Unlike other cancers, where personalized medicine has markedly improved outcomes, small cell lung cancer patients are treated homogeneously, with little understanding of the patients that might best benefit from a specific therapy. Immunotherapy, which has so greatly impacted many other cancers, has shown modest, but promising efficacy for small cell lung cancer patients. We have demonstrated previously that in small cell lung cancer models, immunotherapy response may be enhanced using a class of drugs known as DNA damage repair (DDR) inhibitors. Furthermore, we have developed a potential strategy for optimally identifying patients for DDR inhibitors and immunotherapy using a molecular subtyping approach, which needs validation in patients. We propose using our unique collection of patient-derived mouse models of SCLC, as well as an upcoming trial pairing DDR inhibitors and immunotherapy, to validate our hypothesis. We predict that specific molecular subtypes predict innate sensitivity/resistance and that the ability of SCLC to switch subtypes may underlie acquired resistance. We will examine mouse models and patient samples representing each of the four molecular subtypes and validate predictions for best responses, while performing careful comparisons between samples collected pre- and post-treatment to explore mechanisms of resistance in an attempt to guide future clinical trials aimed at personalization of SCLC therapy.

Technical Abstract

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

Key words

Acquired resistance

Biomarker or biomarker testing

Circulating tumor DNA

Immune checkpoint inhibitors

Immunotherapy

Small cell lung cancer (SCLC)

Tumor microenvironment