Fred Hutchinson Cancer Research Center
Principal Investigator
A. McGarry Houghton, M.D.
Full Professor, Clinical Research Division
Fred Hutchinson Cancer Research Center
1100 Fairview Ave. N., Mail Stop D4-100
Seattle, WA 98109
206-667-3175
Overview
The Fred Hutchinson (Fred Hutch) Lung Specialized Program of Research Excellence (SPORE) has leveraged the strengths of the investigators and our Center to tackle three critical barriers precluding meaningful improvements in lung cancer survival rates: lack of effective therapies for small cell lung cancer (SCLC), sub-optimal response rates of non-small cell lung cancer (NSCLC) patients to immune checkpoint inhibitor therapy, and the lack of effective targeted therapies for KRAS mutant lung cancers.
To overcome these barriers, we have developed three innovative translational research projects:
- Project 1. Targeting Neutrophils to Enhance ICI Efficacy in NSCLC
- Project 2. Treating Metastatic Lung Cancer by Targeting Mutated KRAS with Engineered T Cells
- Project 3. Targeting LSD1 to Augment Responses to PD-L1 Inhibition in Small Cell Lung Cancer
These projects will be supported by an Administrative Core, a Biostatistics and Data Science Core, and a Histopathology and Biospecimen Core. Our SPORE also includes a Developmental Research Program (DRP), as well as a Career Enhancement Program (CEP).
Project 1: Targeting the Neutrophils to Enhance ICI Efficacy in NSCLC
Project Co-Leaders
- A. McGarry Houghton, M.D. (Basic Co-Leader)
- Christina Baik, M.D., M.P.H. (Clinical Co-Leader)
Specific Aims
The goal of this project is to show that neutrophil lineage cells prevent tumor reactive lymphocytes from accessing the malignant portions of tumor and that antagonizing neutrophil recruitment and function will improve anti-PD1 response rates. Our group has discovered that approximately 30% of non-small cell lung cancers (NSCLC) display evidence of myeloid lineage cell infiltration, which includes an abundance of neutrophils. We have termed such tumors Myeloid to distinguish them from Active tumors, which frequently respond to immune checkpoint inhibitor therapy. We have generated data in pre-clinical mouse models showing that inhibiting or depleting neutrophils synergizes with ICI treatment to reduce tumor burden. Here, we will develop an Immune Phenotype Classifier to reliably identify Myeloid lung cancers and perform a Phase 2 clinical trial combining the novel CXCR1/2 inhibitor SX-682 with atezolizumab for NSCLC patients in the 2nd line, designed to rescue ICI treatment failure in Myeloid cancers. The Classifier will be designed to be translational relevant and transportable. We will develop a multiplexed-immunohistochemistry (M-IHC) panel that only requires one FFPE slide as input, something that is universally available even at rural hospitals. Using this Classifier, we will test the concept that Myeloid immune subtype patients will demonstrate favorable treatment outcomes upon the addition of the CXCR1/2 inhibitor.
Project 2: Treating Metastatic Lung Cancer by Targeting Mutated KRAS with Engineered T Cells
Project Co-Leaders
- Phil Greenberg, M.D. (Basic Co-Leader)
- Sylvia Lee, M.D. (Clinical Co-Leader)
Specific Aims
The goal of this project is to show that T cells engineered to recognize a mutation in KRAS can effectively treat metastatic KRAS mutant lung cancers. Our lab has been developing cell therapies for viral and malignant diseases for several decades, with a current focus on genetic engineering. Principles to reproducibly achieve tumor eradication have emerged, including targeting antigens essential to the tumor, providing durable T cell responses, and overcoming obstacles to T cell activity. We propose combining synthetic biology with cell engineering to address each of these obstacles. First, we will engineer both CD4 and CD8 T cells to function with the same Class I-restricted TCR and be specific for mutated KRAS, the most common oncogenic driver in NSCLC, thereby creating a coordinated CD4 and CD8 T cell response that can sustain anti-tumor activity. Second, we will use multi-omics technologies to generate high dimensional data sets describing events in the blood and at the tumor site to illuminate reasons for success and/or resistance. Third, we will develop next generation strategies to enhance efficacy by engineering T cells to express synthetic molecules that convert inhibitory and/or death signals to costimulatory and survival signals to promote durable T cell responses.
Project 3: Targeting LSD1 to Augment Responses to PD-L1 Inhibition in Small Cell Lung Cancer
Project Co-Leaders
- David MacPherson, Ph.D. (Basic Co-Leader)
- Keith Eaton, MD, Ph.D. (Clinical Co-Leader)
Specific Aims
The goal of this project is to study LSD1 inhibition across heterogeneous immune competent SCLC models and to link biological features of SCLC to patient responses towards LSD1 inhibition and anti-PD1 treatment in a clinical trial. Small cell lung cancer (SCLC) exhibits exceptionally poor prognosis. Addition of immune checkpoint blockade (ICB) to standard of care improved clinical responses, but few patients achieve durable benefit, in part, because SCLC tends to suppress expression of antigen presentation machinery. This proposal is focused on using a targeted therapy, LSD1 demethylase inhibition, to improve responses to immunotherapy in SCLC. SCLC patients that benefited from ICB exhibited tumors with the following features: 1) suppression of neuroendocrine gene expression 2) activation of NOTCH, and 3) expression of MHC-I. We showed that LSD1 inhibition suppresses neuroendocrine features, activates NOTCH, increases MHC-I on tumor cells, and improves response to PD-1 inhibition in vivo, demonstrating potential for LSD1 inhibition to switch immune cold SCLC to become immune responsive. Beyond effects on tumor cells, LSD1 inhibition has been shown to directly regulate multiple immune populations that contribute to anti-tumor immunity. Additionally, there is increasing appreciation of biological heterogeneity in SCLC, in part, driven by activation of different transcription factors (i.e. ASLC1, NEUROD1 POU2F3 and REST, a repressor of neuroendocrine state). We need to know how SCLC transcriptional subtype impacts responsiveness to LSD1/PD-1 inhibition if we are to better direct this treatment approach to the right population of patients. We developed a novel blood-based assay, based on targeted nucleosome profiling of regulatory regions of ctDNA to correlate SCLC phenotypes with patient responses. We will employ this assay to analyze longitudinally collected samples from a Phase II clinical trial to be conducted in the maintenance setting in patients to be randomized to LSD1i/anti-PDL1 vs. anti-PDL1 following initial chemoimmunotherapy. We will also identify biological phenotypes that are associated with strong clinical responses.
Administrative Core
Core Director
Specific Aims
The Administrative Core of the Fred Hutch Lung SPORE will provide the necessary infrastructure, organization, coordination, and fiscal management necessary to successfully complete the tasks proposed. Collectively, the Fred Hutch Lung SPORE leadership will coordinate all SPORE related activities. Advice received from advisory boards will be implemented into the program through the administrative core. Specific tasks of the Administrative Core will include: 1) to provide coordination and oversight to all Lung SPORE activities to meet the scientific and administrative needs of the individual projects and cores, 2) to provide fiscal management of grant funds for projects and cores, 3) to prepare and file regulatory documents and progress reports, 4) to administer the Developmental Research Program and Career Enhancement Program, 5) to coordinate SPORE interaction with the Fred Hutch/UW Cancer Consortium, 6) to arrange the monthly Lung SPORE Research Meeting and the annual Lung SPORE Retreat, and 7) to provide oversight for all necessary regulatory requirements and documentation.
Histopathology and Biospecimen Core
Core Co-Directors
Specific Aims
The Histopathology and Biospecimen Core (HBC) represents an integral component of the Fred Hutch Lung SPORE, supporting the translational goals of the Projects as well as future SPORE-funded development projects. The mission of the HBC is to facilitate discovery and rapid translation of discoveries into clinical care. To this end, the HBC manages the acquisition, annotation, processing and distribution of biospecimens from patient-derived and SPORE-funded experimental mouse models. The HBC partners with NWBioTrust (NWBT), and Fred Hutchinson/University of Washington Cancer Consortium (CCSG) – a funded collaborative resource for obtaining high-quality, well-annotated and appropriately-consented and de-identified biospecimens for innovative research. In addition to biobanking activities, the HBC is responsible for managing the performance of downstream tissue-based assays, leveraging a suite of cutting-edge histopathologic and imaging capabilities supported by the Fred Hutch in its extensive network of Shared Resources. These capabilities include, but are not limited to, routine histopathologic services, pathology review and consultation, immunohistochemistry (IHC), branch-chain in-situ hybridization (ISH), DNA/RNA extraction, Nanostring-based transcriptional profiling, multiplex immunohistochemistry (M-IHC) and digital image analysis. The HBC will provide SPORE investigators with biospecimens (e.g. serum), derivatives of biospecimens (e.g. unstained slides, DNA, RNA) as well as quality-controlled data (e.g. images and image analysis-based data).
Biostatistics and Data Science Core
Core Co-Directors
Specific Aims
The Biostatistics and Data Science Core (BDSC) will provide statistical and bioinformatics support for all projects within the Core and all SPORE investigators. The Core is comprised of biostatisticians with expertise in lung cancer, clinical trials, higher dimensional data processing and analysis, population studies. Statistical and data science leadership ensures that SPORE study design and data analysis yield valid and unequivocal answers to hypotheses being tested in projects. BDSC faculty and staff will provide statistical leadership to all SPORE projects, linking study design, data collection and analysis to scientific goals of the SPORE program. The BDSC will play an integral role in the collection, quality control, and analysis of data for SPORE projects, including career enhancement and developmental research projects. Our scientific projects will require and utilize a variety of assays, including high-throughput and multiparametric technologies, along with cutting-edge computational tools and modeling strategies that can be used to analyze and integrate heterogeneous datasets and/or predict responses. Consequently, large-data management and computational analysis will be an integral part of this research program. The efficient design of clinical trials is also an important component in taking any intervention from bench to bedside. The BDSC will serve as the quantitative piece of this collaboration by providing experimental and clinical trial design as well as analysis and interpretation of data from all experiments and clinical trials that are conducted in the SPORE.
Developmental Research Program
Program Director
The availability of mature projects of potentially high translational impact forms the cornerstone of any successful SPORE. The Developmental Research Program (DRP) of the Fred Hutch Lung SPORE will ensure that such projects are always available for inclusion in future iterations of the SPORE or as replacements for faltering projects. To accomplish this, we have assembled a DRP Committee that includes a broad array of research expertise as pertains to lung cancer. Dr. Lampe and Dr. Houghton will serve as the Chair and Co-Chair respectively. Both Dr. Lampe and Dr. Houghton serve on the Executive Committee as well, which will ensure effective communication with SPORE leadership, as the development of new projects is such an essential requirement for programmatic success. In conjunction with appropriate administrative support, the DRP Committee will solicit applications and select the most highly meritorious proposals for funding. Each DRP Awardee will be integrated into the Lung SPORE and gain access to all SPORE core facilities. Importantly, SPORE investigators will ensure that all DRP Awardees identify necessary collaborators for the successful completion of the project and for guidance to reach putative translational endpoints.
Career Enhancement Program
Program Director
The development of talented junior faculty into future leaders in their respective fields is a key goal of essential all successful research organizations. The Fred Hutch Lung SPORE Career Enhancement Program (CEP) will aspire to identify and nurture the careers of promising junior investigators and senior faculty interested in refocusing their programs on lung cancer translational research. This will be accomplished through a calculated solicitation process to identify all talented junior investigators at the post-doctoral fellow level (must be in last year of training) and junior faculty level. We will also solicit applications from senior investigators who wish to re-focus their research programs on translational lung cancer research. A thorough review process will be performed by a highly accomplished panel of senior leaders at our Center who comprise the CEP Committee. In conjunction with the Executive Committee (EC), final award decisions will be made. The CEP Committee will closely monitor the progress of CEP Awardees throughout the duration of the award. The EC and CEP Committee will ensure that the awardees become immersed within the Lung SPORE and benefit the research expertise and available core resources. Self-assessments will be made by the Committee such that the effectiveness of the program can be carefully monitored and necessary adjustments made.