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Last Updated: 09/20/22

Fred Hutchinson Cancer Research Center Lung SPORE

Fred Hutchinson Cancer Research Center

Principal Investigator:

A. McGarry Houghton, MD
A. McGarry Houghton, MD

Principal Investigators Contact Information

A. McGarry Houghton, MD
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 Hutch Lung SPORE has leveraged the strengths of the investigators and our Center to tackle three critical barriers precluding meaningful improvements in lung cancer survival rates: facilitation of pulmonary nodule evaluation for lung cancer early detection and screening, lack of effective therapies for small cell lung cancer (SCLC), and the sub-optimal response rates of non-small cell lung cancer (NSCLC) patients to novel immune-based therapies.

To overcome these barriers, we have developed four innovative translational research projects:

  • Project 1. Targeting the Neutrophil Lineage to Enhance Immune Checkpoint Inhibitor Efficacy in NSCLC
  • Project 2. Targeting Neoantigens for Lung Cancer Immunotherapy
  • Project 3. Identifying Determinants of Sensitivity to LSD1 Inhibition in SCLC
  • Project 4. Risk Stratification for Pulmonary Nodules Detected by CT Imaging Using Plasma and Imaging Biomarkers

These projects will be supported by an Administrative Core, a Biostatistics and Bioinformatics Core, and a Histopathology and Biospecimen Core. Our SPORE also includes a Developmental Research Program, as well as a Career Enhancement Program.

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Project 1: Targeting the Neutrophil Lineage to Enhance Immune Checkpoint Inhibitor Efficacy in NSCLC

Project Co-Leaders:
A. McGarry Houghton, MD (Basic Co-Leader)
Christina Baik, MD, MPH (Clinical Co-Leader)

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 depleting neutrophils from the tumor microenvironment will improve anti-PD1 response rates. Although immune checkpoint inhibitor (ICI) therapy has been a tremendous clinical success, just ~20% of non-small cell lung cancer (NSCLC) patients respond to anti-PD1/PDL1 therapy. In efforts to improve upon this figure, the field has launched over 800 clinical trials (across all cancer types) testing novel therapeutics in conjunction with immune checkpoint blockade. Effectively none of these trials adequately address the neutrophil lineage as a substantial contributor to ICI treatment failure. We have generated preliminary data showing that neutrophils are the most prevalent immune cell type in NSCLC, inversely correlate with CD8+ cellular content, and preclude the presence of the IFNg signature, previously shown to correlate with favorable ICI treatment response. We will perform multiplex-immunohistochemistry on a dataset of FFPE slides obtained from patients treated with anti-PD1/PDL1 therapy to show that neutrophils associate with poor outcomes. We will utilize a novel mouse model in which the tumor harbors hundreds of mutations to identify the mechanistic determinants of ICI treatment response and test a novel CXCR1/CXCR2 antagonist to synergize with anti-PD1 treatment. Lastly, we will perform a Phase 2 clinical trial testing the combination of the novel CXCR1/CXCR2 antagonist (SX-682, Syntrix Pharmaceuticals) and an anti-PD1 antibody in advanced stage NSCLC patients who have previously failed anti-PD1/PDL1 therapy.

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Project 2: Targeting Neoantigens for Lung Cancer Immunotherapy

Project Co-Leaders:
Stanley R. Riddell, MD (Basic Co-Leader)
Sylvia Lee, MD (Clinical Co-Leader)

The goal of this project is to develop a novel immunotherapy for advanced non-small cell lung cancer by engineering an autologous cell based vaccine that is delivered systemically and expresses candidate neoantigens present in the patient’s tumor; the objective is to elicit T cell immunity that either alone, or when combined with immune checkpoint therapy, would promote tumor regression. Immunotherapy with immune checkpoint inhibitors (ICI) is revolutionizing the treatment of many cancers, including non-small cell lung cancer (NSCLC) where a small subset of patients with metastatic disease have significant responses. The antitumor activity of ICI is thought in part to be mediated by CD4+ and CD8+ T cells that recognize neoantigens, which are peptides derived from mutations in expressed genes in tumor cells and presented by class I or II MHC molecules. Thus, the failure of most patients to respond to ICI may result from an insufficient pre-existing tumor-specific T cell response, irreversible dysfunction of previously activated T cells, or local immunosuppressive mechanisms. A therapeutic vaccine capable of boosting or inducing de novo functional T cell responses to neoantigens could be beneficial alone, or in combination with ICI or other modalities that overcome immunosuppression in the tumor microenvironment.

We have developed a novel approach to neoantigen vaccination that utilizes the systemic administration of autologous T cells engineered to express cancer-specific mutations (Tvax). This strategy was suggested by clinical data from our lab showing that adoptive transfer of human T cells expressing transgenes encoding foreign proteins induced potent CD8+ and CD4+ T cell responses specific for the transgene product that were boosted by subsequent infusions, even in patients with severely compromised immunity. T cells provide a versatile platform for personalized medicines, including cell-based vaccines because they can be easily genetically modified and expanded in cGMP conditions, safely administered systemically, and traffic efficiently to lymph node sites to deliver antigens where immune responses are initiated. This project will translate this unique approach for vaccination to neoantigens in preclinical models and patients with NSCLC.

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Project 3: Identifying Determinants of Sensitivity to LSD1 Inhibition in SCLC

Project Co-Leaders:
David MacPherson, PhD (Basic Co-Leader)
Rafael Santana-Davila, MD (Clinical Co-Leader)

The goal of this project is to use patient derived xenograft and genetically engineered mouse models to identify and understand genetically defined subsets of SCLC with strong responses to LSD1 inhibition. We will also conduct an Investigator Initiated clinical trial to test the efficacy of an LSD1 inhibitor in SCLC patients and to link tumor mutations to clinical responses. Small cell lung cancer (SCLC) leads to >30,000 deaths in the USA each year and therapies resulting in durable responses are greatly needed. This proposal is focused on a potent and selective LSD1 inhibitor, ORY1001. In preliminary data, we found efficacy of ORY1001 as monotherapy in a subset of patient derived xenograft (PDX) models of SCLC. PDX models differed greatly in sensitivity to ORY1001, with one model exhibiting complete and durable regression upon ORY1001 treatment. We found that strong tumor regression was linked to robust NOTCH pathway activation, which led to suppression of ASCL1, a transcription factor critical for SCLC. We hypothesize that robust activation of NOTCH and suppression of ASCL1 drives strong response to LSD1 inhibition in a subset of SCLC models. We also hypothesize that mutation in chromatin regulating genes may contribute to robust NOTCH pathway activation and increased sensitivity to LSD1 inhibition in SCLC.

Here, we will use genetically engineered mouse and PDX models to test the efficacy of ORY1001 in SCLC. Mutations in chromatin regulating genes such as CREBBP and KMT2D will be assessed. We will also test a novel Crebbp-deficient genetically engineered mouse model of SCLC that we generated to clearly determine whether inactivation of Crebbp increases response to LSD1 inhibition in SCLC. Additional mechanistic studies will be performed to assess the contribution of the LSD1-NOTCH-ASCL1 axis in control of SCLC cell viability. We will also attempt to utilize circulating tumor cells (CTCs) to identify biomarkers of response to LSD1 inhibition in the associated clinical trial. The design of this trial may be modified based on work performed in SCLC model systems as we identify potential biomarkers that may predict responsiveness. This work aims to direct LSD1 inhibition to SCLC patients most likely to benefit.

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Project 4: Risk stratification for pulmonary nodules detected by CT imaging using plasma and imaging biomarkers

Project Co-Leaders:
Paul D. Lampe, PhD (Basic Co-Leader)
Paul E. Kinahan, PhD (Basic Co-Leader)
A. McGarry Houghton, MD (Clinical Co-Leader)

The goal of this project is to combine plasma, radiomic, semantic and clinical biomarkers to improve the determination of whether pulmonary nodules are cancerous or benign to reduce lung cancer mortality and patient care costs. The National Lung Screening Trial (NLST) utilized CT imaging of the chest in a high-risk population (smokers aged 55-74), which resulted in a 20% reduction in mortality. Unfortunately, pulmonary nodules are relatively common (~50% of smokers) but rarely malignant (<2.5% are actually cancerous). For diagnosis of incidentally detected pulmonary nodules, current guidelines call for additional imaging and/or invasive biopsy procedures. We propose to combine two novel approaches to improve risk stratification for subjects with pulmonary modules. The first involves an antibody array platform for proteomic, glycomic, and autoantibody-antigen complex interrogation that has yielded a four-marker panel with an area under the ROC curve (AUC) of 0.82 in pre-diagnostic samples and 0.83 in a validation diagnostic set of malignant and benign nodules. The second novel component is the analysis of quantitative nodule features extracted from CT images using the methods of 'radiomics'. We have created a rule that combines clinical factors, plasma biomarkers, radiomic CT image semantic and texture features for classification of CT-detected nodules as malignant or benign. The addition of both radiomic and biomarkers to the rule significantly increase the AUC (p<0.005) over clinical and semantic CT measures alone. This rule will be tested in a Vanderbilt CVC incidental/diagnostic cohort, then fixed and tested in the Detection of Early lung Cancer Among Military Personnel Study 1 (DECAMP-1) cohort (Aim 1) with the goal of improving nodule evaluation. We will also test the rule in the NLST screening cohort (Aim 2) to create a final rule that models lung cancer early detection. In Aim 3 we will test the fixed rules from aims 1 and 2 in University of Colorado diagnostic and DECAMP-2 (pre-diagnostic) cohorts, respectively.

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Administrative Core

Core Directors:
A. McGarry Houghton, MD
Christina Baik, MD, MPH

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. Ultimately, the responsibility for the successful completion of all SPORE related activities belongs to Dr. Houghton, the SPORE PI. Dr. Baik will assist him in this endeavor. Additionally, the Lung SPORE Administrator, Jessica Paulishen, will carry out all administrative responsibilities. 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 arranged the monthly Lung SPORE Research Meeting and the annual Lung SPORE Retreat, and 7) to provide oversight for all necessary regulatory requirements and documentation.

The Administrative Core of the Fred Hutch Lung SPORE will provide the necessary infrastructure, organization, coordination, and fiscal management necessary to successfully complete the proposed projects. The overall function of the Administrative Core is to coordinate a collaborative effort between Fred Hutch Lung SPORE investigators and leadership, through leaders of our Center who compose the Internal Advisory Board, and scientific experts assembled to serve on the External Advisory Board. The Administrative Core will ensure that the collective plans agreed upon by SPORE leadership are efficiently executed, and that appropriate documents are filed, fiscal responsibilities are adequately met, and the Developmental Research and Career Enhancement Programs are appropriately managed.

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Biostatistics and Bioinformatics Core

Core Directors:
Mary W. Redman, PhD
Tim Randolph, PhD

The Biostatistics and Bioinformatics Core (BBC) 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 bioinformatics leadership ensures that SPORE study design and data analysis yield valid and unequivocal answers to hypotheses being tested in projects. BBC 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 BBC will play an integral role in the collection, quality control, and analysis of data for SPORE projects, including career enhancement and developmental research projects (CEP and DRP). It is our experience that statistical leadership in research from the concept phase yields studies that are better designed, more likely to answer the scientific questions of interest, and more compelling in their conclusions. 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 BCC 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.

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Histopathology and Biospecimen Core

Core Director:
Haodong Xu, MD, PhD

The Histopathology and Biospecimen Core (HBC) represents an integral component of the Fred Hutchinson Cancer Center (FHCC) lung cancer 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 the for managing the performance of downstream tissue-based assays, leveraging a suite of cutting-edge histopathologic and imaging capabilities supported by the Fred Hutchinson Cancer Center (FHCC) 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 (mIHC) 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).

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Developmental Research Program

Program Director:
A. McGarry Houghton, MD

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. Houghton and Dr. Lampe, both SPORE project PIs will serve as the Chair and Co-Chair respectively. Both Dr. Houghton and Dr. Lampe 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.

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Career Enhancement Program

Program Director:
Alice Berger, PhD

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. Ongoing efforts at our Center will be leveraged to promote an environment of inclusion in which gender and ethnic diversity is promoted within the Lung SPORE.

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Institutional SPORE Website

https://www.fredhutch.org/en/research/institutes-networks-ircs/lung-spore.html

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