Lung SPORE

Overview: Immunotherapy drugs called checkpoint inhibitors are revolutionizing the treatment of certain cancers. But the drugs only work to shrink tumors in about 20% of patients with non-small cell lung cancer, or NSCLC. Dr. McGarry Houghton and Dr. Christina Baik will study whether certain immune cells called neutrophils interfere with the efficacy of these drugs in this type of lung cancer. They also plan to launch a clinical trial that pairs a checkpoint inhibitor with a drug that reduces levels of tumor-associated neutrophils.

A. McGarry Houghton, MD (Basic Co-Leader)
Christina Baik, MD (Clinical Co-Leader)

Goals: 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. 

Overview: Drs. Stan Riddell and Sylvia Lee aim to develop a vaccine that can get a patient’s immune system to target NSCLC. The researchers plan to first identify cancer-specific markers called antigens on the surface of a patient’s NSCLC cells. Then they’ll engineer some of the patient’s own T cells to deliver those antigens throughout the body like a battle flag, rousing the patient’s immune system to fight the cancer. In other words, the engineered T cells would act like the inactive flu virus in your annual flu shot. Riddell and Lee plan to test this approach in patients in a clinical trial by the end of the grant period. 

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

Goals: 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. Putative neoantigens are prevalent in NSCLC due to the high mutation burden and may be superior to self-antigens as vaccine targets because the T cell repertoire capable of responding is not affected by central tolerance mechanisms. Moreover, multiple neoantigens can theoretically be targeted by a vaccine, which could overcome heterogeneity in antigen and MHC expression on tumors, and in the quality of a single neoantigen. Multiple candidate neoantigens can be identified using whole exome sequencing of tumors to detect coding mutations, and algorithms that predict peptides likely to bind to MHC molecules. Initial clinical applications of therapeutic neoantigen vaccines in melanoma have recently provided proof-of-principle, revealing the potential of this personalized approach to cancer immunotherapy.

We have developed a novel approach to neoantigen vaccination that utilizes the systemic administration of autologous T cells engineered to express cancer-specific mutations. 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.

Overview: Small cell lung cancer is a deadly disease with few effective treatment options. But up to a third of these cancers have a particular genetic mutation that could potentially be targeted by a certain experimental new drug. Drs. David MacPherson and Renato Martins will map out how this drug works and identify telltale molecular signs that can predict who will respond to this treatment. They plan to test this new therapy in SCLC patients through a clinical trial.

David MacPherson, PhD (Basic Co-Leader)
Renato Martins, MD (Clinical Co-Leader)

Goals: 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.

Specific Aims:

1. To use genetically engineered mouse and PDX models to test the efficacy of ORY1001 in SCLC. We will expand our PDX studies to identify additional strongly responding models and will include models with mutations in chromatin-regulating genes such as CREBBP and KMT2D that we hypothesize may contribute to strong responses. This aim 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.
2. To understand roles for LSD1-NOTCH-ASCL1 axis in control of SCLC cell viability. We will use tumors from PDX and GEM models treated in vivo and PDX tumors treated ex vivo with ORY1001 to interrogate roles for a NOTCH-ASCL1 axis in conferring strong responses to ORY1001 in SCLC. We will also perform studies in PDX models of SCLC studied ex vivo, to identify and better understand differences between strongly responding and non-responsive models. This Aim will include RNAseq and ChIPseq studies that will identify key differences between these groups.
3. Perform an Investigator-initiated clinical trial to test ORY1001 in SCLC patients. Here, we will study circulating tumor cells (CTCs) for biomarkers of response to LSD1 inhibition in a 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.

Overview: Periodic CT scans in people at high risk of lung cancer can detect cancers early, when they’re most treatable. But most lung nodules detected in scans turn out to be benign. Drs. Paul Lampe and Paul Kinahan of the University of Washington want to make this screening process more precise, saving patients with low-risk nodules from invasive biopsies, additional imaging, more medical bills and anxiety about cancer risk. They are developing a strategy that combines machine-learning technology with imaging data, novel blood biomarkers and medical history into a risk calculator for a lung nodule’s likelihood of malignancy. They will then test their new screening method in high-risk patients.

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

Goals: 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) employed low-dose Computed Tomography (CT) imaging of the chest to screen for lung cancer in a high-risk population (smokers aged 55-74). This study demonstrated a 20% reduction in mortality in the group receiving CTs when compared to standard care and has led to generalized acceptance of lung cancer screening in heavy smokers. Unfortunately, pulmonary nodules are a relatively common finding with 25-56% of smokers >50 years of age having CT identifiable pulmonary nodules but less than 2.5% of these actually were cancerous. For diagnosis of incidentally detected pulmonary nodules, current guidelines call for additional imaging and/or invasive biopsy procedures.

For both of these scenarios, 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 developed a validated radiomics pipeline that used machine learning algorithms for image texture features that when combined with radiologist-described shape, or semantic features yielded an AUC of 0.82 using the same diagnostic sample set described above. We have created a rule that combines clinical factors (age, smoking etc.), 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 first 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 the University of Colorado diagnostic and DECAMP-2 (pre-diagnostic) cohorts, respectively.

A. McGarry Houghton, MD (DRP 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. 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.

Renato Martins, MD (CEP 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. 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.