The Fred Hutch Lung Specialized Project of Research Excellence (SPORE) brings together experts from across Fred Hutch and its partner organizations to fast-track the latest breakthroughs in its labs to patients and those at risk of developing lung cancer. The Lung SPORE has leveraged the strengths of its investigators and Fred Hutch 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.
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.
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.
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.
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.
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.