Lung SPORE

Overview: Immunotherapy drugs called immune checkpoint inhibitors are revolutionizing the treatment of certain cancers. Unfortunately, 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.

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 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 (formalin-fixed paraffin-embedded) tissue sample slide as an 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.

Overview: Drs. Philip Greenberg and Sylvia Lee have developed methods to engineer T cells to target the mutated genes most commonly driving cancer. This can result in long-lasting immune responses in patients, supporting sustained anti-tumor activity that can potentially eradicate the tumors. Greenberg and Lee plan to test this approach in patients in a clinical trial by the end of the grant period. 

Phillip Greenberg, MD (Basic Co-Leader)
Sylvia Lee, MD (Clinical Co-Leader)

Goals: 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. The Greenberg 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.

Overview: Small cell lung cancer (SCLC) is a deadly disease with few effective treatment options. Up to one third of these cancers have a particular genetic mutation that could potentially be targeted by a certain experimental new drug. Drs. David MacPherson and Keith Eaton will map out how this drug works and identify telltale molecular signs that can predict who will respond to this treatment.

David MacPherson, PhD (Basic Co-Leader)
Keith Eaton, MD (Clinical Co-Leader)

Goals: 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 toward 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 who 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 (e.g., 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 2 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.

Paul Lampe, PhD  (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 lung cancer research expertise. 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 because 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.

Alice Berger, PhD (CEP Director)

The development of talented junior faculty into future leaders in their respective fields is a key goal of 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 postdoctoral 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 from the research expertise and available core resources. The Committee will make self-assessments to carefully monitor program effectiveness and make necessary adjustments. 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.