Yale SPORE in Skin Cancer

Co-Directors: Marcus Bosenberg, MD, PhD; Harriet Kluger, MD; Mario Sznol, MD

SPORE Administrator: Anna Arnal Estapé, PhD

The Administrative Core (Core A) is critical to the success of YSPORE. The primary purpose of the Core is to support and facilitate transdisciplinary research efforts in skin cancer and identify new challenges and opportunities as they emerge. The Administrative Core serves as the central coordination point for YSPORE investigators, responsible for monitoring the progress of all projects and cores toward a translational/clinical endpoint. These services include provision of:

• Fiscal management
• Clerical and organizational support
• Mechanisms for internal and external review
• Support for enhancement of scientific interactions and collaborations among the Project/Core leaders
• Mechanisms to monitor projects and cores for scientific progress
• Coordination of outreach efforts
• Mechanisms to expand research in skin cancer beyond the activities of the SPORE, both within Yale and outside of Yale.

Core A will organize joint scientific research in progress meetings held with the SPORE researchers, the annual inter-SPORE workshops in collaboration with Administrative Cores at other sites, and the annual meetings with the Internal and External Advisory Boards.

Co-Directors: Ruth Halaban, PhD; Marcus Bosenberg, MD, PhD; Harriet Kluger, MD

The Biospecimen Core (Core B) is the cornerstone of all YSPORE activities. It addresses the broad melanoma patient specimen needs of all the projects that are not met by current shared facilities at Yale. In addition to collecting, storing, and distributing a wide range of specimens and reagents, the Core performs quality assurance testing and a wide range of molecular analyses of specimens. The Core interacts extensively with investigators in each project, the Bioinformatics and Biostatistics Core, the Clinical Trial Office, and Yale Cancer Center shared resource cores, such as Yale Pathology Tissue Services and Yale Center for Genome Analysis. The services of the Biospecimen Resource Core not only enhance the efficient operation of the translational studies by YSPORE investigators in a cost-effective manner; they also expedite the application of discoveries from the bench to clinical practice, and from clinical results to basic research.

Co-Directors: Shuangge Ma, PhD; Yuval Kluger, PhD

The goals of the Biostatistics and Bioinformatics Core are to address the study design and analysis needs of the YSPORE projects, the Developmental Research Program (DRP), and the Career Enhancement Program (CEP), as well as the analytical and data management needs of the Biospecimen Core. Drs. Kluger and Ma will continue to serve as co-directors of this core and will be assisted by statisticians and bioinformaticians with unique expertise and extensive experience. The Biostatistics and Bioinformatics Core specifically aims to provide optimal biostatistical and bioinformatics support to all SPORE projects and investigators; provide effective data management for all of the SPORE projects; develop innovative biostatistics and bioinformatics methods; and promote program-specific research opportunities involving biostatistics and bioinformatics trainees and faculty.

Co-Leaders: Qin Yan, PhD (basic co-leader); Marcus Bosenberg, MD, PhD (applied co-leader)

Despite remarkable progress in treating advanced melanoma, prognosis remains variable. Specifically, nearly all metastatic melanoma patients develop resistance to targeted therapy with time, while approximately half do not respond to immunotherapy. These challenges highlight an urgent need to develop novel therapeutic interventions, improve current treatments, and develop biomarkers that predict response. Emerging evidence suggests that epigenetic regulators KDM5B and SETDB1 are therapeutic targets, and endogenous retroelements (REs) may serve as biomarkers of response to immunotherapies. Our long-term goal is to translate our findings of novel mechanisms involved in melanoma progression to the clinic. The objectives of this project are to dissect the cellular mechanisms by which KDM5B and SETDB1 loss induce anti-melanoma immunity, develop biomarkers to predict response to immune checkpoint inhibitors, and to evaluate the therapeutic potential of depleting KDM5B in melanoma. Our central hypotheses are that KDM5B and SETDB1 targeting de-repress the expression of retroelements to initiate robust anti-melanoma immune responses, and retroelements can be harnessed to predict response to immunotherapy. The hypothesis is supported by previous studies, as well as our own preliminary data from patient-derived melanomas and preclinical melanoma models. The rationale is that better understanding of how KDM5B and SETDB1 suppress melanoma growth and anti-tumor immune responses will result in new and innovative approaches to treating melanoma.

The hypotheses will be tested by:

1. Dissecting the mechanisms of immune responses induced by KDM5B and SETDB1 loss
2. Evaluating the therapeutic potential of depleting KDM5B in melanoma
3. Evaluating retroelements suppressed by KDM5B and SETDB1 as predictive biomarkers in human melanoma

The proposed research is conceptually, technically, and clinically innovative because it aims to examine the therapeutic potential of KDM5B depletion using “first in class” KDM5B degraders, and to evaluate retroelement levels as novel predictive biomarkers for response to immunotherapy. The results from these studies could impact the treatment of patients with melanoma and increase our understanding of the factors that regulate anti-tumor immune responses.

Co-Leaders: Harriet Kluger, MD (Clinical Co-leader); Aaron Ring, MD, PhD (Basic Co-leader)

Major changes have occurred in the treatment of unresectable melanoma over the last decade. Unfortunately, almost half of melanoma patients do not respond to immune checkpoint inhibitors (ICI) upfront, and others develop recurrent or resistant disease over time. Therefore, immunotherapies that can stimulate immunity in ICI-resistant melanoma are still urgently needed. Cytokines have potent immunostimulatory activities that make them attractive candidates for use in combination with ICIs. Interleukin 18 (IL-18) is particularly appealing because the IL-18 receptor is specifically upregulated in CD8 tumor infiltrating lymphocytes and is widely expressed on natural killer (NK) cells. However, clinical trials of recombinant IL-18 were unsuccessful, likely due to upregulation of the endogenous IL-18 receptor antagonist, or IL-18 binding protein, IL-18BP, which inhibits the immunostimulatory effects of IL-18. A clinical grade “decoy resistant” IL-18 (DR18) has been developed and licensed to Simcha Therapeutics by Yale University (ST-067). ST-067 is currently being investigated in a first-in-human clinical trial as monotherapy. In pre-clinical models, DR18 synergizes with anti-PD-1. Furthermore, in murine models, DR-18 is highly effective in treating ICI-resistant MHC class I deficient tumors, consistent with the ability of IL-18 to also activate NK cells. We hypothesize that combining DR-18 with immune checkpoint inhibitors can overcome ICI resistance in melanoma via activation of NK cells, T effector cells, and stem-like memory T cells. We propose conducting a series of pre-clinical studies (Aim 1), utilizing novel animal models developed in house with clinically relevant melanoma mutations to determine the mechanism of response and resistance of the combination of DR-18 with clinically approved ICIs (inhibitors of PD-1, CTLA-4 and LAG-3). In Aim 2, we will conduct a Phase I/II clinical trial of ST-067 with immune checkpoint inhibitors in patients whose disease has progressed on a prior regimen containing anti-PD-1. If successful, these studies will support further development of ST-067 with ICIs in patient subsets carefully defined by immune cell characteristics. This approach can also be applied to patients with other types of anti-PD-1 resistant tumors.