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Dana-Farber/Harvard Cancer Center/Beth Israel Deaconess Kidney Cancer SPORE

Beth Israel Deaconess Medical Center/Dana-Farber Cancer Institute/Harvard Medical School

Principal Investigators

 

David F. McDermott, M.D.
Chief, Medical Oncology
Professor of Medicine, Harvard Medical School
Beth Israel Deaconess Medical Center
330 Brookline Ave. Kirstein 207
Boston, MA 02215
617-667-0226

 

William G. Kaelin, Jr., M.D.
Sidney Farber Professor of Medicine
Dana-Farber Cancer Institute 
Harvard Medical School
Investigator, Howard Hughes Medical Institute
450 Brookline
Dana-Farber Cancer Institute
450 Brookline Ave, Mayer 457
Boston, MA 02215
617-632-3743

Overview

This application is resubmission of a competing renewal application for a Specialized Program of Research Excellence (SPORE) in Kidney Cancer from the Kidney Cancer Program of Dana-Farber/Harvard Cancer Center (DF/HCC). The DF/HCC Kidney Cancer SPORE has been funded for four cycles since 2003. Dr. David McDermott, who has led the DF/HCC Kidney Cancer Program and SPORE since 2012, is joined as SPORE Director by Dr. William Kaelin, a laboratory scientist at DFCI and has served with Dr. McDermott as Director of the SPORE since early 2014. Dr. Kaelin is a world renowned basic and translational investigator with longstanding interest in kidney cancer and a leader within the DF/HCC community. Drs. McDermott and Kaelin report directly to Dr. Ben Ebert, Director of DF/HCC and President of DFCI.

The DF/HCC Kidney Cancer SPORE has a broad and deep talent base and there is extensive institutional commitment. We take advantage of a large patient population and cutting-edge technologies that are available to us as part of DF/HCC. We propose 3 Projects which address critical problems in kidney cancer and have translational components. They focus on important future priorities including early detection of renal cell carcinoma (RCC) through the application of promising blood- based biomarkers (e.g., KIM-1), identification of effective strategies for targeting the HIF2α pathway (Project 1), overcoming immunosuppression in the tumor microenvironment (Projects 1 – 3 and DRP), and translating recent insights about the vulnerabilities of rare tumors (e.g. chromophobe and translocation RCC) into effective therapies (DRP and CEP).

The projects are supported by three Cores - an Administrative Core, a Biostatistics and Computational Biology Core, and a Tissue Acquisition, Pathology and Clinical Data Core. We also have a highly successful Career Enhancement Program that selects talented physician scientists and mentors them to independence as well as a Developmental Research Program that generates new ideas for the SPORE in the future. The existence of the SPORE has provided opportunities and incentives to extend basic science and clinical research ideas into the translational realm and facilitated the entry of young, as well as some seasoned investigators into the kidney cancer field where they have made major contributions.

Project 1: Targeting the HIF2 Pathway in Kidney Cancer

Project Co-Leaders

Specific Aims

Inactivation of the VHL tumor suppressor gene is the initiating genetic event in the most common form of kidney cancer, ccRCC (clear cell RCC). The VHL gene product, pVHL, is the substrate recognition subunit of a ubiquitin ligase that targets HIF1α and HIF2α for proteasomal degradation when oxygen is present. HIF2α, when bound to its heterodimeric partner ARNT, forms the HIF2 transcription factor, which binds to DNA in a sequence-specific manner and activates transcription. In the previous funding cycles, we and others performed preclinical studies that validated HIF2 as a therapeutic target in ccRCC. Several HIF2 inhibitors are in various stages of development. The most advanced of these, belzutifan, is an allosteric HIF2 inhibitor that binds directly to a hydrophobic pocket in HIF2α. Belzutifan is now approved for tumors, including ccRCC, arising in patients with germline VHL mutations (VHL Disease) and for sporadic ccRCC. In the trials that led to these approvals the ccRCC clinical response rate to belzutifan was higher in patients with VHL Disease, whose tumors were confined to the kidney and naïve with respect to medical therapy, than in sporadic ccRCC patients, who had advanced disease and had received prior systemic therapy.

  • Aim 1 will be the first rigorous tissue-based biomarker study of innate and acquired HIF2α inhibitor resistance through a clinical trial of belzutifan in patients with metastatic, sporadic ccRCC who are VEGFR TKI-naïve.
  • Aim 2 uses recently described methods to capture and identify proteins in specific cellular compartments, now applied to isogenic cell systems to identify novel secreted and membrane-bound ccRCC biomarkers. We will leverage samples collected from the trial in Aim 1 to validate these biomarkers. It also exploits our recently developed platform for identifying ERV-derived, HLA-bound peptides.
  • Aim 3 uses an innovative in vivo CRISPR screening technology to enrich VHL synthetic lethals that are true both in vitro AND in vivo. It also might deliver a first in class HIF2α degrader and new ccRCC membrane targets for active and passive immunotherapy for study in Project 3 and utilize belzutifan-resistant samples from Aim 1 to identify patients most in need of benefit from these novel therapies.

Project 2: Optimizing Anti-PD-1 Based Therapy in High-Risk and Metastatic RCC

Project Co-Leaders

Specific Aims

The therapeutic landscape for metastatic ccRCC has rapidly evolved over the past 15 years with the incorporation of VEGFR TKIs and immune checkpoint inhibitors (ICI). However, only a subset of pts achieve long- term benefit, highlighting the need for more effective anti-PD-1-based immunotherapies with higher rates of cure. Of note, adjuvant anti-PD-1 therapy was also recently approved and predictive biomarkers are urgently needed to limit overtreatment of pts that are cured by surgery alone and to identify pts who are likely to be resistant to anti-PD-1 monotherapy. We have recently identified immune features of ccRCC tumors that are associated with (and may mediate) response or resistance to anti-PD-1 monotherapy, including: (i) antigen-experienced but non- terminally exhausted CD8+ T cells (i.e. CD8+PD1+TIM3-LAG3- cells) and tertiary lymphoid structures (TLS), associated with response; and (ii) PD1+Tregs, SLAMF7+CD8+ T cells, and HHLA2+ tumor cells, associated with resistance. Based on these data, we hypothesize that key components of the tumor immune microenvironment, including the candidate immune markers listed above, can predict outcomes of pts with ccRCC treated with ICI regimens, both in the metastatic and the adjuvant setting.

We plan to test this hypothesis; by analyzing tumor and blood samples obtained from three phase 3 clinical trials of ICI including COSMIC-313 and the anti-PD1 and placebo control arms of two adjuvant studies, CM-914 and KN-564 (Aim 1). In addition, we aim to improve the efficacy of ICI therapy relative to Nivo/Ipi for patients with metastatic RCC by specifically targeting factors associated with ICI resistance in 2 investigator-initiated multisite randomized clinical trials. As part of these trials, we are collecting tumor and blood specimens for study in Aim 2 to confirm that novel combinations can overcome these ICI resistance mechanisms. Finally, in Aim 3, we plan to further enhance the efficacy of anti-PD-1-based therapy by identifying and targeting other factors that limit CD8+ T cell function using sophisticated in vivo screens, novel preclinical models and patient tumor samples. Taken together, these Aims will comprehensively evaluate and identify ways to optimize durable immune responses to anti-PD-1-based therapy in pts with ccRCC.

Project 3: Discovering and Targeting Personal Versus Shared Antigens for Antigen Targeting Therapy for RCC

Project Co-Leaders

Specific Aims

For renal cell carcinoma (RCC), immune checkpoint inhibitors (ICIs) have been transformative but lead to durable responses in only <25% of patients. Thus, innovative therapies that can increase the remission rate for RCC remain a clinically unmet need. Promising approaches include cancer vaccines and cellular therapy. For each of these modalities, knowledge of tumor-specific antigens as high priority targets for devising novel therapies that may directly address tumor heterogeneity is critically needed. Recent technologic breakthroughs from our group now coalesce to address this salient challenge, including: (i) maturation of immunopeptidomic approaches to sensitively detect candidate antigens; (ii) widely-available single cell (sc) RNA sequencing approaches that enable the detection of populations of T cells with specific phenotypes; (iii) the devising of a powerful approach to simultaneously screen T cell receptor (TCR) specificity against tumor cells or against hundreds of candidate antigens; (iv) spatial genomic platforms to evaluate the in situ organization of infiltrating immune cells within tumors. We hypothesize that generating increased polyclonality and enrichment of T cells with anti-RCC reactivity and specificity for tumor-specific antigens, whether through adoptive cellular therapy or cancer vaccines, will improve clinical outcomes. 

While canonical tumor neoantigens, arising from of single nucleotide variants (SNVs) and Indels may be a predominant tumor antigen source for high mutation burden tumors (i.e. melanoma), our recent investigations suggest that alternative neoantigens, arising from alternative splicing, products of endogenous retrovirus or transposon elements (ERV/TEs) or from alterative translation (i.e. nuORFs) may be more relevant for lower mutation burden tumors (such as RCC). We will therefore devote our immunopeptidomic capabilities to directly evaluating this question (Aim 1). Since antigenicity is not equivalent to immunogenicity, we will evaluate whether the discovered antigens can mount T cell responses, through analysis of tumor infiltrating lymphocytes (Aim 2). These studies will aid our active efforts to launch effective personalized therapy for metastatic RCC lacking durable response to ICI therapy, whether through the generation of TIL products; or future combination with personal tumor antigen-targeting vaccines (Aim 3).

Administrative Core

Core Co-Directors

Specific Aims

The purpose of the Administration, Evaluation and Planning (Administrative) Core is to assure the coordination of the Dana Farber/Harvard Cancer Center (DF/HCC) Kidney Cancer SPORE components and to continue to provide oversight and leadership for the scientific, administrative and fiscal aspects of the SPORE. The Administrative Core allows for the provision of stimulating intellectual activities, organization of venues for planning future research through seminars and retreats, and the oversight of research and spending. Drs. McDermott and Kaelin, the SPORE Directors, are committed to the success of the SPORE and will personally monitor the progress of the Projects and Cores, oversee the Career Enhancement and Developmental Research Programs, and oversee all other proposed activities. As both SPORE Directors and Leaders of the Kidney Cancer Program within DF/HCC, Drs. McDermott and Kaelin have the authority and resources to ensure the success of this SPORE. 

The Administrative Core of the DF/HCC Kidney Cancer SPORE will accomplish the goals of the SPORE by following six specific aims: 

  • Monitor research progress and plan for the future,
  • Foster collaborative research within and between SPOREs,
  • Integrate the DF/HCC Kidney Cancer SPORE into the structure of DF/HCC,
  • Provide necessary resources and fiscal oversight,  
  • Promote patient participation in Kidney Cancer research and treatment, and
  • Promote rapid dissemination of significant research findings and free and open communication and resource exchange between the DF/HCC SPORE and other institutions. 

As they have since early 2014, Drs. McDermott and Kaelin will provide the tools to foster collaborations between the institutions inside and outside of the SPORE, to leverage the considerable power of the SPORE in order to promote kidney cancer research.

Tissue, Acquisition, Pathology and Clinical Data Core

Core Co-Directors:

Specific Aims

The first and foremost goal of the Tissue Acquisition, Pathology, and Clinical Data (TAPCD) Core is to maintain and expand the existing repository for specimens, including tissues, blood and urine from patients with kidney tumors that have given consent to link their samples to clinical data. Included in this component are the collection, freezing, and storage of fresh samples of kidney cancer and paired non-tumor tissue; the collection, processing and storage of blood and urine; the identification and provision of samples of fixed tissues, including construction of tissue microarrays (TMAs) from biopsy and nephrectomy samples obtained from patients who have consented to allow analysis of these tissues. The caTissue system, which is the NCI caBIG's biorepository tool for biospecimen inventory management, is currently used to track specimens through every step of the requesting, shipping, and receiving process through the use of barcode technology. The protection of patient confidentiality is guarded throughout the whole process, from specimen collection to use in research projects.

Finally, the TAPCD Core has provided and will continue to provide SPORE investigators a variety of services critical to successful molecular analysis of human kidney tumors as well as animal model tissues. These services include: 

  • histopathologic review and quality control analysis of all tumor samples utilized in experimental studies;
  • macrodissection of frozen tissue samples and slide microdissection of formalin-fixed paraffin-embedded (FFPE) or frozen tissues to ensure high neoplastic cellularity for samples utilized in experimental studies; 
  • extraction of DNA/RNA from both FFPE and frozen tissues, performance of immunohistochemistry (IHC), multiparametric and high-plex immunofluorescence (IF) stains, and spatial transcriptomics analyses on human kidney cancers (TMAs or whole tissue sections); 
  • optimization and validation of antibodies to known and novel proteins for use in IHC and IF; 
  • analysis of a broad range of IHC and IF stains using computer-assisted image analysis. 

The Core also assists investigators with the evaluation of non-invasive biomarkers with plasma-based assay. Finally, the Core works very closely with the Biostatistics Core on the analysis of spatial transcriptomics and proteomics data and the integration of results of various tissue-based analyses.

Biostatistics and Bioinformatics Core

Core Director

Specific Aims

The Dana-Farber/Harvard Cancer Center SPORE in Kidney Cancer Biostatistics and Bioinformatics Core collaborates and provides consultation on all research activities within the SPORE, including SPORE Projects, the Developmental Research and Career Enhancement Programs, and other SPORE Cores to ensure the highest standards of scientific rigor in areas of study design, data management and integrity, as well as data analysis and interpretation. 

The specific aims are to: 

  • Provide biostatistical and bioinformatic expertise for the planning and design, conduct, analysis, and reporting of laboratory, genomic, animal, translational, clinical (including associated correlative studies), and epidemiological studies for SPORE Projects, Developmental Research and Career Enhancement Program projects, and other SPORE Cores
  • Provide consultation on all issues of data management and integrity, including data collection, storage, transfer, and quality assurance, on statistical and bioinformatic software and programs, and on coordination of laboratory results with parameters and outcomes from clinical studies or translational research databases
  • Provide short- term biostatistical and bioinformatic consulting to SPORE researchers
  • Provide expertise and guidance on provenance and best practices, assuring that all data activities follow the FAIR principles 

Organizing biostatistical and bioinformatics expertise as a shared resource core provides a cost-effective way to ensure collaboration is readily available to SPORE investigators while promoting strong integration across projects with interrelated analytic goals. This centralized approach enables oversight of data generation and consistent adherence to best practices, spanning experimental design, group balancing, subject variability, and data analysis, management, and storage. At the same time, advances in statistical and bioinformatics methodologies for cancer research have expanded the role of biostatisticians and computational biologists and raised expectations for scientific rigor.

Beyond classical statistical approaches applied in observational studies, clinical trials, and small-scale laboratory research, translational studies within the SPORE increasingly require specialized methods from genomics, transcriptomics, epigenomics, metabolomics, and other high-throughput bulk, single-cell, and spatial tissue profiling platforms. BCB biostatisticians and computational biologists remain committed to staying at the forefront of these developments, applying their expertise to evaluate assumptions, ensure appropriate application, and interpret both results and limitations; a challenge often beyond the scope of wet-laboratory and clinical investigators.

Developmental Research Program

Program Co-Directors

To ensure a continual renewal of high-quality scientific endeavors in the DF/HCC Kidney Cancer SPORE and to fund efforts that will complement or enhance the overall quality of the DF/HCC Kidney Cancer SPORE. In general, the DRP has funded established investigators. Based on our review, we will be mindful of including more junior investigators. This Program will rely on the infrastructure created by the Administrative, Evaluation, and Planning Core (Admin Core) to:

  • Solicit applications and/or identify novel kidney cancer research projects
  • Evaluate these projects for funding
  • Fund innovative developmental projects
  • Re-evaluate projects for possible transition into full project status
  • Evaluate the success of the program

Career Enhancement Program

Program Co-Directors

Specific Aims

The investigators assembled in the DF/HCC Kidney Cancer SPORE have a substantial record in mentorship and enhancement of junior faculty working in the kidney cancer field (detailed below). The goal of the Career Enhancement Program (CEP) of our SPORE is to build upon this record and continue a formal process for the identification, selection, funding, and mentoring of individuals pursuing careers in the study of the basic, translational, and clinical aspects of kidney cancer. This Program will rely on the infrastructure created by the Administrative, Evaluation, and Planning Core (Admin Core) to:

  • Solicit CEP Award Applications
  • Evaluate Applicants and Select Awardees
  • Conduct CEP Evaluation and Review
  • Mentor CEP Awardees and promote Career Progress

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