Sloan Kettering Institute for Cancer Research
Principal Investigators
Jonathan Rosenberg, MD
Chief, Genitourinary Oncology Service
Division of Solid Tumor Oncology
Department of Medicine
Enno W. Wrckientz, Jr. Chair
Memorial Sloan Kettering Cancer Center
1275 York Avenue
New York, NY 10065
(646) 422-4784
David Solit, MD
Co-Director, Kravis Center for Molecular Oncology
Chief, Molecular Medicine Service, HOPP
Geoffrey Beene Chair for Cancer Research
1275 York Avenue
New York, NY 10065
(646) 888-5435
Overview
The past 10 years have witnessed a significant evolution in the systemic treatment of patients with urothelial cancer. Successful clinical trials have resulted in FDA approval of novel therapies spanning three mechanistically distinct drug classes: immune checkpoint inhibitors, antibody-drug conjugates (ADCs), and kinase inhibitors. The combination of the NECTIN4-targeted ADC enfortumab vedotin (EV) plus the anti-PD-1 antibody pembrolizumab (P) has supplanted chemotherapy as initial systemic therapy for most patients with locally advanced and metastatic urothelial cancer. The overall translational objective of our SPORE in Bladder Cancer is to build on recent improvements in clinical outcomes for patients across the urothelial cancer disease spectrum by 1) elucidating the role of tumor and immunologic heterogeneity in mediating resistance to immunotherapies and ADCs, and 2) minimizing the morbidity of treatment through the development and validation of tissue-based, noninvasive predictive biomarkers. Our three research projects, together with the Developmental Research and Career Enhancement programs, address all clinical states of urothelial cancer.
Project 1 will use tumor and blood samples collected from patients treated with EV+P, as well as laboratory studies of immunocompetent syngeneic mouse models, to identify immune-mediated mechanisms of treatment response and to understand the immune ecosystem of tumors resistant to EV+P.
Project 2 will study the effects of agonist anti-CD40 antibodies alone or in combination with gemcitabine to guide the development of novel immune-based combinations.
Project 3 will examine the role of lineage plasticity and other forms of phenotypic plasticity in mediating EV+P resistance and identify novel therapeutic approaches for bladder cancers with variant histologic features.
Each project will be supported by the Biospecimen Repository, which will assist with the preparation and analysis of tumor and blood samples, the Biostatistics & Bioinformatics Core, which will associate molecular features with treatment response data, and the Administrative Core, which will ensure integration across the entire SPORE program and facilitate data sharing and collaboration.
Finally, the DRP and CEP are fully integrated into our SPORE program to ensure that new and established investigators with innovative approaches can advance our long-term objectives: 1) enhancing patient outcomes while reducing treatment morbidity; and 2) eliminating urothelial cancer as a cause of premature death.
Project 1: Elucidating Mechanisms of Sensitivity and Resistance to Combination Antibody-Drug Conjugate Therapy and Immunotherapy in Urothelial Cancer
Project 1 Leaders:
- Jonathan Rosenberg, MD (Clinical Science)
- Benjamin D. Greenbaum, PhD (Basic Science)
- David H. Aggen, MD, PhD (Clinical Science)
Specific Aims
Combination therapy with antibody-drug conjugates (ADCs) and immune checkpoint blockade has transformed the care of patients with urothelial cancer. ADCs consist of a cytotoxic payload attached via a peptide linker to a monoclonal antibody targeting a cell surface protein. Recent clinical trials of ADCs containing a monomethyl auristatin E (MMAE) payload with immune checkpoint blockade suggest a potentiation of anti-tumor response with the combination of enfortumab vedotin (EV, anti-NECTIN4) + pembrolizumab (EV+P), demonstrating an unprecedented doubling of overall survival compared to platinum-based chemotherapy. While EV+P represents a major therapeutic advance, resistance develops in over half of patients. We hypothesize that MMAE—the cytotoxic payload of EV—stimulates antitumor immunity and enhances immune checkpoint blockade by boosting antigen-specific T cell responses, and that durable responses to EV+P require effective T cell responses directed against tumor neoantigens. We will test these hypotheses through integrated analyses of pre- and post-treatment tumors and serial blood samples through three complementary specific aims.
Aim 1: To identify immune-specific determinants of sensitivity to EV+P in metastatic urothelial carcinoma. We will perform whole exome sequencing, RNA sequencing, NOMIC peripheral blood proteomic profiling, and TCR (T cell receptor) sequencing of pretreatment tumor samples and serial blood samples to compare neoantigen quality and TCR responses in patients with either a complete response or no response to EV+P. One goal will be to identify predictive biomarkers of EV+P response that can be used to guide therapy selection.
Aim 2: To characterize the tumor intrinsic factors and immune ecosystems associated with resistance to EV+P. We will identify distinct tumor-intrinsic and microenvironmental immune features that drive acquired resistance by analyzing tumor pairs collected pre-treatment and at disease progression. We will quantify changes in neoantigen burden before and after treatment and characterize features of the EV+P-resistant tumor microenvironment using novel spatial transcriptomics of paired tumor samples and proteomics of longitudinal blood samples with near single-cell resolution.
Aim 3: To identify ADC-based combinations that enhance antitumor immunity using immunocompetent mouse models of urothelial carcinoma. We will evaluate the immunogenicity of different ADC cytotoxic payloads with the goal of identifying novel strategies to enhance the activity of EV+P as a guide to future clinical trials of multidrug therapy.
In sum, through in-depth studies of tumors and blood collected from patients and immunocompetent mice, we seek to identify immune-mediated mechanisms of sensitivity and resistance to EV+P with the translational goal of informing novel combination approaches designed to maximize efficacy while minimizing therapy-associated toxicity.
Project 2: Developing Novel Combination-Immunotherapeutics for Non-Muscle-Invasive Bladder Cancer
Project Leaders:
- Bernard H. Bochner, MD (MSK) Clinical Science
- Jeffrey V. Ravetch, MD, PhD (RU) Basic Science
- Juan C. Osorio, MD (MSK) Basic Science
Specific Aims
For 50 years, intravesical bacillus Calmette-Guérin (BCG) has been the primary treatment for non–muscle-invasive bladder cancer (NMIBC). However, BCG therapy is limited by toxicity, global shortages, and high failure rates, with 75% of patients eventually becoming unresponsive to the treatment. Agonistic antibodies targeting CD40, which is a tumor necrosis factor superfamily receptor, hold potential as a cancer immunotherapy by activating dendritic cells and enhancing T cell–mediated antitumor immunity. We developed 2141-V11, an engineered anti-CD40 agonistic antibody that enhances DC activation and CD8 T cell antitumor immunity. This antibody demonstrates superior antitumor activity compared to other clinical CD40 antibodies in preclinical models, including models of BCG-naïve and BCG-refractory NMIBC. However, responses to 2141-V11 are not uniform, and the mechanisms underlying these responses remain incompletely understood. We hypothesized that CD40 agonism promotes antitumor immunity by enhancing dendritic cell activation and dendritic cell–T-cell spatial organization, leading to formation of functional immune hubs, and that rational combinations that relieve immune suppression will amplify these effects.
Aim 1. We will determine how dendritic cells support CD8 T cell responses in the bladder tumor microenvironment and regional lymph nodes, and identify mechanisms by which immune-based therapies modulate dendritic cell function to stimulate T cell antitumor immunity.
Aim 2. Using immunocompetent mouse models of NMIBC, we will identify and test immunotherapy combinations (CD40 agonists in combination with gemcitabine and other agents) targeting the bladder tumor microenvironment to relieve intratumoral immune suppression.
Aim 3. We will evaluate the safety and antitumor activity of 2141-V11, alone and in combination with gemcitabine, in patients with high-grade NMIBC. We will also evaluate the effects of this novel combination therapy on dendritic cell activation, immune hub formation, and tumor-microenvironment remodeling.
In sum, by dissecting the mechanisms that mediate effective antitumor immunity of dendritic cells during treatment with anti-CD40, BCG, and other therapies for NMIBC, the proposed studies will guide the development of more effective immunotherapy combinations to prevent disease recurrence or progression in patients with NMIBC.
Project 3: Lineage Plasticity as a Determinant of Antibody-Drug Conjugate Response in Bladder Cancer
Project Leaders:
- David Solit, MD (Basic Science)
- Hikmat Al-Ahmadie, MD (Clinical Science)
Specific Aims
Approximately one-third of bladder cancers exhibit regions of urothelial carcinoma adjacent to or intermixed with regions of divergent differentiation or histologic subtypes. While the presence of select histologic subtypes confers a greater risk of metastasis and bladder cancer–specific death, the therapeutic implications of this phenotypic plasticity remain poorly understood. We hypothesize that patients with bladder cancer with certain histologic subtypes will be less likely to achieve durable responses to the combination of enfortumab vedotin (EV; an anti-Nectin-4-targeted antibody-drug conjugate) plus pembrolizumab (P; an immune checkpoint inhibitor), which has emerged as a new standard of care for muscle invasive and metastatic urothelial cancers. This project aims to characterize the mechanistic links between phenotypic plasticity and therapy response in bladder cancer, focusing on the role of lineage and other forms of cellular plasticity in mediating resistance to antibody-drug conjugates (ADCs) targeting Nectin-4 when administered in combination with immune checkpoint blockade. Our three specific aims will also investigate the role of phenotypic plasticity in mediating resistance to EV+P.
Aim 1: To perform detailed histologic review of tumors collected prior to treatment with EV+P to map and quantitate regions of variant histology and evidence of lineage plasticity. The translational goal will be to define the association between phenotypic plasticity as a histologic feature, luminal-to-basal or other forms of lineage plasticity as defined by RNA sequencing and multiplexed immunophenotyping, and duration of response to EV+P.
Aim 2: To define the clonal relatedness and phenotypic similarity of patient-matched tumor pairs collected pre-treatment and at disease progression on EV+P in patients with variant histology bladder cancers, focusing on tumors with squamous and sarcomatoid differentiation. One goal will be to identify novel therapeutic strategies for patients whose bladder cancers harbor variant histology and who exhibit resistance to EV+P.
Aim 3: To build on preliminary data identifying activation of JAK-STAT3 signaling as a driver of squamous and sarcomatoid differentiation and loss of Nectin-4 cell surface expression. We will perform co-clinical trials using patient-derived models to determine if inhibition of STAT3 signaling can enhance sensitivity to EV via reversion of lineage plasticity.
In sum, completion of these aims will reveal mechanistic links between morphologic heterogeneity, lineage plasticity, and systemic therapy response in urothelial cancer, with the long-term translational goal of informing the design of future clinical trials of novel ADCs and ADC-based combinations.
Administrative Core
Core Directors:
The Administrative Core will help achieve the translational objectives of the MSK SPORE in Bladder Cancer by providing oversight for its operations and by facilitating the sharing of clinical and molecular data and other resources among SPORE investigators, as well as with external collaborators and the broader scientific community.
The Administrative Core will provide to the larger SPORE team:
1) financial management, by serving as the centralized SPORE budgetary coordinator and financial manager;
2) grants administration, by serving as liaison to the National Cancer Institute, ensuring compliance with institutional and federal regulations;
3) editorial services, including preparation of manuscripts and progress reports;
4) coordination of requests for applications for the Developmental Research and Career Enhancement Programs and organizing scientific review of ongoing SPORE projects with the Internal and External Advisory Boards;
5) communication within the MSK SPORE in Bladder Cancer as well as with other SPOREs and the wider scientific community;
6) data management oversight, including oversight of a unified clinical and molecular database that facilitates multi-disciplinary collaboration among SPORE investigators and the broader institutional research community.
Biospecimen Repository Core
Core Directors:
Specific Aims
The Biospecimen Repository Core plays a central role in selecting, collecting, annotating, storing, distributing, and tracking urothelial cancer biospecimens (tissue, urine, blood) from patients enrolled in biospecimen banking and therapeutic research protocols at our institution. Detailed biospecimen annotation, including documentation of pre-analytic processing variables, pathology findings, and clinical data, are recorded in robust relational databases. The core also provides SPORE investigators with expert histopathological and immunohistochemical evaluation of tumor samples and performs and interprets in situ hybridization assays. Finally, the core plays a key role in piloting new profiling methods, such as spatial transcriptomics and multiplexed immunofluorescence, to ensure that SPORE investigators have access to the most robust molecular profiling platforms. The core will help achieve the translational aims of the MSK SPORE in Bladder Cancer by maintaining and enhancing a biospecimen repository, by assisting research projects and pilot projects with molecular characterization of tumors, and by facilitating the sharing of the resulting data and resources with the broader scientific community.
Biostatistics and Bioinformatics Core
Core Directors:
The Biostatistics & Bioinformatics Core provides expert biostatistical and computational support to SPORE investigators and collaborates with them across the full range of research studies, including animal and molecular laboratory experiments, the design and analysis of prospective clinical trials, and retrospective analyses of real-world datasets. Prior to initiation of all trials and studies conducted by the SPORE research projects or pilot projects, core staff will consult with the SPORE investigators to:
1) discuss the underlying scientific rationale and translational goals of the project,
2) help investigators select the most efficient and robust analytical methods, and
3) estimate sample sizes to ensure adequate statistical power.
For molecular studies using human tissues, the core will work closely with the Biospecimen Repository Core and will have primary responsibility for maintaining systems for integrating multimodal data.
For clinical studies, the core will establish, maintain, and monitor systems to track and store all required data elements in a HIPAA-compliant manner.
The Biostatistics & Bioinformatics Core will be critical to achieving the translational goals of the SPORE in Bladder Cancer by ensuring experimental rigor through the generation of high quality, unbiased, and reproducible data, and by sharing data and novel analytic tools among the SPORE research team and with the broader scientific community.
Developmental Research Program
Program Directors:
Specific Aims
The Developmental Research Program (DRP) will support innovative translational research projects in urothelial cancer by establishing mechanisms for rapid funding. The DRP will solicit high-impact pilot projects that are critical to the generation of new ideas for the prevention, diagnosis, and treatment of urothelial cancer. Preference will be given to innovative projects that address an unmet clinical need for patients. The DRP will be key to achieving the translational aims of the SPORE in Bladder Cancer by providing seed funding to new and established investigators for innovative translational research projects in the field of urothelial cancer.
Career Enhancement Program
Program Directors:
Specific Aims
The Career Enhancement Program (CEP) will provide support for the most promising and motivated clinicians and scientists to pursue careers in translational research in urothelial cancer. We have designed the CEP to form both an interdepartmental and an inter-institutional training ground for talented investigators from either basic or clinical research backgrounds who are committed to translating new scientific developments in urothelial cancer research into clinically relevant therapeutic strategies. The CEP will be open to investigators pursuing research questions relevant to all clinical states of the disease, from non-muscle invasive urothelial cancers to treatment-refractory metastatic disease. The CEP will be key to achieving the translational aims of the SPORE in Bladder Cancer by encouraging and providing support to promising junior investigators to enter the field of translational urothelial cancer research.