Mayo Clinic - Rochester - Arizona - Jacksonville
Principal Investigator
Peter Leif Bergsagel, M.D.
Co-Director, Advanced Clinical Trials and Translational Science Research Program
Mayo Clinic Comprehensive Cancer Center
Mayo Clinic Arizona, 13400 East Shea Boulevard
Scottsdale, Arizona 85259
480-301-4704
Overview
The Mayo Clinic Multiple Myeloma SPORE is a highly productive research program based at the NCI-designated Mayo Clinic Comprehensive Cancer Center located in Minnesota, Florida and Arizona. It is designed to address critical translational questions in multiple myeloma (MM) biology and therapy ranging from the epidemiology of MM that impacts MM risk assessment, prognostication, and survivorship to the discovery of new biologic concepts that can be tested in patients through novel clinical trials. This is accomplished by a multi-disciplinary team of scientists and clinicians that have spent the past twenty years building a collaborative MM basic, clinical, and population science research infrastructure.
The overall goal of this SPORE is to have a major impact on clinical outcomes for myeloma by supporting innovative, interactive, rigorous translational myeloma research that leverages the exceptional laboratory, translational, and clinical expertise that we have at the Mayo Clinic. The unifying theme of the SPORE since its inception is to conduct research exploring the translational implications of host factors, tumor biology, and their relationship with the tumor microenvironment.
We are applying our steadily improving genomic characterization of MM to allow the early detection and risk-stratification of smoldering multiple myeloma (SMM), developing a new genomic definition of biologic malignancy (genomic MM), differentiation from biologic premalignancy (genomic MGUS), assessing mechanisms of progression, and monitoring and tailoring therapy based on underlying genomic abnormalities (Project 3). These studies are complemented by efforts aimed at identifying novel ways of modulating the host immune response using chimeric antigen receptor T (CAR-T) cell therapy and identifying and overcoming resistance to this new and promising mode of therapy for the disease (Projects 1 and 2). The SPORE also includes Developmental Research and Career Enhancement Programs to pursue novel translational concepts in MM research and new investigators through the programs respectively. Finally, the SPORE enhances the infrastructure that supports translational MM research through shared core resources in Administration, Biostatistics & Bioinformatics, and Biospecimens & Clinical Database.
At the opposite end of the spectrum, we are characterizing the genetic features which contribute to ultra-high-risk MM, which does not benefit from current therapy. These studies are complemented by efforts aimed to identify novel ways of modulating the host immune response using virotherapy and bispecific antibodies.
Project 1: Identifying Mechanisms of Response and Resistance with In Vivo CAR-T for Myeloma
Project Co-Leaders
- Yi Lin, M.D., Ph.S. (Clinical Co-Leader)
- Kah Whye Peng, Ph.D. (Basic Science Co-Leader)
Specific Aims:
The current method of generating CAR-T cells is costly and time consuming as requires harvest of cells from patients and manipulation of the cells outside the body to generate these CAR-T cells. We propose a novel method using a targeted lentiviral vector capable of identifying CD3 T cells for generation of CAR-T cells directly inside a patient’s body. We will test this in a phase I clinical trial and examine mechanisms of action and resistance with this approach.
Aim 1: Identify the CAR+ and CARneg T cell profiles induced with in vivo CAR-T and correlate with clinical response. We will examine the phenotype and TCR repertoire of the CAR+ and CARneg T cells systemically (in blood) and in the myeloma microenvironment (TME: bone marrow, and if present, plasmacytoma) with treatment. Anti-myeloma activities of the T cells will be tested in vitro and compared with clinical response.
Aim 2: Identify the cellular (non-T cells) and humoral immune profiles induced with in vivo CAR-T and correlate with clinical response. We will quantitate cytokine and chemokine levels and phenotype of myeloid cells and NK cells systemically and in the TME. Any correlation with clinical response will be tested in the in vitro myeloma cytotoxicity assay.
Aim 3: Examine myeloma cell intrinsic profiles that correlate with resistance versus response. Myeloma cells in the bone marrow and plasmacytoma will be examined for known risk factors for response (proliferation index, mutations, senescent-like/dormant transcriptome profiles, BCMA expression levels) and correlation with clinical response.
Direct in vivo generation of CAR-T cells using a single infusion of a T cell targeted lentivirus vector (LV) has the potential to change the landscape of CAR-T therapy. Based on the promising preclinical studies, we anticipate that we will identify a dose level for in vivo engineered CAR-T that is safe in patients with evidence of anti-myeloma activities. If positive, the treatment will be advanced to Phase II clinical trial testing. If inadequate anti-myeloma response is seen, the studies from the proposed Myeloma SPORE project will provide key mechanisms of resistance to inform rational design of follow-up therapeutic development.
Project 2: Overcoming Resistance to CAR-T Cell Therapy in Multiple Myeloma
Project Co-Leaders
- Saad Kenderian, M.B., Ch.B. (Clinical Co-Leader)
- Leo Sakemura, M/D., Ph.D. (Basic Science Co-Leader)
Specific Aims:
Our goal is to characterize the role of bone marrow-derived cancer-associated fibroblasts (BM-CAFs) in B-cell maturation antigen-targeted chimeric antigen receptor T (BCMA-CART) cell failure in multiple myeloma (MM) and to develop novel strategies to improve BCMA-CART cell efficacy and safety through engineering BCMA-CART cells to secrete molecules (STriKEs) which activate the innate immune system against BM-CAFs.
Aim 1: Study the mechanisms of BM-CAF-mediated BCMA-CART inhibition. We will use our established in vitro assays, in vivo models, and patient samples to interrogate specific contributions of cytokines, inhibitory pathways, and apoptosis proteins from BM-CAFs on the function of BCMA-CART cells and define how BM-CAFs alter other suppressive cells within the TME.
Aim 2: Determine the effects of BCMA-CART STriKEs on CART cell functions and MM tumor microenvironment (TME). We will launch and complete a Phase I clinical trial for BCMA-CART STriKEs in patients with r/r MM. In this aim, we will utilize humanized mouse models and patient samples from this trial to study CART cell function, innate immune cell activation, and changes in the TME using cytokine assays, ex vivo functional experiments, and single cell transcriptomic studies.
Our proposal seeks to develop strategies to promote durable response to CART cell therapy in MM, a significant unmet need. Upon study completion, we expect to better understand BM-CAF-mediated resistance to BCMA-CART cell therapy and to demonstrate the safety of BCMA-CART STriKEs in a Phase I clinical trial in r/r MM.
Project 3: Early Detection and Prevention of Multiple Myeloma Progression
Project Co-Leaders
- Vincent Rajkumar, M.D. (Clinical Science Co-Leader)
- Leif Bergsagel, M.D. (Basic Science Co-Leader)
Specific Aims:
This project is focused on using non-invasive serial blood analysis to identify patients with SMM showing genomic progression or immune deficiencies that may benefit most from early intervention. We hypothesize that clonal evolution and impending progression in SMM can be identified early by determining clonal fraction and changes in copy number alterations in cfDNA from peripheral blood plasma. With the arrival of early intervention, we will also study response to early intervention based on underlying genomic abnormalities, immune function parameters, and clone size.
Aim 1: Define systemic immune dysfunction in peripheral blood mononuclear cells associated with progression from SMM to MM. We will perform ex vivo functional profiling of cryopreserved PBMCs from well-annotated SMM patient cohorts with known clinical outcomes. Our strategy integrates established immunological assays (cytokine production, proliferation, cytotoxicity) with robust clinical metadata and plans for discovery and validation in independent cohorts.
Aim 2: Determine clonal fraction and changes in copy number alterations in cfDNA from peripheral blood plasma as biomarkers of clonal evolution in SMM. Using WGS we will profile cfDNA from serially collected plasma samples in patients with SMM to (1) estimate tumor fraction; (2) identify recurrent and evolving copy number alterations (CNAs); and (3) correlate these with clinical progression and immune dysfunction defined in Aim 1.
Aim 3: Identify response to early intervention in SMM based on underlying genomic abnormalities, and immune function parameters. We will utilize WGS/WES data that has been generated from CD138-selected BM samples of patients enrolled on randomized trials that we have led. In addition, we will conduct WES/WGS on Mayo biobank samples and classify all SMM patients into genomic MGUS and genomic MM.
Our proposal will have considerable clinical impact by yielding a non-invasive, functionally grounded, and genomically informed peripheral blood-based biomarker platform to detect progression in SMM. Our approach would inform early intervention strategies, reduce unnecessary treatment in indolent cases, and ultimately improve outcomes in patients with plasma cell dyscrasias.
Administrative Core
Core Co-Directors
Specific Aims:
The goal of the Administrative Core is to stimulate research in myeloma and to expedite the translation of discoveries into new and better methods of prevention, detection, and treatment of myeloma. It coordinates the activities of the research projects, scientific cores, and developmental programs (Developmental Research Program, Career Enhancement Program). It is responsible for coordinating the function of the SPORE committees including the Executive Committee, the External Advisory Committee, and the Patient Advocate Group.
The Administrative Core will:
(1) Provide leadership, organizational support, and financial management for SPORE investigators
(2) Coordinate communication and collaboration between Mayo Clinic Arizona, Rochester and Florida, including support for exchange of ideas between investigators, design of new projects, conduct of translational research, and reporting of translational research findings
(3) Provide information transfer to the scientific community and the public
(4) Provide leadership and organizational support for interactions with the External Advisory Committee
(5) Establish and nurture collaborations to facilitate and expand myeloma research including interactions between Mayo sites
(6) Work closely with SPORE patient advocates so that they are aware of the progress of the SPORE, and facilitate their ability to provide input
(7) Foster young investigator development
(8) Communicate with the NCI
Biospecimens, Pathology and Clinical Database Core
Core Co-Directors
Specific Aims
The Biospecimens, Pathology and Clinical Database (BSP) Core furnishes essential services for individual projects by managing patient data, safety, and samples. The Core provides a coordinated, centralized, and dedicated mechanism for the procurement, processing, and annotation of biospecimens from patients with plasma cell disorders. It provides a link between clinical data and research outcomes and interfaces with the BSI Core to allow formal interactions between existing datasets to develop relational networks. This Core provides a mechanism of consistent and compatible data handling, thereby facilitating management of collected data and integration with data from existing Mayo resources. It serves as a resource of expertise, collaborative support and service for full projects as well as Career Enhancement and Developmental Research Awardee research. The BSP Core interfaces with the clinical research components of other SPORE grantees and cancer centers to facilitate multi-institutional clinical research arising out of national myeloma research efforts.
Biostatistics and Bioinformatics Core
Core Co-Directors
Specific Aims:
The Biostatistics and Bioinformatics (BSI) Core is responsible for all BSI-related analytical activities for each of the SPORE projects, developmental research award-funded projects, and career development award-funded projects. The SPORE projects encompass a wide range of analytical areas, including clinical trial-focused studies, associated lab-based correlative studies, and various omics studies. Accordingly, BSI scientists provide oversight of all SPORE-related statistical and bioinformatics activities and coordinate and integrate efforts for each project based on specific needs. The BSI Core supports investigators in managing clinical trials by determining optimal designs, defining the data to be collected, and creating and implementing appropriate analysis plans. It oversees the collection and management of clinical information required for each study. Additionally, the BSI Core assists SPORE investigators with the analysis and interpretation of omics data, while leveraging internal and external biological information sources to promote cancer discoveries that impact patient care. Bioinformatics utilizes the extensive omics analytical capabilities developed by the Institutional Bioinformatics Program to ensure robust data processing.
Developmental Research Program
Program Co-Directors
Specific Aims:
The Multiple Myeloma SPORE Developmental Research Program (DRP) supports innovative, scientifically sound projects that investigate any area pertaining to translational myeloma research. Funding from this program stimulates developmental research that incorporates techniques and theoretical approaches that may not have been previously utilized in myeloma research. In so doing it provides a mechanism by which the SPORE can increase the number of scientists and clinical investigators who are committed to translational myeloma research.
The primary goals of the DRP are:
(1) to encourage innovative translational clinical and laboratory studies that are promising and have the potential to improve outcome in myeloma and mature into independently funded projects in the future;
(2) Foster extensive collaboration between basic science and clinical disciplines in translational research in myeloma in the context of the myeloma SPORE program;
(3) Encourage investigators to evaluate the potential of applying their research findings in other tumor types to translational research in myeloma;
(4) Generate new hypotheses that can be tested and provide the foundation for future large-scale research projects or clinical trials in order to reduce myeloma incidence and mortality rates.
Career Enhancement Program
Program Co-Directors
Specific Aims:
The Multiple Myeloma SPORE Career Enhancement Program (CEP) aims to offer both financial assistance and comprehensive mentorship to highly qualified scientists seeking to advance their careers in translational myeloma research, guided by SPORE investigators. This approach establishes a mechanism for the SPORE to enhance the number of scientists and clinical investigators dedicated to translational myeloma research, who will ultimately evolve into independent, peer-reviewed, funded researchers. The Career Enhancement Program aims to foster the development of qualified candidates, coordinate project evaluations and selections, provide funding recommendations to the Executive Committee, and oversee research progress. Specifically, the primary goals of the CEP are to
(1) Promote the involvement of emerging researchers in myeloma studies;
(2) Promote collaboration between basic science and clinical disciplines in translational research on myeloma within the myeloma SPORE program to enhance the development of junior investigators;
(3) Motivate emerging researchers to pursue a career in translational research, aiming to achieve independence as peer-reviewed principal investigators; (4) Formulate novel hypotheses suitable for empirical testing, establishing a basis for subsequent extensive research initiatives.