Lymphoma Outcomes SPORE

The University of Texas MD Anderson Cancer Center

Principal Investigators

Christopher Flowers M.D., M.S., FASCO 
Division Head, Division of Cancer Medicine
Chair, Professor, Department of Lymphoma/Myeloma
John Brooks Williams and Elizabeth Williams Distinguished University 
Chair in Cancer Medicine
1515 Holcombe Blvd., Unit 421
Houston, Texas 77030
(713) 563-1727

Jean Koff M.D., M.Sc.   
Associate Professor in the Department of     
Winship Cancer Institute of Emory University
Hematology and Medical Oncology
Director of the Lymphoma Program’s Translational Research Team
1365 Clifton Rd. NE, Suite B4000D
Atlanta, Georgia 30322
(404) 778-5173    

Overview

Differences in survival for patients with lymphoma may be caused by complex links between personal, biological, and medical factors, but these are not well understood. Some patient groups are not well included in lymphoma clinical trials or in studies to help us understand how lymphoma starts and how to treat it. They often go to clinics with fewer resources or with no blood cancer experts. This can lead to late or wrong lymphoma diagnoses that affect how they are treated. 

The main goal of this SPORE is to fix these problems in knowledge, survival, and access to research-driven cancer care by using a connected approach from lab to clinic to community. We will study how ancestry, lymphoma biology, and patient outcomes are connected. We will look at ways to help more people join clinical trials and improve survival. We will also create group-specific models, easy-to-use tests, targeted treatments. Finally, we will work with local cancer clinics to improve care for all patients.

These goals helped shape three SPORE Projects. These Projects will collect research data to fill important gaps in knowledge and help fix the differences seen in lymphoma outcomes for people with the most common blood cancers. Even though the projects are separate, they share SPORE goals, patient groups, and resources. This creates new ways to work together across projects. 

Three Research Cores support the main projects and also help with projects from researchers in our Career Enhancement and Developmental Research Programs (CEP/DRP), which find and support researchers across the country, who will improve research on how lymphoma affects health.

Together, these goals show the special strength and impact of our SPORE team.

Project 1: Precision Targeting of Therapeutic Vulnerabilities Specific to African Ancestry Lymphoma Patients

Project Co-leaders

Ari Melnick, M.D.  (Clinical Co-Leader)
Roberta Zappasodi, Ph.D. (Basic Co-Leader)

Diffuse large B cell lymphomas (DLBCLs) can be very different from patient to patient. Many patients still cannot be cured, and those who survive often face long-term health problems. People of African ancestry are more likely to get this cancer at a younger age and often have worse outcomes, but we do not fully know why. 

Our research shows that DLBCL in African ancestry patients has different gene changes. These changes - especially in genes like SETD2, ATM and MGA - make it harder for cells to fix DNA damage. This can make chemotherapy less effective and lead to worse outcomes. We also found that these tumors have a special inner environment, with cancer and immune cells showing a pattern called senescence associated secretory phenotype (SASP), which helps the cancer cells hide from the immune system and grow.

In this project we plan to: 

1. Find out what causes SASP in African ancestry DLBCL
2. Study how the tumor environment helps cancer cells avoid the immune system
3. Test if drugs that block SASP can make treatment work better and current treatment and prevent the cancer from growing back. 

Why this Project matters:

•  We are finding a new type of DLBCL that is common in African ancestry patients. This type has special gene changes (like SETD2, ATM, MGA) and a tumor environment that helps cancer hide from the immune system.
• We are the first to describe SASP in this cancer and how it helps the tumor avoid the immune system.
• We are studying how SASP affects the immune system by pulling in immune cells like CD4+ T cells, and wearing them out, a process guided by signals like IL-6, IL-10, and IL20.
• We are working to make better treatments by finding new biological markers that show weak spots in these DLBCL tumors and by creating the first treatment that targets SASP.

Project 2: Translating Genomics to Practice to Improve Outcomes in DLBCL

Project Co-Leaders

Christopher Flowers M.D., M.S., FASCO (Clinical Co-Leader)
Jean Koff M.D., M.Sc.   (Clinical Co-Leader)
Michael Green, Ph.D. (Basic Co-Leader)

Patients with diffuse large B-cell lymphoma (DLBCL) can have very different outcomes. Some are cured with initial treatment, but about 40% see their cancer return and have a poor outlook. Research on why this happens has been hard because some groups are not well represented even in large studies and trials. Our team is ready to help solve this problem. We have access to large collections of patient samples and data that reflect the U.S. population. We also work with clinical trial networks that include community cancer clinics where many patients get care.

In this project we will study genetic data from DLBCL patients to see if current tools to predict outcomes work for everyone. We will also grow our collection of mouse tumor models based on real patients to better understand how DLBCL starts and reacts to treatment in different groups. We will test ways to help more patients join a DLBCL clinical trial that uses genetic information to choose the best first treatment in community clinics. 

Using a cells-to society approach, Project 2 will:

1. Identify specific molecular and immune features of DLBCL and its environment in different groups,
2. Test treatment weaknesses using new ancestry-based models, and
3. Create diagnosis and treatment plans suited for community clinics.

Why this Project matters:

•  We are creating the first genetic system to group DLBCL by genetics and ancestry. This will help show how certain traits in the tumor and body affect outcomes in high-risk groups.
• We are creating the first mouse models based on different ancestry groups to test targeted treatments.
• We are launching the first clinical trial to see how using genetic testing (RNA/DNA sequencing) can guide first treatments and improve results for DLBCL patients in community clinics.

Project 3: AI Digital Pathology Tools to Address Disparities in Lymphoma Diagnosis and Classification for Underserved Communities

Project Co-Leaders

David Jaye, M.D.  (Clinical Co-Leader)
Lee Cooper, Ph.D. (Basic Co-Leader)

About 1 in 5 patients diagnosed with lymphoma at local clinics are given the wrong diagnosis, which can affect their treatment. Turning glass slides into digital images (called whole-slide imaging or WSI) makes it faster to share them for expert review. However, online sharing does not fully solve the problem. Delays in getting second opinions and a shortage of trained pathologists make it harder to meet the growing need.

Pathology is one of the most promising areas for artificial intelligence (AI) in medicine. AI tools have been developed for diagnosis, outcome prediction and treatment planning, mostly for solid tumors. But blood cancers, especially lymphomas, are less studied. This is due to limited WSI datasets with clinical details, complex systems, and the need for special staining. AI models that use H&E-stained slides to find biomarkers could offer a low-cost alternative to other tests. But to build strong models, we need large sets of data with good clinical details from thousands of cases. 

Our team is well prepared to face these challenges, with experience in digital pathology, building AI tools, and working with both local and academic blood cancer labs. We also have access to the Lymphoma Epidemiology of Outcomes (LEO) study, the largest study of lymphoma patients in the United States. Using standard H&E stains we will study how adding data from new genetic and imaging tools to WSI can improve H&E-based models that predict outcomes based on the tumor environment. These models will be designed to fit the needs of local clinics.

In Project 3 we aim to:

1. Create a tool to distinguish different types of lymphoma, made for use in local clinics to improve diagnosis.
2. Study if AI can find tumor environment markers from H&E WSIs.

Why this Project matters:

• We will create the largest AI-based lymphoma diagnosis study and test it in often overlooked patient groups.
• We will build a pathology AI tool made to fit the needs of patients and doctors in community clinics.
• We will make H&E images more useful by training models with detailed gene data that maps activity in different parts of the tissue.

Administrative Core

Core Co-Directors

Christopher Flowers M.D., M.S., FASCO  
Jean Koff M.D., M.Sc.  

The Administrative Core is in charge of planning and keeping track of scientific work. It also helps guide the research, making sure it includes different fields and connects well across all teams and with the NCI Translational Research Programs. The Core is led by Dr. Christopher Flowers and Dr. Jean Koff, who will make sure the science in the lymphoma SPORE is strong and accurate. They will also help all parts of the SPORE program work together and share information. 

The main goal of this Core is to make sure all SPORE components are well managed and work smoothly. This includes the SPORE Projects, Cores, Career Enhancement and Developmental Research Program.

The Core will help by:

1.  Giving expert help with budget management;
2. Making sure communication is clear; and
3. Helping with overall planning and organization. 

The Core will lead and organize the work of the Executive Committee (made up of Project and Core Co-Leaders), the External Advisory Board, and the Community Advisory Board.

Biospecimens and Pathology Core

Core Co-Directors

Francsico Vega, M.D., Ph.D.  (Co-Director)
Giorgio Inghirami, M.D. (Co-Director)

Studying the tissue and genes of lymphoma samples is key to each SPORE Project. It helps researchers find what causes lymphoma and create new ways to diagnose and treat it. The Biospecimens and Pathology Core helps collect tissue, ensure that the lymphoma diagnosis is correct and run advanced tests. These include special imaging, mapping gene activity in tissue, and creating lab mouse models from patient samples. Working with other SPORE Cores, Core 2 will turn tissue slides into digital images and combine clinical and sample data. This will help researchers to quickly and correctly find samples with certain gene changes, cell features or clinical traits for research.

The goals of the Core are: 

1. Create and manage a SPORE specimens bank and database with tissue samples, digital slides, and connected clinical data to help choose samples and support research team work;
2. Use blood cancer experts to give a clear and accurate diagnosis for all lymphoma samples, based on the latest international guidelines; and
3. Study lymphoma samples from patients, lab grown tumors; and mouse models using advanced tests and combine the results with computer tools.

Community Outreach and Engagement Core

Core Co-Directors

Lorna McNeill, Ph.D.  (Co-Director)
Jonathon Cohen, M.D. (Co-Director)

The main goals of the Community Outreach and Engagement (COE) Core are to: 

1. Help SPORE researchers work with communities,
2. Build strong partnerships, and
3. Support finding and keeping patients in clinical studies. 

The COE Core will also help share and collect ideas and information from the community, community advisors and community scientist for all SPORE Projects.

The Core plays a key role in this SPORE by:

• Involving patients and community members in the SPORE and the Developmental Research Program (DRP) by working with the Community Advisory Board and local groups.
• Helping research teams learn how to better recruit people for clinical trials through training and work with patients and communities.
• Doing regular surveys to understand the people in the area. This will help us find out the rates of cancer and why some don’t join trials. After that, we will use and improve proven, lymphoma programs to help more people join trials.
• Sharing the best ways to get more people to join clinical trials and giving ideas to improve policies for other trial networks.

Biostatistics and Bioinformatics Core

Core Co-directors

Ryan Sun, Ph.D. (Co-Director)
Christopher Mason, Ph.D. (Co-Director)

The Biostatistics and Bioinformatics Core (Core 3) helps the SPORE by managing data, doing statistical work, and helping with computer tools to study large and complex data. Core 3 looks at many types of data. This includes biological data, medical records, tissue samples, genes, and images. It uses this data to support all SPORE Projects and the Career Enhancement and Developmental Research Programs. 

This Core works as a team and uses tools already in place to keep patient information safe and analyze data from advanced genetic and molecular tests. The team know how to study genes, analyze data, and work with large amounts of information from both medical and lab research. This team works closely together to provide support to the SPORE Projects and help turn lab discoveries into patient care. With years of experience working with complex data for big research teams, Core 3 is ready to help make important discoveries and help reach the SPORE research goals. 

Developmental Research Program

Program Director

Jean Koff M.D., M.Sc.  

The goal of the Developmental Research Program (DRP) is to support small new projects. These projects make the most of new opportunities offered by the SPORE. Each year, the DRP will fund projects that bring together different areas of science to study and treat lymphoma in new and promising ways. These projects will use one or more SPORE Core Facilities which offer special tools and resources so the research can be done successfully. DRP studies are meant to build ideas for future SPORE projects. They will support new, high-quality research to improve prevention, early detection, diagnosis, and treatment of lymphoma in specific patient populations.

Career Enhancement Program

CEP Director

Christopher Flowers M.D., M.S., FASCO 

The Career Enhancement Program (CEP) helps early-career and experienced researchers changing their research focus to find better ways to diagnose, treat and follow up with patients who have lymphoma. Each year, the CEP will fund investigators across areas of science to study and treat lymphoma in new and promising ways. Expert mentors lead the program. They have extensive experience in getting research funding, working in teams, and guiding others in cancer research. The CEP gives structured support, research tools and career guidance to help grow the next group of leaders in lymphoma outcomes research.