B-Cell Lymphoma Research Projects
MOON SHOTS PROGRAM
B-cell Lymphoma Flagship Projects
Our research projects address the crucial issues facing B-cell lymphoma patients by focusing our largest efforts on the treatment approaches that have near‐term measurable success. Research efforts of the B-Cell Lymphoma Moon Shot® are aimed at enhancing our understanding of the molecular and genomic signatures of the disease and deploying novel targeted therapies, cellular therapies and immunotherapies against it.
Preventing disease resistance in B-cell lymphoma patients through targeted therapy
Enhancing the immune system to better fight B-cell lymphoma through cellular therapy
Guiding immunotherapy treatment strategy through biomarker discovery
In the past, treatment decisions were based on results from a pathologist's visual analysis of tumor tissue; however, this approach is often tedious and does not provide the clinician with enough information to effectively treat the patient. Now, we are using genetic analysis of the tumor to aid in the selection of the most appropriate targeted therapy approach. Targeted therapies attack cancer with increased precision and reduced toxicity by taking aim at the tumor-specific signals promoting cancer cell growth and survival.
A major research breakthrough of our B-Cell Lymphoma Moon Shot was the development of the targeted therapy called ibrutinib, which was approved for lymphoma treatment by the FDA. Ibrutinib works by disabling the action of Bruton’s tyrosine kinase (BTK), a mediator that impacts B-cell development. The result of this inhibition is cell death and reduced migration and adhesion of the malignant B-cells. When given in combination with rituximab, ibrutinib yields a response rate of almost 90% in patients with relapsed or refractory mantle cell lymphoma, which is an aggressive form of B-cell lymphoma.
But targeted therapy approaches are still lacking, as cancer cells learn to use alternative survival pathways to outsmart these targeted therapies. To stay one step ahead of B-cell lymphoma, our Moon Shot® team is identifying emerging mechanisms of resistance to ibrutinib and rituximab and using this information to guide the design of next generation targeted therapies. They are doing this through patient derived xenograft (PDX) models, in which ibrutinib-resistant lymphoma cells from patients are injected into a unique mantle cell lymphoma mouse line.
Using these PDX models, our Moon Shot researchers are collaborating with the Cancer Genomics Laboratory and Proteomics platforms within the Moon Shots Program® to define the genetic and molecular profiles of a patient’s specific lymphoma cells. This patient-specific analysis allows our researchers to test various drug combinations and determine the most beneficial targeted therapy, or combination of therapies, for a specific patient throughout treatment.
Our EXPLORE (A Pilot Study Evaluating Xenografts to Personalize Therapies in Relapsed Mantle Cell Lymphoma to Optimize Response) trial is the first patient-specific PDX-directed trial in lymphoma and is using extensive tumor profiling and “big data” to determine the most optimal patient-specific therapy for relapsed mantle cell lymphoma.
T cells are cancer killing cells that play an important role in the immune system's fight against B cell lymphoma. We are engineering T cells to better fight this cancer through adoptive cellular therapy. This sophisticated method employs a unique gene transfer system that was developed at MD Anderson, which modifies T cells to more efficiently recognize proteins found on the surface of all B-cell lymphoma cells, such as a protein called CD19. In this case, a patient’s T cells are collected and modified to contain a chimeric antigen receptor (CAR) that recognizes CD19 specifically. Upon reinfusion, these engineered immune cells have an enhanced ability to seek and destroy B-cell lymphoma cells. This treatment method is commonly called CAR T cell therapy. To expedite the process of adoptive cellular therapy, our investigators are also developing a system to produce “off-the-shelf” engineered T cells from a universal donor that could be given to any patient in need.
Natural killer (NK) cells are another cell type from the immune system that also kill cancer cells. Unlike T cells, NK cells can be obtained from a donor or umbilical cord blood and infused into a patient without causing abnormal reactvity. This allows us to produce a bank of NK cells that can be immediately available for B-cell lymphoma patient treatment. We are adding these cells to stem cell transplants to increase effectiveness of these infusions to fight B-cell lymphoma. We are also using CAR technology to further augment the anti-cancer killing potential of NK cells, and a new clinical trial with these enhanced CAR-NK cells is currently being initiated.
With the growing number of immunotherapy options available for B-cell lymphoma treatment, physicians need predictive tools to make calculated decisions regarding the best immunotherapy option for each patient. Physicians also need to be able to determine whether the chosen treatment needs adjustment based on the patient’s response. Before we can do this, our team must identify the molecular signals that indicate whether response or resistance is occurring in a patient receiving a particular immunotherapy. With this information in hand, our clinicians will then be able to make strategic choices concerning the initial and continued personalized treatment options for each patient.
Our B-cell lymphoma team and experts from the Moon Shots Program's Immunotherapy platform will collaboratively initiate clinical trials designed to uncover the biomarkers that indicate whether a patient is responsive, unresponsive or developing resistance to a particular immunotherapy. Initially, these trials will be focused on patients with follicular lymphoma and diffuse B-cell lymphoma, the two most common forms of B-cell lymphoma. The therapy response-related biomarkers uncovered in these trials will be developed into predictive tools that clinicians can rely upon to guide their treatment strategy.