From Discovery to Clinical Impact: AACR Special Conference Captured the Spectrum of Lymphoma Research
It’s a busy time in Philadelphia. In addition to semiquincentennial-related events and World Cup games, another crowd recently gathered in the city for the fifth Advances in Malignant Lymphoma: From Discovery to Clinical Impact conference, organized by the American Association for Cancer Research (AACR) in cooperation with the International Conference on Malignant Lymphoma.
The meeting, held June 24-27, convened experts from academia, industry, government, and foundations to explore advances across the spectrum of lymphoma research that are driving progress toward improved outcomes for patients with lymphoma, a broad term encompassing more than 100 different cancers that begin in white blood cells called lymphocytes.
The meeting brought together basic and translational researchers and fostered rich discussions on how the field will move the latest discoveries into new therapies, said conference chair Michael Green, PhD, professor and vice chair for research at the Lymphoma and Myeloma Department of The University of Texas MD Anderson Cancer Center.
“Ten years ago, we didn’t have approvals for chimeric antigen receptor (CAR) T cells or bispecific antibodies. We’ve seen those move from being experimental therapeutics to approved therapies,” Green said. “Now, and in this meeting, we’re talking about some very interesting therapeutics like next-generation bispecific antibodies, BCL-6-targeted agents, and other things … that are going to become tomorrow’s therapies.”
Opening Keynote Examined How Monoclonal Antibodies Transformed Lymphoma Treatment
The meeting kicked off with an opening keynote address by Ronald Levy, MD, FAACR, the Robert K. and Helen K. Summy Professor in the School of Medicine and director of the Lymphoma Program at Stanford University.
Levy provided a historical overview of monoclonal antibody treatments for lymphoma, touching on early experiments in the 1970s that revealed the ability of antibodies to localize to tumors and the power of hybridoma technology to continuously produce a monoclonal antibody; the successful treatment of the first patient, Phillip Karr, with an anti-CD20 monoclonal antibody called rituximab; the approval of rituximab in 1998 under the brand name Rituxan; and the pivotal phase III study that confirmed superior outcomes in patients treated with the drug.
Now, he said, antibodies continue to show promise as researchers explore radiolabeled antibodies, antibody-drug conjugates, bispecific antibodies, and CAR T cells for cancer treatment. Levy also discussed the potential of in situ vaccination with a TLR9 agonist to induce an abscopal (or systemic) effect and shared insights from recent work to understand clonal evolution of follicular lymphoma.
Closing Keynote Explored Balancing Affinity and Diversity in the Antibody Response
The closing keynote address was delivered by Michel C. Nussenzweig, MD, PhD, Zanvil A. Cohn and Ralph M. Steinman Professor of Immunology at The Rockefeller University and a Howard Hughes Medical Investigator, whose work on B cells has helped to define the dynamics and characteristics of the cells in which lymphoma often develops. During his talk, Nussenzweig addressed a foundational question of B-cell biology: How do antibodies acquire both affinity and diversity?
Nussenzweig reviewed his work on the processes that take place inside of lymph nodes’ germinal centers, which produce high-affinity antibodies that bind to antigens in the course of the body’s immune responses. His lab showed that, in chronic or persistent infections, antibodies that formed in the germinal centers gradually lost affinity for the primary target within the antigen to which they were meant to bind.
According to Nussenzweig, the gradual loss of affinity was likely a natural adaptation by the immune system to keep up with rapidly mutating pathogens. If a virus changes the structure of its antigens as it evolves, for example, then the immune system could stand a better chance of continuing to respond to a mutating virus by casting a wider net of antibody structures, Nussenzweig said—a process that biologically justifies the production of both high- and lower-affinity antibodies. He concluded his presentation by sharing early-stage work showing that antibody production could be modified through gene editing to turn B cells into “protein factories for treating cancer.”
A Repository of PDX Models to Study Lymphoma
The meeting also showcased various antibody modalities, recent advances in cell therapy, novel targeted therapeutic strategies, insights into rare lymphomas, and more.
A session on epigenetics included a presentation by Green, who shared recent work from his lab. Their focus is on understanding how genetic and epigenetic changes affect B-cell differentiation and give rise to B-cell lymphoma and myeloma.
“Our model systems for this work have traditionally been cell lines, which are very homogeneous. Recently, we’ve developed a large repository of patient-derived xenograft (PDX) models of large B-cell lymphoma (LBCL) that has been helpful in elucidating how epigenetic-targeted therapies drive resistance,” said Green. The findings were concurrently published in the AACR journal Blood Cancer Discovery.
Using this repository, Green and team uncovered epigenetic plasticity as a resistance mechanism to BCL-6-targeted therapy, which can be addressed by combination treatment with other targeted therapies, such as lenalidomide (Revlimid). “There is a significant degree of heterogeneity at baseline and a plasticity to move between phenotypes, but one that we can take advantage of therapeutically,” Green explained.
Learn more about this study and other advances in lymphoma research in a special collection of articles published in Blood Cancer Discovery.
