NIH grant will support fundamental lymphoma research

Weill Cornell Medicine has received a five-year, $12.4 million grant from the National Cancer Institute, part of the National Institutes of Health, for an extensive program of basic and translational research on the biology of diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma.

The investigator-initiated Program Project grant, led by Dr. Leandro Cerchietti, the Richard A. Stratton Associate Professor in Hematology and Oncology at Weill Cornell Medicine, and Dr. Christopher Flowers, professor and chair of the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, is meant to support a collaborative, multi-faceted effort towards a major biomedical research goal.  

DLBCL represents a significant challenge for cancer biologists because about 40% of patients either don’t respond well to initial chemotherapy or end up relapsing. Response rates also can vary dramatically among different DLBCL subtypes. Researchers expect that the development of significantly better treatments will require a more comprehensive understanding of the complex processes that trigger and sustain the disease.

DLBCL cells are known to originate from antibody-producing B cells residing in lymph node structures called germinal centers. As part of the normal immune response, for example to fight infection, B cells gather in these centers, briefly proliferating and mutating their antibody-coding genes to diversify their ability to bind to antigens. This ultimately allows the antibody response to effectively neutralize its targets. But B cells in this high-mutation state are especially vulnerable to cancerous changes. The collective work of lymphoma scientists has shown in prior studies that lymphoma-driving gene mutations often work by reprogramming B cells so that they linger in germinal centers, eventually accumulating full malignancy.

As part of the newly funded research program, the researchers intend to reveal this lymphomagenesis process in unprecedented detail, showing how different combinations of gene mutations and interactions with partner immune cells can combine to turn germinal center B cells into different DLBCL subtypes. They will focus strongly on the role of chromatin—the overall packaging of DNA, which programs gene activity and gives cells their basic identity—as the key integrator and modulator of these interactions in germinal center B and DLBCL cells.

The laboratories of Drs. Ari Melnick, Steven Josefowicz, Ethel Cesarman, Giorgio Inghirami, Sanjay Patel. John Leonard and Christopher Mason at Weill Cornell Medicine will collaborate on the various projects funded by the grant, These investigators, as well as Dr. Cerchietti, are members of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. Dr. Michael Green, an associate professor in the Division of Cancer Medicine at MD Anderson will contribute his laboratory’s expertise to the projects as well.

The researchers expect their progress in understanding DLBCL origins to illuminate vulnerabilities in these cancers that can be exploited with new and precise treatments—with emphasis on milder, non-chemotherapy treatments that will be more tolerable, especially for older patients. For example, Dr. Cerchietti and colleagues aim to develop methods for reprogramming lymph node-resident T cells so that they attack DLBCL cells.

Dr. Cerchietti noted that he and his colleagues will be able to make use of the unique collections of patient tumor samples and novel preclinical models of lymphoma that have been developed over years of collaboration by the investigators participating in this grant under the scientific umbrella of the Weill Cornell Medicine Lymphoma Program, as well as from the MD Anderson team. 

“This generous grant will allow us to make real advances in understanding lymphoma biology, but it is built on substantial foundations we’ve laid in recent years with our collaborative basic and preclinical research, as well as clinical trials,” Dr. Cerchietti said.