Doctor (standing) speaking to patient

New Drug Enhances Immunotherapy to Treat Non-Hodgkin Lymphoma

December 12, 2022

A novel drug discovered at Columbia University has shown promise in the preclinical setting when paired with immunotherapy to treat an aggressive type of B-cell lymphoma. Based on these results — presented at this year’s American Society of Hematology (ASH) Annual Meeting, held December 10-13 in New Orleans, LA — the drug has been approved to proceed in clinical trials in patients with relapsed or refractory lymphoma.

Non-Hodgkin lymphoma, one of the most common cancers in the U.S., starts in white blood cells called lymphocytes. The majority of patients are diagnosed with diffuse large B-cell lymphoma (DLBCL), an aggressive type found mostly in older adults. DLBCL is known to have limited sensitivity to immunotherapy agents known as PD-1 inhibitors, which work by “releasing the brakes” on the patient’s own immune system to attack cancer cells.

“Nearly half of aggressive B-cell lymphomas have mutations in the genes EP300 and CREBBP that code for enzymes that control how genes are expressed. These mutations decrease the effectiveness of these critical enzymes,” says Jennifer E. Amengual, MD, Herbert Irving Assistant Professor of Medicine at Columbia’s Vagelos College of Physicians and Surgeons and member of the Herbert Irving Comprehensive Cancer Center (HICCC). “One consequence of this is that lymphomas with these mutations can evade immune detection and this allows unfettered tumor growth.”

Portrait of Brian Estrella, PhD

Brian Estrella, PhD, the study's first author and postdoctoral research scientist in the Department of Medicine and in the Amengual lab

Dr. Amengual and team have been working with the novel compound, YF2, identified by the lab of Ottavio Arancio at Columbia Univeristy, that can synergize with a PD-1 inhibitor and prolong survival in mice with lymphoma. YF2 works by enhancing the effectiveness of the enzymes, overcoming the  impact of EP300 and CREBBP mutations.

For 28 days, mice were treated with either saline, YF2, a PD-1 inhibitor, or a combination of YF2 and a PD-1 inhibitor. The combination of YF2 and a PD-1 inhibitor resulted in the greatest increase in medial survival when compared to a control group.

In addition, the researchers administered YF2 to tumor samples that originated from human patients in the laboratory, finding that the drug induced cytotoxicity across various lymphoma subtypes, including DLBCL.

“Aggressive B-cells lymphomas are known to evade immune surveillance,” says Dr. Amengual. “We hope that YF2 can manipulate the immune system to better recognize B-cell lymphomas and improve the effects of immunotherapy.”


First-in-Class Histone Acetyltransferase (HAT) Activator, YF2, Modulates Immune Evasion in DLBCL, Enhancing the Effects of Immune Checkpoint Blockade

Collaborators, all at Columbia University unless noted otherwise: Brian Estrella, PhD, Manuel A. Pazos II, MS, Edd C. Ricker, PhD, Yun Kyoung Ryu, MD, Ted B. Piorczynski, PhD, Yuxuan Liu, PhD (Stanford University), Seda Tolu, MD, and Jennifer E. Amengual, MD

Presented at the 64th ASH Annual Meeting and Exposition, held Dec. 10-13, 2022