New Approaches Discovered to Enhance Immunotherapy to Treat Aggressive Form of B-Cell Lymphoma

Jennifer E. Amengual, MD

Some of the most promising advances in cancer treatment involve immunotherapy, drugs that harness the power of the patient’s own immune system to attack cancer cells. Confounding physicians for decades is diffuse large B-cell lymphoma (DLBCL), an aggressive form of non-Hodgkin’s lymphoma that has limited sensitivity to a type of immunotherapy called PD-1 inhibitors. Jennifer E. Amengual, MD, a medical oncologist at NewYork-Presbyterian/Columbia, and a team of researchers at NewYork-Presbyterian/Columbia have discovered that the novel drug YF2 can unlock the sensitivity of DLBCL to PD-1 inhibitors. The synergistic combination therapy is poised to broaden potential treatment options for patients with DLBCL.

Nearly half of aggressive DLBCL 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. Dr. Amengual and the research team have been working with the YF2 compound, first identified by the lab of Ottavio Arancio, MD, PhD, at NewYork-Presbyterian/Columbia. YF2 is a EP300 and CREBBP histone acetyltransferase (HAT) activator that works by demonstrating “selective cytotoxicity in HAT-mutated DLBCL cell lines and induces histone acetylation in vitro and in vivo.” The researchers hypothesized that YF2 can manipulate the immune system to better recognize B-cell lymphomas and improve the effects of immune checkpoint blockade inhibitors, effectively "releasing the brakes" on the immune system to better fight the cancer.

Micrograph of diffuse large B-cell lymphoma

“Diffuse large B-cell lymphomas often evade immune recognition and respond poorly to immune checkpoint blockade,” explains Dr. Amengual, an RO1-funded physician scientist who is focused on translating the latest scientific discoveries regarding cancer cell behavior into novel treatments. “Our study found that YF2 increased markers on the surface of the lymphoma cell, allowing it to be recognized by the immune system. YF2 increased the number and activity of T-cells in the blood and the tumor, leading to enhanced effects of PD-1 blockade.”