Combination Therapy Could Be Promising Treatment for Advanced Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia accounts for one in five adult leukemia and is the most common pediatric cancer in the United States. Newer immune therapies have helped improve survival rates, but some patients do not respond to existing treatment regimens. In addition, drug-related toxicities and drug resistance are widespread in these patients, creating an urgent need for new treatment options.

Researchers at Case Western Reserve University School of Medicine have developed a new treatment regimen that combines the immune system's ability to eliminate leukemias that do not respond to standard treatments. The diet includes a therapeutic antibody designed to attract natural killer immune cells to cancer cells. The antibody specifically bound to acute lymphoblastic cancer cells as early as 30 minutes after treatment and remained attached for two days, serving as a flag to attract natural killer immune cells. The researchers were able to maximize the effectiveness of the antibody by adding a second anti-tumor molecule to the treatment regimen.

Results published in Cancer Immunology Research describe how the antibody binds to a specific protein on the surface of acute lymphoblastic leukemia cells (B-cell activation factor, or BAFF-R). Once the antibody binds to a cancer cell, natural killer cells also attach to it and this antibody acts as a bridge between cancer cells and natural killer cells, where it acts quickly to destroy the cell. cancerous. The antibody connects to natural killer cells via a second protein usually present on their surface (CD16).

The researchers, Reshmi Parameswaran, PhD, an badistant professor in the department of medicine and a medical student / doctorate in his laboratory and in the pathology department, Yorleny Vicioso, have created a new murine model of acute lymphoblastic leukemia. They used mouse models with drug-resistant, growth-resistant cancer cells taken from human patients. They then tested the treatments during the course of the disease, starting with the antibody alone.

If we started treating mice with the antibody early in the development of the disease, leukemia was almost eradicated by this method of treatment; however, if the treatment was administered late, while the tumor had grown and created its own microenvironment, the antibody alone was less effective. "

Reshmi Parameswaran, Ph.D., member of the Case Comprehensive Cancer Center and St. Baldrick's Scholar

When cancer cells grow, they secrete molecules that disrupt and disrupt the body's natural immune responses. The area around an established tumor – its surrounding "microenvironment" – may contain a myriad of molecules that inhibit immune cells. The Parameswaran team has discovered unusually high levels of an inhibitory molecule called TGF-beta in the blood of mice. Closer inspection revealed that the cancer cells secreted directly TGF-beta, which accumulated over time in their microenvironments to defend against natural killer cells. TGF-beta in the microenvironment inhibits more than half the ability of natural killer cells to kill cancer cells.

"The microenvironment of the tumor clearly had a negative effect on the killing ability of natural killer cells," Parameswaran said. "We therefore added a TGF-beta receptor inhibitor to our antibody treatment."

Using their mouse disease model, the researchers showed that the combination of these two treatments increased the destruction of acute lymphoblastic leukemia cells – even though the disease was advanced. Treatment with TGF-beta receptor and antibody inhibitor increased up to 35% activity of natural killer cells against cancer cells. The researchers confirmed the effectiveness of the combination in mice injected with acute lymphoblastic leukemia cells from four different patients.

The combination therapy may be a promising new pattern for acute advanced lymphoblastic leukemia, especially for adults who do not respond to existing options. Data from the new study suggest that the antibody, which binds to BAFF-R on cancer cells, might be more effective in older patients.

"We examined the expression of BAFF-R in a small group of 16 patients and all expressed this receptor.This is a promising therapeutic means for the treatment of advanced-stage disease," said Parameswaran. Data from larger patient groups will help us make a definitive conclusion. "

The custom BAFF-R antibody is currently being tested as a therapy for treating autoimmune diseases and rheumatoid arthritis in two clinical trials. The TGF-beta inhibitor has recently been tested in a first clinical trial in humans for the treatment of advanced solid tumors. The new mouse model study provides critical preclinical data for the combination of both treatments in human trials, Parameswaran said.