How are bispecific antibodies being used to treat blood cancers?

Many of the immunotherapy drugs that are transforming the treatment of certain types of cancer are based on antibodies — artificial proteins that latch onto a molecular target, called an antigen. Bispecific antibodies, which can bind to two antigens at the same time, are being tested and moving toward clinical use in some blood cancers.

Antibody drugs that are currently in wide use in immunotherapy are limited to latching on to a single target, or antigen. For example, some of these drugs latch onto a protein called PD-L1, which is part of a system that cancer exploits to shut down the immune response. Antibodies that target PD-L1 remove the brakes so the immune system — mainly white blood cells called T cells — can attack the cancer.

Bispecific antibodies expand the power of antibody drugs by grabbing two molecules at once, which opens up a new avenue of therapeutic possibilities. Today, these drugs are only approved by the U.S. Food and Drug Administration for certain patients with acute lymphoblastic leukemia (ALL), but are showing promise in early trials for patients with other types of leukemia and multiple myeloma.

For example, one class of bispecific antibodies — termed bispecific T-cell engagers, or BiTEs — can latch onto a T cell and a tumor cell simultaneously. This close proximity enables the T cells to directly attack and kill the tumor cell. Normally, T cells can only go on the attack after an antigen — a piece of the microbe or cancer cell — has been “presented” to it by another specialized cell called a dendritic cell. The BiTE bypasses that step and brings the tumor cell and T cell together without the intermediate step.

“With BiTEs, you’re bringing the T cell to the game,” says Daniel D’Angelo, MD, PhD, chief of the Division of Leukemia at Dana-Farber Cancer Institute. “These T-cell engagers bring the patient’s immune cells to target the relapsed cells. The advantages are that you can administer it whenever you want, and you can always turn it off.”

One such drug, blinatumomab, has been FDA-approved to treat adult and pediatric patients with a certain form of ALL. Others are being developed and tested for other blood cancers, such as acute myeloid leukemia (AML) and some solid tumors, such as small cell lung cancer and glioblastoma.

BiTEs could be an “off-the-shelf” form of immunotherapy if approved, unlike another immunotherapy strategy, CAR T-cell therapy. The latter, which has been remarkably successful in treating some advanced blood cancers, involves a process in which the patient’s immune cells are removed and genetically altered in the laboratory, then returned to the body to seek out and attack cancer cells. This is a lengthy process that must be individualized for each patient; BiTEs are like drugs that can be prescribed without having to be manufactured using the patient’s own immune cells.

Jacob Laubach, MD, clinical director for the Multiple Myeloma Program at Dana-Farber, is leading some early clinical trials of BiTEs for multiple myeloma. The first trial will test an experimental BiTE in patients who have relapsed following treatment with three lines of therapy. This bispecific antibody will target a molecule on the myeloma cell and another molecule on the surface of the T cell, bringing them together with the aim of killing the cancer cell.

Researchers reported early clinical trials results involving BiTEs at the 2018 meeting of the American Society of Hematology. “They did see a high level of response, including some patients who had complete responses,” meaning their cancer was no longer detectable, Laubach says. In these clinical trials, the drug had to be continuously infused during an inpatient hospital stay; Laubach also notes that researchers also don’t know how sustained the patient responses will be.

“BiTEs represent a very exciting and promising new approach,” says Paul Richardson, MD, clinical program leader in the Jerome Lipper Multiple Myeloma Center at Dana-Farber. “But it’s important to note that it’s not one versus the other — we will need both CAR T cells and BiTEs in multiple myeloma.”