When it comes to biological systems, the human immune system surely ranks as one of the most remarkably complex and potent—able to detect and kill disease-causing microbes as well as cancer cells. Now, Einstein researchers are working to modulate the immune system as a way to overcome major diseases, a treatment approach known as immunotherapy.

Recent publicity has centered on using immunotherapy to combat cancer by revving up the immune system. According to a New York Times article published last year, the race among major pharmaceutical companies to develop cancer immunotherapies is potentially worth tens of billions of dollars a year in sales. Three such anticancer immunotherapies are now available. But scientists are also working to turn off the immune response to treat autoimmune diseases such as multiple sclerosis, type 1 diabetes and rheumatoid arthritis. Einstein researchers—all members of the Evolution of Immune Therapeutics Working Group—are involved in both immunotherapy approaches.

Tuning In to T Cells

Xingxing Zang, Ph.D.

Cancer immunotherapy doesn’t usually target tumor cells directly. Instead, efforts focus mainly on manipulating T cells, a type of white blood cell that helps destroy invaders such as viruses and bacteria and can eliminate cancer cells as well.

“Optimal T-cell activity is crucially important,” says Xingxing Zang, Ph.D., an associate professor of microbiology & immunology and of medicine (oncology). “Abnormally low T-cell activity makes people vulnerable to cancer or to chronic infections such as tuberculosis and herpes simplex. On the other hand, overly active T cells can trigger an immune attack on normal tissues, resulting in autoimmune diseases.”

T-cell activity depends on the numerous proteins attached to the T-cell surface. Steven C. Almo, Ph.D., a professor of biochemistry and of physiology & biophysics, uses an automobile analogy to describe how these proteins, known as cell-surface receptors, govern T-cell activity.

“One protein on the T-cell surface can be thought of as the ignition, since it recognizes infected and malignant cells and turns on the T cell,” says Dr. Almo, Einstein’s Wollowick Family Foundation Chair. “And just as a car needs an accelerator to go somewhere, T cells have another set of proteins that, when stimulated, rev up T cells so they can actually kill the disease-causing cells they’ve recognized. But at some point you want to turn off the immune response so that T cells don’t attack healthy tissues. So additional proteins on the T-cell surface act as brakes, working in opposition to the accelerator receptors to bring the whole system back to normal again.”

Unfortunately, tumors have learned to evade the body’s immune response by exploiting T cells’ finely calibrated control system. Tumors express cell-surface proteins that stimulate the very receptors that put the brakes on T cells’ attack, allowing the tumors to remain unscathed. Tumors are known to activate two “braking” receptors in particular: CTLA-4 (cytotoxic T-lymphocyte antigen-4) and PD-1 (programmed cell death protein-1). A considerable amount of immunotherapy research, at Einstein and elsewhere, is aimed at preventing cancers from turning on those T-cell receptors.