Basic scientists like Xingxing Zang, M.Med., Ph.D., are accustomed to wearing white lab coats, not “white tie” evening wear. But a few Decembers ago, Dr. Zang was decked out in formal attire at Stockholm, Sweden, where he mingled with scientific and social elites from the world over.
The occasion: celebrating the presentation of the 2018 Nobel Prize in Physiology or Medicine to Dr. Zang’s mentor, James P. Allison, Ph.D., whose research had spawned a new class of cancer therapies—immune checkpoint inhibitors (ICIs)—that unleash the full power of immune cells to attack a wide range of human cancers.
Today, Dr. Zang is creating new ICIs. One inhibitor he designed—a therapy for advanced lung cancer—is now in early-phase clinical trials, while several others are in the drug development pipeline.
Disabling the brakes on T cells
Checkpoints are a normal immune system regulatory mechanism that prevents the immune system from straying beyond its usual “enemy” targets and destroying healthy cells instead. Checkpoints occur when protein receptors on immune cells called T cells bind with proteins expressed by the body’s own normal cells—an interaction that puts the brakes on T cells and prevents them from attacking “self” cells they encounter.
Most types of cancers are able to exploit checkpoint interactions by disguising their cells as “normal.” They do so by expressing surface proteins that bind with T cell receptors, causing a checkpoint interaction that tricks T cells into standing down and not attacking the tumor.
Dr. Allison’s great insight was that cancer treatment could be improved by unleashing the immune system to attack tumor cells. He proposed that this treatment strategy, called immunotherapy, would require checkpoint inhibitors—molecules that short-circuit T-cell/tumor-cell interactions by blocking either the tumor proteins or the T-cell receptors that the proteins target.
“At the time, many people didn’t believe that immunotherapy would work, but we and others pushed the field forward,” says Dr. Zang, who is professor of microbiology & immunology, of medicine, and of urology, the Louis Goldstein Swan Chair in Cancer Research at Albert Einstein College of Medicine, and a member of the National Cancer Institute-designated Albert Einstein Cancer Center.
Taking his discovery from bench to bedside, Dr. Allison created a monoclonal antibody to block the T-cell checkpoint receptor CTLA-4; this led to the development of ipilimumab, the first ICI drug, which was approved in 2011 by the U.S. Food and Drug Administration for treating advanced melanoma. In a field where gains are measured in inches, ipilimumab pushed oncology forward by yards, effectively curing about one in five melanoma patients affected by metastatic disease.
“The beauty of this approach is that when ICIs work, patients most likely develop memory T cells,” says Dr. Zang. “So, if the cancer comes back, patients have memory immune cells that can recognize new tumor cells and quickly kill them.”
A half-dozen more ICIs (aimed at CTLA-4, the T-cell receptor PD-1, or the tumor protein checkpoint PD-L1) have since been approved for treating these additional types of tumors: breast cancer, colon cancer, lung cancer, kidney cancer, liver cancer, head and neck cancer, cervical cancer, bladder cancer, and Hodgkins and non-Hodgkins lymphomas.
Good but not good enough
By historical standards, ICIs are remarkably effective cancer medicines. “The problem is that they don’t work in the majority of patients,” says Dr. Zang. In addition, cancer recurrences in treated patients sometimes prove fatal. But there is hope.
Dr. Zang has discovered several new checkpoint proteins that are highly expressed in many types of human cancer, as well as several receptors on T cells and other immune cells to which tumor proteins bind. His studies show that these checkpoint proteins operate differently from the previously established checkpoints, raising the possibility of new types of ICIs that work in patients not helped by other inhibitors or that can enhance the clinical activity of existing ICIs.
Thus far, Dr. Zang has developed and patented no less than ten ICIs, including one with his mentor, Dr. Allison. Most of these immunotherapies have been licensed by biotechnology companies for further development and eventual clinical testing.
The first of these ICIs to reach clinical trials is a monoclonal antibody against Tim-3, a T-cell checkpoint receptor. An early-phase clinical trial, which began in December 2020 in China, is evaluating Dr. Zang’s antibody in patients with advanced lung cancer who have failed standard treatment or lack effective treatment. The trial is being conducted at the Cancer Hospital of the University of Chinese Academy of Sciences.
The beauty of this approach is that when ICIs work, patients most likely develop memory T cells, So, if the cancer comes back, patients have memory immune cells that can recognize new tumor cells and quickly kill them
Xingxing Zang, M.Med., Ph.D.
The trial’s sponsor is Chia Tai Tianqing Pharmaceutical Group, a top Chinese drug company, which has licensed Dr. Zang’s Tim-3 technology from Einstein. Trials of the antibody for other types of cancer are likely to follow.
Dr. Zang has also launched three biotech startups in the U.S. and Israel to develop early drug prototypes of several of his monoclonal antibodies.
“The majority of our work is in the realm of basic science, which satisfies my intellectual curiosity,” Dr. Zang says. “But I want to do as much as I can to bring novel and better drugs to patients. Most of our studies are supported by the federal government, and I deeply believe it is our obligation to give back to society.” His research is funded by the National Institutes of Health and the Department of Defense, among others.
Venturing further afield, Dr. Zang is developing checkpoint strategies to treat autoimmune diseases such as type 1 diabetes and inflammatory disorders including cardiovascular disease. “The flip side of checkpoints is that they can fail to restrain T cell activity, allowing the immune system to attack a person’s cells and tissues and resulting in autoimmune and inflammatory diseases,” Dr. Zang notes.
Dr. Zang’s strategy for treating both type 1 diabetes and cardiovascular disease involves the same basic approach: develop a fusion protein (a chimeric protein created by joining two or more genes that originally coded for separate proteins) to prevent T cells from attacking either pancreatic cells or cardiovascular tissue.
“Dr. Zang is respected internationally for advancing the field of immunotherapeutics against cancers and other disorders,” says Edward Chu, M.D., director of the Albert Einstein Cancer Center, vice president of cancer medicine at Montefiore, and the Carol and Roger Einiger Professor of Cancer Medicine at Einstein. “My hope is that our cancer center will collaborate with Dr. Zang and his companies to conduct early-phase clinical trials for his various immune checkpoint molecules. His work really epitomizes the tremendous promise of translating our scientific discoveries into novel therapies for our patients here in the Bronx, throughout the U.S. and around the world.”
A focus on collaboration
Dr. Zang’s journey to Einstein began in Zhejiang, China, where he was born and raised. He earned his M.Med. at Shanghai Jiao Tong University School of Medicine, completed his Ph.D. at the University of Edinburgh in the United Kingdom, and came to the U.S. for postdoctoral training at the University of California at Berkeley and Memorial Sloan-Kettering Cancer Center in New York City, both under the tutelage of Dr. Allison.
Dr. Zang arrived at Einstein in 2008, partly because of the opportunity to work with the late Stanley G. Nathenson, M.D., a world-renowned immunologist. He has since collaborated with a dozen or more Einstein scientists and Montefiore physicians, including Steven Almo, Ph.D., Haiying Cheng, M.D., Ph.D., Wenjun Guo, Ph.D., Mark Schoenberg, M.D., Matthew Scharff, M.D., Joseph Sparano, M.D., and Deyou Zheng, Ph.D.
Knowing the value of a good teacher, Dr. Zang takes pride in mentoring the next generation of researchers. In just 12 years, he has trained 45 M.D./Ph.D. and Ph.D. students, postdoctoral fellows, clinical fellows, and visiting scientists, who now work all over the world. “My research and life are continuously being influenced by my trainees, colleagues, collaborators, and cultures,” he says.
Who knows, maybe he’ll be attending another Stockholm celebration in the future.
At left: A T cell has recognized a tumor cell as foreign (T cell receptor has bound to tumor cell antigen) but fails to attack because checkpoint proteins have interacted: The tumor’s PD-L1 protein has bound to the T cell’s PD-1 protein, putting the brakes on T cell activity.
At right: In immunotherapy, monoclonal antibodies block checkpoint protein interactions so that T cells remain active to kill tumor cells. Here, one type of monoclonal antibody (Anti-PD-L1) has been designed to bind to the tumor’s PD-L1 protein, and another type (Anti-PD-1) works by binding to the T cell’s PD-1 protein.
Posted on: Wednesday, March 03, 2021