Advances in Immunotherapy: A New Antibody Connects Key Cells to Fight Cancer
Researchers at the Weizmann Institute developed an antibody based on cross-communication between different immune cells, offering hope for treatments against tumors and autoimmune diseases.
Weizmann Institute antibody unites immune cells, enhancing cancer treatment effectiveness
*This content was produced by experts from the Weizmann Institute of Science, one of the world’s leading centers for basic multidisciplinary research in the natural and exact sciences, located in Rehovot, Israel.
To win the battle, a combination of precise intelligence and determined soldiers is required. But when it comes to the battle against cancer, immune system fighters—the T cells—quickly lose their ability to kill and become exhausted, while dendritic cells, which provide intelligence, are scarce. This is one of the reasons why the great promise of immunotherapy—a new generation of treatments that leverage the body’s immune system to fight cancer—has not fully materialized.
In a study published in Cell, researchers from the Weizmann Institute presented a recently developed antibody that connects T cells with dendritic cells, creating a powerful immune response against cancerous tumors. The research opens a new path in immunotherapy: the development of treatments that connect various immune system cells to create a first-class combat team to defeat cancer and other diseases.
One of the most notable immunotherapies uses antibodies that block PD-1, a regulatory “checkpoint” receptor found on the surface of T cells. When this receptor is expressed on T cells, a widespread protein in the tumor environment can bind to it, causing T cells to enter a state known as exhaustion. PD-1 antibodies prevent this protein from binding to T cells and repressing them, but many cancer patients do not respond to this treatment; in many others, the efficacy is short-lived.
The Weizmann Research Team: (left) Dr. Rony Dahan, Yuval Shapir Itai, Oren Barboy, and Prof. Ido Amit
To develop a more effective immunotherapy, researchers in the laboratories of Dr. Rony Dahan and Prof. Ido Amit at the Weizmann Institute’s Department of Systemic Immunology began by asking why existing treatments were insufficient. To answer this question, they took T cell samples from two mouse cancer models that had been treated with PD-1 antibodies. “Using advanced technologies such as single-cell DNA sequencing and big data algorithms, we examined nearly 130,000 T cells, some of which responded to the treatment and others did not,” explains Amit. “Surprisingly, the group of T cells that did respond to the treatment expressed genes pointing to an interaction with a rare population of dendritic cells.”
Dendritic cells gather information from throughout the body by ingesting molecules belonging to malignant cells. They then present their findings to T cells, warning them of cancer growth and urging them to take action. PD-1 antibodies are supposed to help activate T cells fighting cancerous growths, but when researchers examined a mouse cancer model lacking dendritic cells, they discovered that antibody treatment had lost its effectiveness completely. In other words, they revealed that dendritic cells are vital for the multiplication and activation of specific T cells in the fight against cancer, and therefore necessary for the treatment to be successful.
These findings highlighted a key weakness of existing treatments: the fact that the relevant population of dendritic cells is rarely present in most cancer tumors and in most patients currently receiving PD-1 antibody treatments. Under these conditions, the interaction between these cells and the T cells they activate rarely occurs.
Immunotherapy revolutionized with new approaches maximizing this knowledge, paving the way for engineering a new antibody called BiCE (Bispecific DC-T Cell Engager), whose two arms were designed to connect two different types of cells: one arm binds to T cells, inhibiting the PD-1 receptor, just like existing treatments; the other arm recruits dendritic cells from the rare population vital for activating T cells. The development of the new treatment was led by the research students Yuval Shapir.
Once the antibody was created, researchers studied its mechanism of action. When they used fluorescent markers to label the antibody and immune cells in mice with skin cancer that had received the new treatment, they were able to observe how the antibody physically connected T cells with dendritic cells, increasing the number of such cell pairs around the cancer tumor and in adjacent lymph nodes. They also discovered that the cell pairs created by the antibody were active and triggered an immune response against the tumor. Furthermore, after the treatment, dendritic cells that had been adjacent to the cancerous tumor migrated to the lymph nodes and connected with T cells there, to share information and activate them.
New hope for untreatable diseases
The effectiveness of this new treatment has been tested in various mouse cancer models, including aggressive breast, lung, and skin cancers. Treatment with the new antibody, compared to existing treatments, significantly reduced the growth rate of skin and lung cancers. In contrast, breast tumors that did not respond to the existing treatment also did not respond to the new antibody. Researchers believe this is due to the very small number of active dendritic cells around these tumors. Therefore, they attempted to combine their new antibody with an existing treatment that enhances the activity of dendritic cells around the growth. This combined treatment proved to be more effective than existing options. It showed that even in cancers that had not responded to immunotherapy until now, the synergy between active T cells and dendritic cells creates a powerful immune response against the tumor.
The next phase of the study was to examine whether, alongside a strong immune response against the primary cancer tumor, the new antibody also prevents the recurrence of the disease. Many cancer patients suffer from such recurrence, even after the primary tumor has been removed and known metastases treated. The main danger is the existence of small remnants of the disease that escape detection and begin to develop later, causing the tumor to reappear. It has been found that BiCE, unlike existing treatments, is effective in preventing the development of metastases in the lungs after the primary tumor is removed. This could be proof that the antibody creates a systemic immune response against cancer throughout the body and that, after the treatment, immune cells remain that remember how to identify cancer and respond accordingly.
Yeda Research and Development, responsible for the commercialization of the intellectual property of the Weizmann Institute scientists, has filed a patent application and is working to develop an innovative treatment based on the Weizmann antibody.
“We are presenting a new approach that emphasizes a systemic view of immunotherapy,” says Dahan. “Instead of looking for a single pathway, we designed antibodies that serve as a communication platform between the immune cells we choose. This development offers hope not only for cancer patients, who need their immune systems activated to fight growth, but also for people with other diseases, such as autoimmune diseases, where patients need suppression of the immune response against their own body. There are ways to suppress the entire immune system, but our new approach should allow for the suppression or activation of a targeted immune response, without the broad and dangerous ramifications of general immune system suppression and activation.”
The effectiveness of this new treatment has been tested in various mouse cancer models, including aggressive breast, lung, and skin cancers (Illustrative Image, Infobae)
The study also involved Drs. Ran Salomon, Ken Xie, and Eitan Winter from the Weizmann Institute’s Department of Systemic Immunology; Akhiad Bercovich and Professor Amos Tanay from the Department of Computer Science and Applied Mathematics at Weizmann; Tamar Shami and Professor Neta Erez from the Tel Aviv University School of Medicine; and Dr. Ziv Porat from the Weizmann Institute’s Department of Life Sciences Core Facilities.
Professor Ido Amit holds the Eden and Steven Romick Chair. His research is supported by the Dwek Institute for Cancer Therapy Research; the Moross Integrated Cancer Center; the EKARD Institute for Cancer Diagnostics Research; the Morris Kahn Institute for Human Immunology; the Swiss Society for Cancer Prevention Research Institute; the Elsie and Marvin Dekelboum Family Foundation; the Lotte and John Hecht Memorial Foundation; and the Schwartz Reisman Collaborative Science Program.
Dr. Rony Dahan holds the Rina Gudinski Professional Development Chair. His research is supported by the Moross Integrated Cancer Center.