Scientists discover potential new target for cancer immunotherapy
Scientists have found a way to target elusive cells that suppress immune response, depleting them with peptides that spare other important cells and shrink tumors in preclinical experiments, according to a paper published online by Nature Medicine.
“We’ve known about these cells blocking immune response for a decade, but haven’t been able to shut them down for lack of an identified target,” said the paper’s senior author, Larry Kwak, M.D., Ph.D., chair of Lymphoma/Myeloma and director of the Center for Cancer Immunology Research at The University of Texas MD Anderson Cancer Center.
The cells, called myeloid-derived suppressor cells (MDSCs), are found abundantly in the microenvironment around tumors. Created with other blood cells in the bone marrow, they interfere with activation and proliferation of T cells, the immune system’s attack cells. MDSCs have been shown in mouse models to accelerate cancer progression and metastasis.
“This is the first demonstration of a molecule on these cells that allows us to make an antibody, in this case a peptide, to bind to them and get rid of them,” Kwak said. “It’s a brand new immunotherapy target.”
Kwak has developed anti-cancer therapeutic vaccines to spark an immune system attack against tumors, but their effectiveness has been hindered by factors such as MDSCs that stifle immune response. “The key to taking cancer vaccines to another level is combining them with immunotherapies that target the tumor microenvironment,” Kwak said.
Antibodies only bind to target cells
Peptide antibodies developed by Kwak and co-discoverer, Hong Qin, Ph.D., assistant professor of Lymphoma/Myeloma, wipe out MDSCs in the blood, spleen and tumor cells of mice without binding to other white blood cells or dendritic cells involved in immune response.
What is Immunotherapy?
This section has been reviewed and approved by the Cancer.Net Editorial Board, 3/2013
Immunotherapy (also called biologic therapy or biotherapy) is a type of cancer treatment designed to boost the body’s natural defenses to fight the cancer. It uses materials either made by the body or in a laboratory to improve, target, or restore immune system function. Although it is not entirely clear how immunotherapy treats cancer, it may work by stopping or slowing the growth of cancer cells, stopping cancer from spreading to other parts of the body, or helping the immune system increase its effectiveness at eliminating cancer cells.
There are several types of immunotherapy, including monoclonal antibodies, non-specific immunotherapies, and cancer vaccines.
When the body’s immune system detects antigens (harmful substances, such as bacteria, viruses, fungi, or parasites), it produces antibodies (proteins that fight infection). Monoclonal antibodies are made in a laboratory, and when they are given to patients, they act like the antibodies the body produces naturally. Monoclonal antibodies are given intravenously (through a vein) and work by targeting specific proteins on the surface of cancer cells or cells that support the growth of cancer cells. When monoclonal antibodies attach to a cancer cell, they may accomplish the following goals:
Allow the immune system to destroy the cancer cell. The immune system doesn’t always recognize cancer cells as being harmful. To make it easier for the immune system to find and destroy cancer cells, a monoclonal antibody can mark or tag them by attaching to specific parts of cancer cells that are not found on healthy cells.
Prevent cancer cells from growing rapidly. Chemicals in the body called growth factors attach to receptors on the surface of cells and send signals that tell the cells to grow. Some cancer cells make extra copies of the growth factor receptor, which makes the cancer cells grow faster than normal cells. Monoclonal antibodies can block these receptors and prevent the growth signal from getting through.
Deliver radiation directly to cancer cells. This treatment, called radioimmunotherapy, uses monoclonal antibodies to deliver radiation directly to cancer cells. By attaching radioactive molecules to monoclonal antibodies in a laboratory, they can deliver low doses of radiation specifically to the tumor while leaving healthy cells alone. Examples of these radioactive molecules include ibritumomab tiuxetan (Zevalin) and tositumomab (Bexxar).
“That’s really exciting because it’s so specific for MDSCs that we would expect few, if any, side effects,” Kwak said. The team is working to develop the same target for use in humans.
With no candidate targets, the team took an objective approach by applying a peptide phage library to MDSCs, which permitted mass screening for candidate peptides - short sequences of amino acids - that bind to the surface of the MDSCs.
Peptide phage gathered from the MDSCs were expanded, enriched and then sequenced to identify predominant peptides. The team found two, labeled G3 and H6, that bound only to MDSCs; other candidates were eliminated because they also tied in to other types of cell.
They fused the two peptides to a portion of mouse immune globulin to generate experimental “peptibodies.” Both peptibodies bound to both types of MDSC - monocytic white blood cells, which engulf large foreign bodies or cell debris, and granulocytic white cells loaded with tiny granules.
The researchers treated mice with two types of thymus tumor with each peptibody, a control peptibody and an antibody against Gr-1. The G3 and H6 peptibodies depleted both types of MDSC in the blood and spleens of mice in both tumor models, while the Gr-1 antibody only worked against granulocytic MDSC.
Both peptibodies also wiped out the MDSCs in both types of thymic tumor and in the blood and spleen of mice with lymphoma.
Shrinking tumors, identifying alarmins
To see whether MDSC depletion would impede tumor growth, they treated mice with thymic tumors with the peptides every other day for two weeks. Mice treated with either pep-G3 or pep-H6 had tumors that were about half the size and weight of those in mice treated with controls or the Gr-1 antibody.
IMMUNOTHERAPY IS ONE OF THE MOST RECENT ADVANCES IN CANCER THERAPY
Radiation, chemotherapy, and surgery are the traditional tools in the fight against cancer. Radiation was discovered in the 1800’s by Marie Curie. Chemotherapy evolved from mustard gas (World War 1), and surgery dates back to the ancient Egyptians.
These treatment modalities are all based on destroying cancer cells by burning them (irradiation), poisoning them (chemotherapy) or removing them (surgery). While they can effectively kill or remove cancer cells, the use of these treatments often is limited because large numbers of healthy cells also tend to be destroyed. This often results in extreme morbidity and/or disfigurement of the patients treated with them. In the worst cases, these treatments can sometimes result in the patient’s death.
To date, there is no “magic bullet” in the treatment of cancer, and because of the complexity of cancer biology, it will likely not be attainable. It is now generally agreed that the future of cancer therapy lies in the combination of therapies with different mechanisms of action.
Immunotherapy is one of the more recent approaches to cancer therapy. It is based on the generally-accepted hypothesis that the immune system is the best tool humans have for fighting disease.
Immunotherapies have the potential to be used to fight cancer by either applying an external stimulus to the immune system to make it act more ‘forcefully’ or ‘smarter’, or by providing the immune system with man-made or naturally-derived tumor specific proteins made outside of the body so that the immune system can recognize the tumor as a foreign entity and destroy it.
Immunotherapy is sometimes used by itself to treat cancer, but it is most often used in combination with traditional treatments like radiation, chemotherapy, and surgery in order to enhance their effects. One of the possible benefits of immunotherapy is that it has the potential not to be as toxic as radiation, chemotherapy, and surgery. In addition, immunotherapy often may offer a different mode of attack on the tumor, thereby affording both patients and doctors alike a potential new treatment in the fight against cancer.
Analysis of surface proteins on the MDSCs identified S100A9 and S100A8 as the likely binding targets for the two peptibodies. They’re members of the S100 family of proteins, called alarmins, which are released outside the cell as a danger signal in response to inflammation.
MDSCs’ mechanisms for blocking immune response are not well-characterized because they’ve been hard to study for lack of a targeting method, Kwak said.
Kwak and colleagues are working to extend their findings to human MDSCs.
A new class of drugs called immune checkpoint inhibitors block molecules on T cells that shut down immune response, freeing the immune system to attack tumors. The first of these drugs, ipilimumab (Yervoy®) was approved by federal regulators to treat advanced melanoma. It’s the only drug ever to lengthen survival for those patients. Additional immune checkpoint inhibitors are under development.
“Immune checkpoint blockade is great,” Kwak said. “There have been dramatic response rates, but those drugs also have side effects. Targeting MDSCs could provide an additional way to unleash the immune system.”
Co-authors with Kwak and first author Qin are Beatrisa Lerman, Ippei Sakamaki, M.D., Ph.D., Guowei Wei, Ph.D., Soungchul Cha, Ph.D., Sheetal Rao, Jianfei Qian, Ph.D., and Qing Yi, M.D., Ph.D., all of Lymphoma/Melanoma; Yared Hailemichael, Ph.D., and Willem Overwijk, Ph.D., of Melanoma Medical Oncology; Roza Nurieva, Ph.D., of Immunology; and Karen Dwyer, Ph.D., and Johannes Roth, Ph.D., of Stem Cell Transplantation and Cellular Therapy; all are associated with the Center for Cancer Immunology Research.
Lerman is a graduate student in The University of Texas Graduate School of Biomedical Sciences, a joint program of MD Anderson and The University of Texas Health Science Center at Houston.
Funding for this research was provided by MD Anderson’s Specialized Program in Research Excellence in Lymphoma from the National Cancer Institute of the National Institutes of Health (P50 CA136411).
About MD Anderson
The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 41 comprehensive cancer centers designated by the National Cancer Institute (NCI). For ten of the past 12 years, including 2013, MD Anderson has ranked No. 1 in cancer care in “Best Hospitals,” a survey published annually in U.S. News & World Report. MD Anderson receives a cancer center support grant from the NCI of the National Institutes of Health (P30 CA016672).
University of Texas M. D. Anderson Cancer Center
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