The recent emergence of immunotherapy has marked a sea change in research and care for many forms of cancer, bringing new hope to patients and families around the world. For those who respond to treatment, the results can be dramatic.
Activation of a patient’s immune system against cancer can kill or shrink tumors and, in some cases, lead to complete remission.
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Understanding Immunotherap
Immunotherapy, also called biologic therapy, is a type of cancer treatment that boosts the body’s natural defenses to fight cancer. It uses substances made by the body or in a laboratory to improve or restore immune system function. Immunotherapy may work by:
- Stopping or slowing the growth of cancer cells
- Stopping cancer from spreading to other parts of the body
- Helping the immune system work better at destroying cancer cells
There are several types of immunotherapy, including:
- Monoclonal antibodies and tumor-agnostic therapies
- Non-specific immunotherapies
- Oncolytic virus therapy
- T-cell therapy
- Cancer vaccines
Monoclonal antibodies and tumor-agnostic therapies
When the body’s immune system detects something harmful, it produces antibodies. Antibodies are proteins that fight infection.
Monoclonal antibodies are a specific type of therapy made in a laboratory. They may be used in a variety of ways. For example, monoclonal antibodies can be used as a targeted therapy to block an abnormal protein in a cancer cell.
Monoclonal antibodies can also be used as an immunotherapy. For example, some monoclonal antibodies attach to specific proteins on cancer cells. This flags the cells so the immune system can find and destroy those cells.
Other types of antibodies work by releasing the brakes on the immune system so it can destroy cancer cells. PD-1/PD-L1 and CTLA-4 pathways are critical to the immune system’s ability to control cancer growth.
These pathways are often called immune checkpoints. Many cancers use these pathways to escape the immune system.
The immune system responds to the cancer by blocking these pathways with specific antibodies called immune checkpoint inhibitors. Once the immune system is able to find and respond to the cancer, it can stop or slow cancer growth.
The following are examples of immune checkpoint inhibitors:
- Ipilimumab (Yervoy)
- Nivolumab (Opdivo)
- Pembrolizumab (Keytruda)
- Atezolizumab (Tecentriq)
- Avelumab (Bavencio)
- Durvalumab (Imfinzi)
Clinical trials of monoclonal antibodies are ongoing for several types of cancers. While many immune checkpoint inhibitors are approved for specific cancers, some are used to treat tumors anywhere in the body by focusing on a specific genetic change.
These are called “tumor-agnostic treatments.” For example, pembrolizumab has has been approved by the FDA to treat metastatic tumors or tumors that cannot be treated with surgery.
These tumors must also have specific genetic changes called microsatellite instability-high (MSI-H) or DNA mismatch repair deficiency (dMMR).
Tumors that have MSI-H or dMMR do not repair damage to their DNA very well.
This means that they often develop many DNA mutations, or changes, in their DNA. These changes make it easier for immune cells to find and attack the tumor.
Nivolumab is a similar drug that has been approved to treat metastatic colorectal cancer with MSI-H or dMMR when chemotherapy does not work. Learn more about tumor-agnostic treatments.
The side effects of monoclonal antibody treatment depends on the purpose of the drug. For example, the side effects of monoclonal antibodies used for targeted therapy are different than those used for immunotherapy.
The side effects of immune checkpoint inhibitors may include side effects similar to an allergic reaction.
Non-specific immunotherapies
Like monoclonal antibodies, non-specific immunotherapies also help the immune system destroy cancer cells. Most non-specific immunotherapies are given after or at the same time as other cancer treatments, such as chemotherapy or radiation therapy. However, some non-specific immunotherapies are given as the main cancer treatment.
Two common non-specific immunotherapies are:
- Interferons. Interferons help the immune system fight cancer and may slow the growth of cancer cells. A type of interferon made in a laboratory is called interferon alpha (Roferon-A [2a], Intron A [2b], Alferon [2a]). This is the most common type of interferon used in cancer treatment. Side effects of interferon treatment may include flu-like symptoms, an increased risk of infection, rashes, and thinning hair.
- Interleukins. Interleukins help the immune system produce cells that destroy cancer. An interleukin made in a laboratory is called interleukin-2, IL-2, or aldesleukin (Proleukin). It is used to treat kidney cancer and skin cancer, including melanoma. Common side effects of IL-2 treatment include weight gain and low blood pressure. Some people may also experience flu-like symptoms.
Oncolytic virus therapy
Oncolytic virus therapy uses genetically modified viruses to kill cancer cells. First, the doctor injects a virus into the tumor.
The virus then enters the cancer cells and makes copies of itself. As a result, the cells burst and die.
As the cells die, they release specific substances called antigens. This triggers the patient’s immune system to target all the cancer cells in the body that have those same antigens. The virus does not enter healthy cells.
In 2015, the U.S. Food and Drug Administration approved the first oncolytic virus therapy to treat melanoma.
The virus used in the treatment is called talimogene laherparepvec (Imlygic), or T-VEC. The virus is a genetically modified version of the herpes simplex virus that causes cold sores.
The doctor can inject T-VEC directly into areas of melanoma that a surgeon cannot remove. People receive a series of injections until there are no areas of melanoma left. Side effects can include:
- Fatigue
- Fever
- Chills
- Nausea
- Flu-like symptoms
- Pain at the injection site
Researchers are testing other oncolytic viruses for different types of cancer in clinical trials. They are also testing the viruses in combination with other treatments, such as chemotherapy.
T-cell therapy
T cells are immune cells that fight infection. In T-cell therapy, some T cells are removed from a patient’s blood.
Then, the cells are changed in a laboratory so they have specific proteins called receptors. The receptors allow those T cells to recognize the cancer cells.
The changed T cells are grown in the laboratory and returned to the patient’s body. Once there, they seek out and destroy cancer cells.
This type of therapy is called chimeric antigen receptor (CAR) T-cell therapy.
The use of T cells for CAR therapy has been very effective in treating certain blood cancers. Researchers are still studying this and other ways of modifying T cells to treat cancer.
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Despite significant advances, only a minority of individuals benefit from immunotherapy, and the reasons why remain unclear.
Immunotherapy research has largely centered on T-cells, a type of immune cell that learns to recognize specific proteins and launch an attack.
Tumors, however, are a complex mixture of many different cell types, including other immune cells known collectively as tumor-infiltrating myeloid cells.
These cells represent alternative targets for immunotherapy, but their role in tumors is still poorly understood.
To shed light on this under-examined family of immune cells, Harvard Medical School researchers based at the Blavatnik Institute, Massachusetts General Hospital, Beth Israel Deaconess Medical Center and Brigham and Women’s Hospital used single-cell sequencing to map the landscape of myeloid cells in tumors from patients with lung cancer.
Their study, published online in Immunity on April 9, reveals 25 myeloid cell subpopulations, many previously undescribed, with distinct gene expression signatures that are consistent across patients.
Most of these subpopulations were also identified in a mouse model of lung cancer, indicating a high degree of similarity in myeloid cells across species.
The findings serve as a foundation for future research to explain the precise roles of myeloid cells in cancer and to assess their potential as targets for new or improved immunotherapies, the authors said.
“Immunotherapy is clearly a transformational approach to cancer treatment, but there are many patients who don’t respond, and the question is why,” said co-corresponding author Allon Klein, assistant professor of systems biology at HMS.
“Part of the answer could certainly lie at the level of myeloid cells, which interact heavily with both tumor cells and T-cells,” Klein continued.
“By identifying the rich complexity of myeloid cell states in tumors, we now have a powerful starting point to better understand their functions and clinical applications.”
Of particular importance, the authors said, was the finding that myeloid subpopulations can be reliably identified in different human patients and in mice – an observation that underscores the fundamental use of mouse models in immunotherapy research.
“Tumor cells were different in each patient analyzed, but the identity of tumor-infiltrating myeloid cells greatly overlapped between the same patients.
Also, many myeloid populations were incredibly well conserved across patients and mice,” said co-corresponding author Mikael Pittet, HMS associate professor of radiology at Mass General.
“This is exciting because a growing body of evidence based on mouse studies suggests that myeloid cells can control cancer progression and affect virtually all types of cancer therapy, including immunotherapy” Pittet added.
Consistent complexity
Myeloid cells – comprised of immune cells including monocytes, macrophages, dendritic cells and granulocytes – are part of the innate immune system, the body’s first and broad line of defense against foreign pathogens.
They play an important role in activating the adaptive immune system, including T-cells, which can precisely target and destroy pathogens.
To better understand the diversity of myeloid cells in tumors, Pittet teamed with Klein, who led the development of InDrops, a key technique for single-cell gene expression analysis.
In the current study, Pittet, Klein and colleagues applied this technique to tumors from a small group of patients and mice with non-small cell lung cancer. In total, they collected gene expression data from more than 56,000 individual cells, one cell at a time.
Their analyses revealed myeloid cell gene expression signatures that fell into 25 distinct clusters, greatly expanding the number of known myeloid cell states.
They found that dendritic cells, for example – which Pittet and colleagues previously found are critical to successful anti-PD-1 immunotherapy in mice – contained four different subtypes that are largely mirrored between humans and mice.
Monocyte subtypes also matched well between humans and mice, while macrophages were both conserved and varied by species.
Neutrophils, which are the most abundant white blood cells in mammals, formed a spectrum of five similar subtypes in humans and mice, with one subset unique to mice. Pittet, in a previous collaboration with Klein, found that neutrophils expressing high levels of the gene Siglecf have tumor-promoting properties.
The new analyses corroborated this finding, showing that these neutrophils are highly enriched in tumors.
“Myeloid cell populations are complex, but we see the same complexity across patients and species, which gives us confidence that insights in mouse models can be translated to humans,” said Pittet, who is director of the Cancer Immunology Program in the Mass General Center for Systems Biology.
“Now that we have this granular landscape, we can better design studies to assess the role of unique subpopulations in tumor progression and look for ways to manipulate specific cells in the hopes of making immunotherapies more effective,” Pittet added.
For example, with the landscape of myeloid cell gene-expression patterns mapped, scientists can mine existing datasets of patients with known clinical outcomes to look for the presence of a given population of myeloid cells and assess their relationship with patient survival.
Klein, Pittet and colleagues examined the feasibility of this approach in their study and found promising candidates but will need larger patient sample sizes to draw conclusive results.
For this effort they teamed with Raphael Bueno, HMS professor of surgery at Brigham and Women’s, and Elena Levantini, HMS instructor in medicine at Beth Israel Deaconess, who were studying patient survival-associated factors in lung cancer specimens.
“Lung cancer remains a common lethal malignancy in the U.S., and this important collaborative effort provides new clues and directions in the development of personalized therapies for patients with lung cancer and no other good therapeutic options,” said Bueno, who is chief of the Division of Thoracic Surgery and the Fredric G. Levin Distinguished Chair in Thoracic Surgery and Lung Cancer Research at Brigham and Women’s.
The team also looked at whether the behavior of myeloid cells in tumors could be gleaned by sampling myeloid cells circulating in blood and found a poor relationship between the two.
In addition to immediate basic and translational research opportunities, the study findings inform the work of initiatives such as the Human Tumor Atlas, an effort to map the landscape of all cell types in the human body, and the Human Tumor Atlas Network, an effort to create atlases of a wide variety of cancer types in cellular and molecular detail.
“This work fits into a single-cell revolution that’s happening in many areas of biomedicine, particularly in immunology,” Klein said. “
To improve immunotherapies, we need to know as much as we can about the cells and processes involved. This requires a true team effort, and our study couldn’t have been possible without fantastic collaborations across the medical school.”
More information: Rapolas Zilionis et al, Single-Cell Transcriptomics of Human and Mouse Lung Cancers Reveals Conserved Myeloid Populations across Individuals and Species, Immunity (2019). DOI: 10.1016/j.immuni.2019.03.009
Provided by Harvard Medical School
