Introduction
Immunotherapy is a promising new field of cancer research that is generating a lot of international headlines. It is a type of cancer treatment that trains and uses a patient’s immune system to fight cancer.
So what does the immune system do? And how can it fight cancer?
The immune system is a network of cells, tissues and organs that helps protect us from infections and diseases. It keeps track of what is “normal” in our bodies and recognizes “foreign” cells or markers. When the immune system detects something out of the ordinary, it raises an alarm and sets about to destroy the invader. For example, bacteria have different markers or traits than our own cells – so when they enter the body, the immune system sees them as foreign and mounts a response to attack them and prevent infection.
Cancer cells hide from the immune system
Cancer cells are also foreign to our bodies but are harder for our immune systems to detect. Cancer cells are our own cells that have acquired genetic changes that cause them to grow and behave abnormally. Since they start off as normal cells, they are better at hiding from the immune system. Sometimes the immune system can identify cancer cells but can’t mount a strong enough response to get rid of them. In other cases, cancer cells hide by hijacking our body’s safety mechanisms.
Immunotherapy treatments help your immune system work smarter and harder. Researchers are studying new ways to help the immune system find, recognize and attack cancer cells. They are using a variety of strategies to do so (the most promising are described in this article), and some are already making big changes to the way cancer is treated.
Immune checkpoint inhibitors
Immune checkpoint inhibitors make it easier for the immune system to attack cancer cells by turning off the mechanism that cancer cells use to hide from immune cells. Molecules on the surface of cells (checkpoints) can turn an immune response on or off.
A few immune checkpoints are currently being used in cancer treatment, including the PD-1 and PD-L1 checkpoint system. PD-1 sits on the surface of immune cells (T cells) and turns off the immune system to prevent it from attacking normal cells in the body. When PD-1 attaches to another surface marker called PD-L1 (found on the surface of normal cells and some cancer cells), it signals to the immune system to leave that cell alone.
This process is important for normal cells, but cancer cells use it to avoid attack by the immune system. Checkpoint inhibitor drugs bind to these surface markers, reactivating the immune system against cancer cells.
Some checkpoint inhibitors approved by Health Canada for patient use include:
- Yervoy (CTLA-4 inhibitor) for metastatic melanoma
- Opdivo (PD-1 inhibitor) for metastatic non-small cell lung cancer
- Keytruda (PD-1 inhibitor) for both metastatic melanoma and non-small cell lung cancer
With checkpoint inhibitors showing success in treating some cancers, they are now being tested in other types.
Clinical trials and research on checkpoint inhibitors
In Canada, clinical trials are currently testing the safety, dosage and effectiveness of checkpoint inhibitors in the following cancers:
- Advanced solid tumours
- Metastatic breast cancer
- Metastatic kidney cancer
- Metastatic head and neck cancers
- Blood cancers (multiple myeloma, acute myelogenous leukemia)
- Adenocarcinoma and squamous cell carcinoma of the esophagus
- Metastatic colon cancer
- Advanced bladder cancer and cancers of the urinary tract
- Ovarian cancer and other gynecologic cancers
- Mesothelioma
- Melanoma
- Non-small cell lung cancer
- Nasopharyngeal cancer
- Prostate cancer
- Pancreatic cancer
- Sarcoma
Although checkpoint inhibitors have effectively treated patients with solid tumours, not all patients respond. Some researchers are targeting other immune checkpoints, such as TIM-3 and TIGIT, to help more patients with more types of cancer. Researchers are trying to create treatments that block these checkpoint molecules and reactivate “exhausted” T cells that no longer recognize or attack cancer cells.
Researchers are also looking for markers that predict if a patient will respond to this type of therapy. This will help doctors identify patients with the best chance of responding to checkpoint inhibitors and select the best treatment for a patient.
Finally, researchers are testing checkpoint inhibitors in combination with other cancer treatments, including immunotherapies and standard therapies. Researchers hope that these combinations will be more effective than if given alone.
Monoclonal antibodies
Monoclonal antibodies are similar to immune system proteins but are made in the lab. They are designed to search out and bind abnormal markers on the surface of cancer cells to allow the immune system to recognize them. As a cancer treatment, monoclonal antibodies may then trigger the immune system to attack and kill cancer cells.
A few different kinds of monoclonal antibodies are being tested for immunotherapy use, including naked and bispecific antibodies. Researchers are trying to figure out the best way to use these different forms in therapy.
Naked vs. bispecific antibodies
Naked monoclonal antibodies work by themselves, meaning they have no drug or radioactive material attached to them. They bind to specific markers on the surface of cancer cells. Antibodies alert the patient’s immune system to cancer cells by attaching to them and acting as a flag, attracting immune cells to attack and destroy them.
Bispecific antibodies are a combination of 2 different monoclonal antibodies, allowing them to bind to 2 different cells at the same time. One part of the antibody can be targeted to the cancer cells, and the other part can bind to immune cells (T cells). When the bispecific antibody binds both cells, it brings them together, helping the immune system attack cancer cells.
Trials for monoclonal antibodies
Clinical trials in Canada are testing the safety and effectiveness of monoclonal antibodies in:
- Metastatic solid tumours
- Childhood B-lymphocytic leukemia
- Osteosarcoma
- Breast cancer
- Prostate cancer
- Pancreatic cancer
- Ovarian and other gynecological cancers such as fallopian, cervical, endometrial and peritoneal
- Colon cancer
- Urinary tract cancer
- Neuroblastoma
- Blood cancers such as lymphoma and acute myelogenous leukemia
To make a monoclonal antibody, researchers have to identify the correct marker to attack. This can be hard to do, and so far monoclonal antibody therapies have only been successful in treating some cancers. As researchers find more markers they can link to cancer, they will be able to make more antibody therapies against more cancer types.
Immunotherapeutic vaccines
Vaccines are usually given to healthy people to prevent infection. But researchers are now using them as a cancer treatment to shrink, slow down or stop tumour growth. These vaccines use special markers on the surface of cancer cells to start an immune response in the body and cause the immune system to attack cancer cells.
Because the immune system has a “memory,” it is hoped that cancer vaccines will not only treat cancers but also prevent them from returning in the long term.
Cancer vaccines are one form of immunotherapy
Several types of cancer vaccines are being studied.
- Tumour cell vaccines are made from cancer cells removed from a patient (autologous vaccine). The cells are altered and killed in the lab in order to make the immune system recognize them and injected back into the patient. The immune system then attacks the patient’s tumour and any other cancer cells in the body. These vaccines are complex and expensive to make.
- Antigen vaccines are made for a certain type of cancer but are not made for a specific patient (allogenic vaccine). Researchers use markers (antigens) from tumour cells rather than a whole tumour cell to make this vaccine.
- Dendritic cell vaccines can also be made from a patient’s own immune cells (autologous vaccine). Dendritic cells are a type of white blood cell that fights infection by producing signals to boost the immune system and turn on a response. Doctors remove dendritic cells from a patient’s blood sample and expose them in the lab to cancer cells or markers (antigens), as well as chemicals to help them grow. They are then injected back into the body where they help the immune system (T cells) attack cancer cells.
Vaccines can be combined with adjuvants, a substance that acts like a danger signal to boost the immune response even further.
Clinical trials for cancer vaccines
Of all the vaccine treatments, dendritic cell vaccines have been most successful in treating cancer. There is one FDA-approved dendritic cell vaccine for cancer therapy. Provenge® is used to treat advanced prostate cancer that has stopped responding to hormone therapy. The vaccine does not cure prostate cancer but can extend patients’ lives by several months.
One clinical trial in Canada is testing the patient response to dendritic cell therapy in kidney cancer.
Vaccines are not yet a major type of treatment for cancer, but many are being tested in preclinical and clinical trials.
There are currently clinical trials in Canada testing the safety of cancer vaccines in:
- Gynecological cancers including ovarian, fallopian and peritoneal cancers
- Diffuse large B-cell lymphoma and other blood cancers
Researchers are looking at how to make these vaccines most effective. By combining cancer vaccines with treatments such as chemotherapy, radiation or with other immunotherapies, they hope to discover if vaccines will work better in a combination therapy.
As all cancers have unique genetic mutations, some patients may be more easily treated with cancer vaccines. Researchers are trying to identify the markers (antigens) on cancer cells that will cause a bigger immune response than others, or markers they could combine in a vaccine to increase how well it works.
Oncolytic virus therapy
Oncolytic virus therapy uses a virus designed in the lab to infect and kill cancer cells while leaving normal cells alone. The virus copies itself inside a cancer cell and eventually kills it. The viruses can also alert the immune system to attack other cancer cells.
Researchers are studying a variety of viruses, including herpes, mumps, measles and reovirus to develop new oncolytic virus therapies.
One oncolytic virus therapy is approved in the United States and Europe to treat melanoma. This viral therapy is called Imlygic and is made from a herpes virus. The herpes virus was modified to make a protein that boosts the immune system. The virus is injected directly into the tumours to target cancer cells locally.
Oncolytic viruses have potential as cancer treatment
In order to increase the effectiveness of oncolytic virus therapy, researchers are studying ways to prevent the immune system from attacking and destroying these oncolytic viruses. They are combining chemotherapy drugs that suppress the immune system with oncolytic virus therapy. Researchers are also trying to find out if coating the oncolytic virus prevents the immune system from destroying it.
Researchers are studying how a patient's immune reaction to an oncolytic virus may improve the treatment. Once the virus has passed into a cancer cell, an immune reaction may help to destroy the cancer cell.
Researchers are also trying to discover the best way to deliver oncolytic virus therapy. The approved therapy injects the virus directly into a tumour, delivering the treatment where it’s needed and reducing potential side effects. However, the location and type of tumour may make this difficult, and there may be benefits to delivering the virus through the blood so it can reach the whole body. Giving a whole body treatment is less specific but may treat patients whose cancer has spread or who have multiple tumours. There may even be a case for treating a patient both ways with an oncolytic virus.
Oncolytic virus clinical trials
Clinical trials are looking at using oncolytic virus therapy in combination with other treatments, such as chemotherapy and radiation therapy.
A first-of-its-kind clinical trial is currently underway in Canada using a combination of viruses to study whether oncolytic virus therapy is safe and effective in stimulating an immune response and killing cancer cells in advanced solid tumours.
Adoptive T-cell transfer therapy
Adoptive T-cell transfer therapy uses a person’s immune cells (T cells) to fight cancer. Researchers in the field of adoptive T-cell therapy have developed different ways to treat patients with T cells.
Researchers have found immune cells deep inside some tumours and have named them tumour-infiltrating lymphocytes (TILs). Researchers can remove T cells from a person’s tumour, determine which ones will best fight cancer and grow these specific cells in the lab. The lab-grown T cells are injected back into the person to mount an immune response and attack the tumour.
Clinical trials in T-cell therapy
There are trials in Canada testing the clinical response to TIL therapy in:
- Metastatic melanoma
- Mesothelioma
- Gynecologic cancers such as ovarian, fallopian or peritoneal cancer
Early TIL therapy studies have been promising, but the effectiveness of this treatment is limited by the ability to get TILs from patients. A tumor sample may not have enough TILs, or it cannot be surgically removed to isolate TILs. Even if a patient has enough TILs, the patient has to be well enough to wait for the T cells to grow in the lab, which can take many weeks.
Training T cells to be used in cancer treatment
Alternatively, researchers have found a new way to train immune cells to fight cancer. They can remove a person’s T cells from a blood sample and, in the lab, insert genes into the T cells to help them recognize an antigen (or foreign marker) from the person’s cancer cells.
These T cells now have a specific antigen receptor (called a chimeric antigen receptor) on their surface. When the genetically changed T cells are given back to the person, they bind to the marker on the surface of a cancer cell, which causes T cells in the body to attack and destroy it. This type of therapy is called chimeric antigen receptor T cell therapy (CAR-T).
A clinical trial in Canada is currently testing the efficacy of CAR-T-cell therapy in diffuse large B-cell lymphoma.
CAR-T therapy has shown promise in early clinical trials against some hard-to-treat forms of leukemia and lymphoma. Some patients have responded well and their cancer is no longer detected after treatment. These patients are still being followed to see if they have been cured in the long term.
However, there have been some serious side effects from this treatment due to the over-activation of the immune system. Some recent high profile studies in the US have been put on hold due to adverse patient reactions.
T-cell therapy needs more work before being used as cancer treatment
Doctors are still trying to tailor these therapies to have the greatest efficacy while reducing harmful side effects. They are studying questions that will factor in to how well the engineered T cells will be able to survive and function in the patient:
- What is the best way to engineer cells and deliver new genes to T cells?
- What are the best targets that will engage the immune system to fight the cancer?
- What is the best way to grow these cells outside of the body?
Adoptive cell transfer therapy is particularly exciting because engineered T cells only need one treatment for long-lasting response. Nearly all patients (more than 90%) with acute lymphoblastic leukemia (ALL) respond to CAR-T therapy, which is a much higher response rate than other immunotherapies. Preclinical trials have also shown that the treatments are more effective when CAR-T and checkpoint inhibitors are used in combination.
Conclusion
A tremendous amount of promising immunotherapy research is underway to discover new effective therapies against many cancers. However, much work still needs to be done to ensure these therapies are safe and effective. A main issue is that success of these therapies varies from patient to patient and cancer to cancer. This affects how drugs are approved for widespread use in Canada.
The good news is that immunotherapy can have a complete response in some patients or make cancer a stable disease with less collateral damage than traditional treatments, and researchers are sure to build on these successes.
Clinical Trial Information
The following websites have information about current cancer clinical trials:
Canadian Cancer Trials
www.canadiancancertrials.ca
(Clinical trials in all Canadian provinces)
National Cancer Institute
http://www.cancer.gov/clinicaltrials/search
(Clinical trials in Canada, United States and around the world)
If you have questions about clinical trials currently being conducted in Canada, please contact the Canadian Cancer Society's Cancer Information Service toll-free at 1 888 939-3333.
Katherine Wright, PhD
