Last updated: July 2021

Immunotherapy is a treatment or intervention designed to help the body’s immune system fight cancer. It does not directly attack cancer cells but focuses instead on helping other cells - called immune cells - detect and destroy cancer cells.

A definition of immunotherapy

Immunotherapy was first used as a cancer treatment about a century ago. A few early studies revealed that deliberately infecting certain cancer patients stimulated their immune system and positively impacted their cancer. As science progressed and effective and accessible treatments such as chemotherapy and radiotherapy were developed, immunotherapy was temporarily shelved. The first trials aimed at prompting the immune system to act on cancer tumours were performed in the 1950s, after which came immune system interventions such as bone marrow transplants.

Immune system stimulation as a means of destroying cancer tumours was thrust into the spotlight in the early 2000s, and quickly proved a promising avenue for scientific research.

Immunotherapy is now on the verge of becoming one of the cornerstones of modern-day oncology, with various parties speaking of advanced immunotherapy and personalized or precision medicine. But to better grasp the role of immunotherapy in an oncology setting, we need to first understand the workings of the human immune system.

The immune system, designed to keep the human body as protected and healthy as possible, consists of cells, tissues and organs that detect, control and kill organisms or cells that can trigger diseases[i]. These can be foreign pathogens, such as bacteria or viruses, or abnormal cells (think cancer cells) before they develop and become harmful.

When the human body is exposed to foreign or abnormal pathogens, the normal immune response presents as:
  • the detection of potentially dangerous pathogens (bacteria, viruses, abnormal cells);
  • the activation of cellular defence systems and antibodies;
  • the attack of the pathogens or abnormal cells;
  • the end of the attack once the threat has been eliminated.
The immune system acts in two very distinct ways.

1. Through innate or natural immunity

This is the immediate action, the body’s first line of defence against infection or disease. The reaction is quick but does not specifically target the attacking pathogen.

2. Through adaptive or specific immunity

The response in this case is slower, but more targeted or specific. The immune response occurs when the body is exposed to certain pathogens or diseases, and while it does not occur immediately, it is increasingly tailored to the infectious agents in question. When confronted by a virus or bacteria, or in the presence of abnormal cells, the immune system generates antibodies that bind to the proteins on the surface of the abnormal cells. These proteins are called antigens, and their detection is what triggers immune defence mechanisms and prompts them to reject or destroy foreign or abnormal cells. This type of adaptive immune response prompts a parallel response called an immunological memory, which allows for a more rapid and forceful reaction if the same infectious agent is encountered at a later date.

The immune system agents with the most important role in the immune response are B lymphocytes (also called B cells) and T lymphocytes (or T cells); they work together to destroy abnormal pathogens or cancer cells. B lymphocytes produce specific antibodies while T lymphocytes have the ability to eradicate abnormal or cancer cells. These lymphocytes are produced in the bone marrow.

Despite this impressive defence system, cancer cells are wily and will sometimes successfully avoid being identified as abnormal cells. When this occurs, they can grow and spread without being hindered or destroyed by the body’s defence mechanisms.
 

Face off between the immune system and cancer cells

Numerous cancers are avoided thanks to the monitoring and destruction of abnormal cells by the immune system, all of it invisible to the human host. Cancer cells are a derivative of normal cells, in other words, cells that developed several anomalies when they multiplied and were ultimately transformed. Scientists know that this transformation process can have several causes but have yet to identify a common reason for this mutation.

When the process begins and remains unchecked by the body’s immune system, abnormal cells gradually morph into cancer cells. These transformed cells no longer fulfill their original functions and begin to develop their own defence, feeding and spreading mechanisms.

Cancer cells can thus develop a resistance to the body’s own immune system and devise ways of hiding. For example:
  • They decrease the expression of tumour antigens (proteins located on the surface of cancer cells) in order to camouflage their identify and trick the immune system by hindering its ability to easily identify abnormal cells.
  • They develop a protein barrier on their surface which allows for deactivating the immune system.
  • They cause other nearby cells to produce substances that counteract the activity of the immune system.
Different methods have, over the last several years, been developed to successfully “cure” cancer. Among the most notable of these are surgery, chemotherapy and radiotherapy.

Immunotherapy in oncology is not a substitute but rather, a complement for other treatments. Unlike the treatments that act on the growth and proliferation of cancer cells, immunotherapy in oncology affects natural anticancer immunity action by stimulating its ability to eradicate cancer cells.

[i] These organisms or cells are called pathogens.
Immunotherapy is essentially a treatment that allows the body’s cells to more effectively fight off cancer cells. Because cancer calls sometimes manage to trick the immune system’s cells, immunotherapy interventions seek to either boost the immune system or reprogram it to flush out and destroy cancer cells.
 

Immunotherapy goals

The goals of immunotherapy are to:
  • provoke an immune reaction that targets cancer cells without harming healthy tissue;
  • generate an immunological memory that will prevent remaining tumour cells, i.e., cells that were not destroyed during the first treatment, from further developing;
  • prevent metastasis.
Immunotherapy can be specific or non-specific, active or passive

1. Specific immunotherapy

The goal of specific immunotherapy is to achieve an increasingly targeted response through the use of antibodies specific for the tumour antigen that make it possible to generate an active or passive immunity.

2.  Non-specific immunotherapy

As alluded to by its name, non-specific immunotherapy acts on the entire immune system rather than solely targeting cancer cells. It is hoped that this will allow for efficiently attacking abnormal cells. The oldest form of immunotherapy, non-specific immunotherapy relies, among other things, on a family of molecules produced by the human body, the cytokines[i] (substances involved in cell-to-cell communication). These molecules, which play a key role in the immune response, can be manufactured in a laboratory and be used to treat certain types of cancer.

3. Active immunotherapy

Active immunotherapy directly stimulates the immune system to provoke a specific immune response to cancer. Examples of this include therapeutic vaccination and new specific immunotherapies such as checkpoint inhibitor therapy and CAR T-cell therapy.

4. Passive immunotherapy

Passive immunotherapy rests on the principle of reinforcing the existing immune response through the use of laboratory-produced substances to mimic several aspects of the immune system and attack specific cells. For example, cytokines and monoclonal antibodies manufactured in a laboratory setting are often used in passive immunotherapy treatments.

[i] Substances involved in cell-to-cell communication.

1. Alpha interferon (Intron-A, Wellferon)

Interferon is a cytokine secreted by the body. Alpha interferon is manufactured in a laboratory and can be used to treat cancers, among them therapy-resistant chronic myeloid leukemia (CML) and melanoma. It is also used in people who cannot tolerate other treatments. With the discovery of other immunotherapy treatments in oncology, alpha interferon is now practically never used in cases of melanoma.
 

2. Interleukin-2 (Proleukin)

Interleukin is another type of cytokine secreted by the body which is also manufactured in a laboratory setting. It is sometimes administered intravenously to treat advanced kidney cancer or given by intralesional administration (directly into the tumour) when treating certain advanced melanomas that generate lesions on the skin or in the subcutaneous tissue.
 

3. Intravesical therapy for bladder cancer (Bacillus Calmette-Guérin or BCG)

BCG is a bacteria transformed in the laboratory to ensure that it cannot trigger any disease. Its use results in a bladder inflammation that triggers the immune system to attack and destroy cancer cells. This therapy is administered inside the bladder (intravesical) at regular intervals to address certain superficial bladder cancers.

4. Checkpoint inhibitor therapies

Checkpoint inhibitor therapies2 are the medications most often used in cancer immunotherapy. When required, the immune system can destroy viruses, bacteria and cells (like cancer cells), but it must first determine whether a cell is foreign (virus or bacteria), abnormal (precancer or cancer) or normal; this is done through a surveillance process ensured by immune checkpoints that stop the immune system from erroneously setting its sights on healthy normal cells. Unfortunately, cancer cells have the ability to trick the immune system by deactivating immune cells, particularly T lymphocytes.

Checkpoint inhibitors are medications that successfully target specific checkpoints and stop them from working. In other words, they prevent these checkpoints from blocking certain actions, which promotes a heightened immune response of the body against cancer cells.

The medications used as checkpoint inhibitor therapy are monoclonal antibodies. Developed in a laboratory setting, they are variants of immune system proteins called antibodies. The manner in which these medications act on immune checkpoints is a fine example of cutting-edge technology in the realm of immunotherapy in oncology.

The checkpoint inhibitor therapies most commonly used are:
  • anti-CTLA-4 therapies, which block the CTLA-4 protein that prevents the immune system’s activation;
  • anti-PD-1 (or anti-programmed cell death protein 1), which block the PD-1 protein, an immune checkpoint that prevents T lymphocytes from attacking other cells;
  • anti-PD-L1 (or anti-programmed cell death ligand 1), which block the ligand (a link on a cell) to which the PD-1 protein attaches. Anti-PD-1 and anti-PD-L1 therapies strengthen the attack and destruction of cancer cells.
They are used to treat, among other things, melanoma, lung cancer, kidney cancer, Hodgkin’s lymphoma, bladder cancer, liver cancer, epidermoid cancer and some head and neck cancers. These will be described in greater detail in the sections on the primary cancers treated by immunotherapy. Clinical trials are also underway on the use of these medications to treat other cancers.

Main medications available:
  • Nivolumab (Opdivo) (anti-PD-1)
  • Pembrolizumab (Keytruda) (anti-PD-1)
  • Atezolizumab (Tecentriq) (anti-PD-L1)
  • Durvalumab (Imfinzi) (anti-PD-L1)
  • Avelumab (Bavencio) (anti-PD-L1)
  • Ipilimumab (Yervoy) (anti-CTLA-4)
  • Cemiplimab (Libtayo) (anti-PD-L1)
This type of immunotherapy, based on checkpoint inhibitors, greatly reduces the body’s natural defences that prevent an exaggerated activation of the immune system. This creates the risk that normal cells will be affected and autoimmune responses triggered. The possible side effects are thus distinct from those resulting from chemotherapy and require stricter clinical monitoring.
 

5. Bispecific antibodies

Consisting of both immunotherapy and targeted therapy, bispecific antibodies activate the immune system so that it can destroy cancer cells. These antibodies are deemed “bispecific” because they can bind to two different types of cells: cancer cells and T lymphocytes, which are immune cells. The antibodies, by fostering the linking of these two types of cells, make it easier for T lymphocytes to eradicate cancer cells. At the time this document was drafted, only one medication in this category had been approved: Blinatumomab (Blincyto) (monoclonal antibody anti-CD-19/3), used to treat cases of acute lymphoblastic leukemia (ALL) referred to as relapsed (returning) or unresponsive (that does not respond well to other treatments). Several other molecules are currently being tested in clinical trials.
 

6. Cellular therapy: adoptive transfer of cells or CAR T-cell therapy

This innovative and continually evolving treatment revolves around T lymphocytes, which are a type of white blood cell and a main component of the immune system. T lymphocytes fight infections and seek to eliminate abnormal cells, including cancer cells.

T lymphocytes are first obtained from the patient’s blood, then transformed in the laboratory by binding chimeric antigen receptors (CAR) to their surface. These receptors enable the modified cells, called CAR T-cells, to detect the specific antigen (protein) expressed by the cancer to be treated. Once modified, these cells are grown in a laboratory until they multiply into the millions. They are then readministered intravenously so that they can continue to grow and, through their receptors, detect, attack and destroy cancer cells.

Since 2019, CAR T-cell therapy is offered in Québec to treat acute lymphoblastic leukemia (ALL) in children and young adults, as well as unresponsive diffuse large B cell non-Hodgkin’s lymphoma (NHL) in adults.

Numerous clinical trials are also underway to develop other therapies using this identical technique to eventually treat other types of cancers.

7.  Therapeutic vaccination against cancer

Many major research projects are currently investigating this specific type of therapy. To date, only one therapeutic vaccine, Provenge3, has been authorized in the United States as a treatment for advanced prostatic cancer. Provenge3 was not yet available in Canada at the time of writing this document.

When we consider the matter of vaccination, we usually think of a preventive measure to protect people from disease or infection (e.g., the flu). In oncology, the HPV vaccine offers protection against cervical cancer and other cancers linked to the human papillomavirus. Oncology research also focuses on developing vaccines to treat cancer. Such therapeutic vaccines do not seek to prevent cancers, as do preventive vaccines, but are produced as a treatment option for existing cancers.

The objective of this therapy is to stimulate the immune system so that it focuses specifically on cancer cells. Its goals are to:
  • prepare the immune system to detect cancer cells;
  • increase the number of immune cells able to detect cancer cells;
  • stimulate immune cells so that they can eliminate cancer cells;
  • prevent the recurrence of cancer.
​Various types of therapeutic vaccines are currently being developed or undergoing clinical trials. Depending on the type of cancer targeted, these vaccines can be developed from different materials, for example, cancer cells, cell fragments, antigens or even immune cells. These vaccines must have the ability to provoke an immune response as faithfully and efficiently as possible so as to counter the tricks used by cancer cells to defy the body’s immune system.

What treatments are best for what types of cancer?

Immunotherapy, a fast-moving research sector, covers various treatments, either for a single type of cancer or for different cancers. It is thus important to avoid comparing one person’s treatment protocol with that of another, for every therapy is designed on the basis of the specific characteristics of given cancer cells. Immunotherapy is for this reason considered personalized medicine.

All treatment options in oncology, including immunotherapy, are assessed by a multidisciplinary team to arrive at the best treatment plan. The final decision as to which approach to adopt is taken with the patient’s input, after he has been given information on the expected benefits, side effects and risks of the various options.
 

Immunotherapy administration

Immunotherapy can be conducted in a number of ways:
  • Subcutaneously (under the skin)
  • Intravenously (in a vein)
  • By intralesion (directly in the tumour) (interleukin-2)
  • With eye drops (alpha interferon)
  • Through the bladder (BCG)
The majority of new-generation immunotherapy medications are administered through an IV (intravenous) infusion lasting anywhere from 30 to 60 minutes. Medications are administered every 2, 3 or 4 weeks, and many of them can be given at an outpatient chemotherapy clinic. Some, however, will require that the patient be hospitalized and closely monitored. Treatments, moreover, are given according to a previously established administration protocol tailored to the patient, and the protocol’s treatment sessions are referred to as “cycles”, with each cycle including the administration time and a recovery period. Immunotherapy can be given on its own or be combined with another type of immunotherapy or alternative treatments such as chemotherapy, targeted therapies or radiotherapy.

The oncology treatment team closely monitors a patient’s reaction to treatment along with any negative side effects. Precautions are taken when conducting this follow-up: the oncologist visits the patient on a regular basis and bloodwork is done prior to every treatment (to measure various parameters such as hemoglobin level or white blood cell count). Treatment must sometimes be postponed, depending on bloodwork findings or if a patient suffers too many side effects at some point. Should a patient prove highly intolerant, the treatment may be stopped temporarily or definitively; it can also be replaced by another type of therapy.

Exams such as a CT scan (CT, CAT scan, scanner, MRI) are regularly prescribed during therapy, as they allow for verifying the effectiveness of the treatment as well as any symptoms or negative side effects.

A meeting is usually held with an oncology pharmacist prior to the onset of treatment. This practitioner will prepare a report of the patient’s current medications, including any natural products being taken. The patient may be asked to stop taking natural products during cancer treatments, as they can negatively impact the therapy’s effectiveness. The pharmacist will also provide clear instructions on the use of various products as needed.

Immunotherapy is not an option for pregnant women, as there are too few studies in this regard.

Sexually active patients are urged to use a contraceptive method during the entire duration of the treatment and for a further 5 months after the therapy is completed. Breastfeeding is also frowned upon during treatment. Patients can, however, continue enjoying an active sex life.
With the recent development of numerous immunotherapies, among them checkpoint inhibitors, several types of cancer are now being treated with immunotherapy as part of the trajectory of care.

Immunotherapy in oncology is a fast-moving research sector. Other types of immunotherapy medication, as well as other cancers, could soon reap the benefits of discoveries in this field[i].

The primary cancers treated by immunotherapy in Québec are:
  • melanoma
  • non-small cell lung cancer 
  • kidney cancer
  • bladder cancer
  • Hodgkin’s lymphoma
  • head and neck cancer
  • hepatocellular carcinoma (liver) 
  • epidermoid cancer 
  • acute lymphoblastic leukemia (see point 5 in the section "Types of medication or immunotherapy treatments in oncology" in Immunotherapy)
  • diffuse large B cell non-Hodgkin’s lymphoma (see point 6 in the section "Types of medication or immunotherapy treatments in oncology" in Immunotherapy)


Immunotherapy to fight melanoma

Melanoma, also known as malignant melanoma, is a cancer of the skin that occurs through the melanocytes, the cells that produce skin pigments and are responsible for skin colour. A melanoma can manifest itself on normal skin, in a beauty mark, in the mucous membranes or in the eye.

There are different types of melanomas, with the most frequent ones being:
  • Superficial spreading melanoma (SSM): this type of melanoma accounts for 70% of all melanoma cases and most often appears on the legs in women and around the chest in men. The associated tumour cells habitually present with BRAF gene mutations (BRAF is a gene that produces a protein active in cell growth and division).
  • Nodular melanoma: this type of melanoma accounts for 15 to 30% of all melanoma cases, and can present just about anywhere on the body. It is a very fast-growing cancer.
Melanomas are some of the cancers that respond the best to immunotherapy.

Since around 2010, clinical research has allowed for discovering various immunotherapy and targeted therapy medications that have changed the treatment landscape for advanced or metastatic melanomas.

This being said, surgery is still the primary treatment in cases of melanoma, and has the advantage of allowing practitioners to determine the stage of the cancer.

Immunotherapy treatments are indicated for treating stage IIb, III and IV melanomas. Immunotherapy can be administered on its own or by combining two immunotherapy medications. Based on the choice of treatment (a single therapy or a combination of two), between 40 and 50% of patients who undergo immunotherapy respond positively to treatment.

This treatment also prolongs life expectancy and for some patients, represents a full remission. These patients are prescribed an adjuvant treatment (following surgery) to address advanced or metastatic melanomas (stage III or IV).

The following immunotherapy medications are used in cases of melanoma:
  • Alpha interferon (Intron-A) (rarely)
  • Interleukin-2 (intralesion)
  • Nivolumab (Opdivo)
  • Pembrolizumab (Keytruda)
  • Ipilimumab (Yervoy)
All of them can be given as a monotherapy (i.e., therapy consisting of a single medication). Nivolumab and Ipilimumab can also be administered together, as a combined treatment. The treatment can last anywhere from a few months to several years.


Immunotherapy for non-small cell lung cancer

Lung cancer manifests itself in various forms. The most frequent forms encountered are non-small cell lung cancer and small cell lung cancer. The terms “non-small cell” and “small cell” refer, among other things, to the difference in cancer cells when examined under a microscope. Non-small cell lung cancer is the most common type (80 to 85% of lung cancer diagnoses are cases of non-small cell lung cancer).

Immunotherapy treatments are indicated for inoperable stage III or metastatic stage IV non-small cell lung cancer.

The immunotherapy medications used to treat non-small cell lung cancer are the following checkpoint inhibitors:
  • Durvalumab (Imfinzi)
  • Atezolizumab (Tecentriq)
  • Nivolumab (Opdivo)
  • Pembrolizumab (Keytruda)
Durvalumab is indicated when monotherapy (one medication only) is used to treat inoperable stage III non-small cell lung cancer after a combination of chemotherapy and radiotherapy has been attempted. Nivolumab, Pembrolizumab and Atezolizumab are used in the palliative phase of stage IV or metastatic non-small cell lung cancer; these can be administered alone or in combination with chemotherapy.
 

Immunotherapy for kidney cancer

There are different types of kidney cancers, the one most frequently encountered being renal cell carcinoma with clear cell morphology (which accounts for over 80% of all kidney cancers). This is a silent cancer with few specific symptoms and which is often diagnosed in its later stages. If discovered early on, however, it can usually be treated with surgery, which entails removing all or part of the kidney. While there used to be very few effective treatments for advanced or metastatic cancers, treating advanced kidney cancers was revolutionized a few years ago by the use of targeted therapies. Immunotherapy was also recently added to the available therapeutic options. These two treatments (targeted therapy and immunotherapy) are indicated for treating advanced or metastatic cancers, i.e., stage III or IV.

Recently, advanced kidney cancer has been shown to benefit from a combination of two treatments, either two immunotherapies (two medications that stimulate the immune system) or an immunotherapy and a targeted antiangiogenesis therapy (which cuts off the blood supply to the cancer).

The following immunotherapy medications are used in cases of kidney cancer:
  • Nivolumab (Opdivo)
  • Pembrolizumab (Keytruda)
  • Ipilimumab (Yervoy)
  • Interleukine-2 (IV)
Nivolumab and Ipilimumab are administered together. Pembrolizumab is administered along with Axitinib (targeted antiangiogenesis therapy). Interleukin-2 is administered alone (monotherapy).
 

Immunotherapy for bladder cancer

Bladder cancer usually develops in the urothelial cells found in the bladder’s inner lining. This cancer is often referred to as urothelial carcinoma. 90% of bladder cancers are urothelial carcinomas. This type of cancer can affect the bladder, but also other parts of the urinary system, such as the ureter and the urethra.

It manifests itself in various forms, which are classified in specific groups based on their scope (progression):
  • Bladder cancer that has not progressed to the bladder muscle (non-invasive): 75 to 85% of urothelial tumours: 
    • non-invasive papillary tumour (70%);
    • flat tumour (in situ) (10%).
  • Bladder cancer that has progressed to the muscle lining (invasive): 20% of urothelial carcinomas.
The immunotherapy medications described below are used to treat bladder cancers in Québec :
  • Bacillus Calmette-Guérin or BCG
BCG is a bacteria transformed in the laboratory to ensure that it cannot trigger any disease. Its use results in a bladder inflammation that in turn triggers the immune system to attack and destroy cancer cells. This therapy is administered inside the bladder (intravesical) at regular intervals to address in situ carcinomas (non-invasive tumours). It is prescribed for use after surgery, i.e., once the tumour has been removed through natural means (transurethral resection of the bladder tumour [TURBT]).
 
  • Avelumab (Bavencio)
It is used as a monotherapy (single therapy) for maintenance of an inoperable or metastatic advanced urothelial carcinoma.
 

Immunotherapy for Hodgkin’s lymphoma

Lymphoma is the general name used for a group of cancers that affect the lymphatic system. There are two major categories of lymphoma, namely Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. Hodgkin’s lymphoma is different than non-Hodgkin’s lymphoma by virtue of the large abnormal lymphocytes that can be seen when looking through a microscope. It most often occurs among young people between the ages of 21 and 30 and in people over 60.

This type of cancer usually responds well to chemotherapy. Immunotherapy can also be an interesting option that gives good results, especially for some relapsed (returning) or unresponsive (that do not respond well to other treatments) lymphomas.

The immunotherapy medications used to treat Hodgkin’s lymphoma are the following checkpoint inhibitors:
  • Nivolumab (Opdivo)
  • Pembrolizumab (Keytruda)
 

Immunotherapy for head and neck cancers

Head and neck cancers are a group of cancers that touch the oto-rhino-laryngological region (ear-nose-throat) or the upper aerodigestive tract. They mainly impact the mouth cavity, larynx and pharynx. 90% of head and neck cancers are epidermoid carcinomas. Of late, immunotherapy has made great strides in conjunction with these types of cancer, and treatments now represent a new alternative for the vast majority of patients with returning or metastatic epidermoid carcinomas of the head and neck.

The immunotherapy medications used to treat head and neck cancers are the following checkpoint inhibitors:
  • Nivolumab (Opdivo)
  • Pembrolizumab (Keytruda)

Nivolumab can be administered as a therapy for epidermoid carcinomas of the head and neck which are either metastatic or locally advanced. Pembrolizumab can be administered alone (monotherapy) or in conjunction with chemotherapy to treat returning or metastatic epidermoid carcinomas of the head and neck.


Immunotherapy for hepatocellular carcinoma

Hepatocellular carcinoma is a malignant liver tumour. Initially appearing in the cells that constitute the majority of the liver, this cancer accounts for over 90% of all liver cancers. The vast majority of these tumours are associated with cirrhosis of the liver due to either hepatitis B, hepatitis C or excessive drinking.
 
Hepatocellular carcinoma is an aggressive cancer that has few symptoms and is often only discovered at an advanced stage. Depending on how far along the disease is, treatment options may include surgery and radiotherapy. There are fewer treatment options for advanced or metastatic cancers, and up until a few years ago, it was practically impossible to positively impact the most advanced cases. Luckily, we can now consider another type of treatment: targeted therapies. Immunotherapy was also recently observed to be a viable therapeutic option, specifically when combined with a targeted therapy. The treatment protocol in question consists of:
  • Atezolizumab (Tecentriq) and Bevacizumab (Avastin)  
This treatment is indicated for advanced or metastatic hepatocellular carcinomas that meet very specific selection criteria.
 

Immunotherapy for epidermoid cancer

Epidermoid cancer is a type of skin cancer. Immunotherapy is used to treat advanced or metastatic epidermoid carcinomas for which neither surgery nor radiotherapy is an option. The medication used for this type of skin cancer is the checkpoint inhibitor:
  • Cemiplimab (Libtayo)
[i]The descriptions of the following treatments hinge on the knowledge of existing practices at the time this document was drafted.
Immunotherapy treatments in oncology can have side effects that are significantly different than those of other cancer treatments such as chemotherapy or radiotherapy.
 
In Québec, oncology patients have access to a tool that allows them to monitor their side effects. Dubbed the Passeport en oncologie (oncology passport), this tool serves as a calendar, provides a summary of available resources and can be used to monitor therapy side effects. Practitioners strongly recommend its use. The passport is usually given to patients when they first visit an oncology clinic, but it can also be ordered online.
 

Side effects of immune checkpoint inhibitors

Checkpoint inhibitors are the specific immunotherapy medications most often used in oncology. They can, however, have side effects associated with the immune system’s reaction; these can sometimes be excessive. The impacts can include inflammation of certain organs in the body as well as autoimmune reactions (where the immune system attacks healthy cells after having mistakenly identified them as foreign cells).

And while such side effects may be mild and reversible, they should never be taken lightly. Patients who undergo immunotherapy to treat a cancer must be informed of possible side effects as well as of the importance of quickly notifying their care team in the event of a problem; the latter may need to react quickly, depending on the severity of the symptoms.

Certain organs, including the skin, the digestive system, the lungs and the endocrine glands are more sensitive to immunotherapy. Negative side effects can occur at any time during treatment and in some cases, only present once the therapy is completed or even months down the road. These negative effects do not necessarily touch everyone who undergoes immunotherapy, nor do they impact everyone to the same degree. Also, the presence or severity of side effects is not an indication of the therapy’s effectiveness or lack thereof.
 
Side effects are often associated with the specific medication administered. While rare, some side effects can be permanent. The main side effects of immune checkpoint inhibitors are:
  • fatigue;
  • skin ailments, including red spots, rash (eruptions) and itchy patches;
  • gastrointestinal symptoms such as nausea or vomiting, loss of appetite, diarrhea and abdominal pain (colitis);
  • endocrine disorders,  among them fatigue, weight loss, excessive thirst or appetite, frequent or excessive miction (urination);
  • respiratory systems issues, including shortness of breath, cough, difficulty breathing;
  • neuropathies, such as numbness and tingling ;
  • other symptoms (generally less frequent), including:
    • headaches,
    • muscle pain or weakness, 
    • painful or swollen joints,
    • inexplicable fever, 
    • bruises,
    • vision problems (loss of vision, inflammation of the eye).

Management and care related to side effects of immune checkpoint inhibitors

 While most side effects are mild, some can develop into more serious and even life-threatening issues. In such cases, emergency interventions may be necessary. The most important and effective method of controlling the side effects of checkpoint inhibitor therapy is early detection combined with rapid action. Patients undergoing this type of immunotherapy must notify the oncology team immediately should existing systems worsen or new symptoms appear.

The following basic principles apply when negative side effects associated with checkpoint inhibitors need to be controlled:
  • Relatively mild or moderate side effects: treat the emerging symptoms while continuing the immunotherapy treatments.
  • Moderate but persistent side effects: treat the emerging symptoms and temporary interrupt the immunotherapy until the side effects have diminished or disappeared.
  • Serious or very serious side effects: cease the treatment. In certain circumstances, notably if the symptoms are quickly resolved according to established criteria, resuming immunotherapy could be considered. Consult appropriate experts, depending on the organ impacted. Possibility of intravenous or oral treatment with corticosteroids or other immunosuppressors (medications that decrease the impact of  immune system activity). Patients often need to be hospitalized.
Patients are urged to immediately contact the care team or make their way to the ER if they present any of the following symptoms:
  • Diarrhea -  more than 6 loose stools per day, accompanied by secretions, blood or abdominal pain
  • Cough or persistent fever
  • Sudden shortness of breath
  • Red spots or itchy patches over at least one-third (30%) of the body
  • Red eyes, blurred vision
  • Any other new or unusual symptom

Side effects of bispecific antibodies (Blinatumomab)

Blinatumomab is used to treat acute lymphoblastic leukemia. Its side effects, unlike those experienced by some chemotherapy patients, are usually moderately severe to severe, but well-tolerated by most patients. They generally present early in the first week of the initial treatment cycle, and become mild and reversible once the treatment ends. On rare occasions, serious side effects can appear, in which case they must be addressed quickly.

Given these potentially serious impacts, hospitalization in a special oncology ward may be necessary for patients at the start of the first two treatment cycles. As for the remainder of the treatment, close monitoring by the oncology team or hospitalization is recommended at the start of all remaining cycles. This recommendation also applies should treatment be resumed following an interruption of 4 hours or more. If treatment can and is to be given at an outside clinic, it must be administered by an infusion pump. Strict precautions must be taken when changing infusion tubes and bags, particularly to avoid dosage errors.

The most frequent side effects are as follows.
  • Immune system disorders: cytokine release syndrome, which occurs when the immune system reacts to the infusion by generating a vast quantity of cytokines (substances produced in reaction to pathogens). This usually occurs during the first days of the first 2 treatment cycles. The symptoms are:
    • fever and chills;
    • hypotension (low blood pressure);
    • muscle and joint pain;
    • vertigo;
    • headaches;
    • skin rash (eruptions);
    • trouble breathing.
In order to prevent cytokine release syndrome, a cortisone-based medication (dexhamethadone) is administered prior to the onset of each treatment cycle, as well as whenever the dose is increased or if treatment is resumed after an interruption of 4 hours or more.
  • Bacterial, fungal or viral infection. 
  • Febrile neutropenia (decrease in the number of neutrophils [white blood cells] present in the case of a fever or other signs of an infection). 
  • Blood disorders such as anemia (decrease in red blood cells), neutropenia (decrease in neutrophils [white blood cells]) and thrombocytopenia (decrease in platelets). 
  • Gastrointestinal symptoms like diarrhea and nausea. 
  • Pancreatitis, the symptoms of which include intense abdominal pain, nausea, vomiting and diarrhea. Symptoms can be severe and the treatment team must be advised immediately. 
  • Tumour lysis syndrome, i.e., the rapid destruction of cancer cells at the onset of treatment. This risk is particularly high in cases of acute leukemia. Preventive measures taken to avoid this side effect consist of administering a medication (Allopurinol) and intravenous hydration.
  • Musculoskeletal problems and more specifically, back and bone pain. 
  • Nervous system issues: these are frequent, and generally touch around half of the persons treated. They usually appear during the first few days after the medication’s administration. Some of them, namely the most severe, must be addressed immediately. The symptoms of nervous system issues are:
    • headaches;
    • trembling;
    • dizziness and loss of balance;
    • confusion;
    • blurred vision;
    • drowsiness;
    • fainting;
    • convulsions.
  • Skin problems and more specifically, a rash.


Side effects of intravesical therapy (BCG)

 The following side effects can appear during the 2-day period following each treatment cycle:
  • Frequent need to urinate
  • Blood in the urine
  • Difficulty fully emptying bladder
  • Mild to moderate lower back or lower stomach pain while urinating
  • Skin irritation in the genital area
  • Slight fever (between 38° and 38.3°C)
  • Symptoms akin to those in the case of a flu (fatigue, chills, headache and sore throat)
These side effects will go away on their own during the first week following treatment. There may sometimes be more severe side effects calling for a medical intervention.

A patient with the following symptoms should contact the treatment team or make his way to the ER:
  • Difficulty or inability to urinate
  • Presence of significant amounts of blood in the urine or an increase in the amount of such blood (as opposed to a decrease)
  • Persistent cough (that does not go away)
  • Fever over a period of 2 days


Side effects of CAR T-cell therapy

CAR T-cell therapy can have major side effects. The majority of patients, in fact, will manifest severe side effects, with two of these likely to appear over the short term. Firstly, patients can present with cytokine release syndrome in the 3- to 9-day period after receiving an injection of modified lymphocytes (CAR T-cell). These lymphocytes can cause the immune system to react and produce a large quantity of cytokines (substances produced in response to pathogens).

The symptoms of this syndrome are:
  • fever and chills;
  • hypotension (low blood pressure), muscle and joint pain and vertigo;
  • headaches;
  • skin rash (eruptions);
  • trouble breathing.
The syndrome can also provoke renal, liver, lung or heart failure.
 
Secondly, neurological side effects can also appear 5 days after the administration of CAR T-cells. These can manifest as convulsions, tremors, confusion, difficulty speaking or fainting.
 
Also, the chemotherapy given as a preliminary treatment often provokes a severe decrease in red blood cells, platelets and white blood cells. The result? An increased risk of suffering from severe infection.

Patients who undergo CAR T-cell treatment must subsequently be hospitalized in a special oncology ward so that treatment personnel can monitor them as needed. Oncologists and other specialized doctors and health care personnel must be adequately trained and have access to the necessary resources to optimally monitor and care for these patients.
 

Most frequent side effects of Alpha interferon and Interleukin-2

  • Pseudo-flu symptoms: fever, chills, muscle pain, headaches
  • Fatigue
  • Gastrointestinal symptoms: decreased appetite, diarrhea, nausea and vomiting, skin rash
  • Blood disorders: anemia (decrease in red blood cells), neutropenia (decrease in neutrophils [white blood cells]) and thrombocytopenia (decrease in platelets)
  • Depression
There may also be more severe symptoms, but only rarely. These could include chest and stomach pains, persistent cough or fever (for more than 24 hours) and sudden episodes of breathing difficulties. Patients with these symptoms must be seen rapidly. They will need to contact a member of the treatment team immediately or make their way to the ER.
 

Specific mention - Interleukin-2

High doses of Interleukin-2 could provoke severe issues such as pulmonary edema, renal failure, generalized swelling leading to severe weight gain and cerebral edema. Because of these potentially serious side effects, hospitalization in a special oncology ward is necessary to allow for continuous monitoring duration the medication’s administration.

To learn more about managing side effects.
 
Questions? Speak with a nurse at our Info-cancer Hotline at 1-800-363-0063.

Sources

Institut National du Cancer - Médecine de précision : thérapies ciblées et immunothérapie spécifique
InfoCancer - Immunothérapie 
Canadian Cancer Society - Immunotherapy 
American Cancer Society - Immunotherapy​ 
Immunooncology.be 
La ligue contre le cancer - L'immunothérapie 
National Cancer Institute - Immunotherapy to Treat Cancer​


Guides prepared for patients:

European Society for Medical Oncology - Les effets secondaires liés à l’immunothérapie
Société leucémie et lymphome Canada - L'immunothérapie 
CHUM - L'immunothérapie pour traiter le cancer 


All of the sources used to prepare this document can be consulted by communicating with the Quebec Cancer Foundation.

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