Treating Cancer – 5 Types of Immunotherapy
Numerous treatments are available to patients with cancer. Several factors including; the type and stage of a patient’s cancer, their general health, and preferences impact treatment options.
Some available treatments harness the immune system – the body’s natural line of defense against infection and disease – to fight cancer.
What is immunotherapy?
Immunotherapy (also sometimes referred to as immuno-oncology) is a type of cancer treatment that exploits the body’s immune system to fight the disease. Some types of immunotherapy can be preventive (e.g. cancer vaccines) but the majority are therapeutic. Immunotherapies help the immune system recognize, attack and destroy cancerous cells.
This list explores the different types of immunotherapy, how each type works, and takes a closer look at some examples of approved immunotherapies.
1. Adoptive Cell Therapy
Adoptive cell therapies use immune cells to fight cancer. There are two main approaches:
- Immune cells are isolated, expanded, and reintroduced into the cancer patient
- Immune cells are genetically modified to “boost” their cancer-fighting ability, and then reintroduced into the cancer patient
Types of adoptive cell therapy
Tumor-infiltrating Lymphocyte (TIL) Therapy (Unmodified Cells)
Naturally occurring T cells that have already infiltrated a patient’s tumor are harvested from resected tumor material, “activated” and then expanded ex vivo. The activated T cells are then re-infused into the patient. There is now a greater number of activated cells available, enhancing the body’s anti-tumor immune response.
Engineered T-cell Receptor (TCR) Therapy (Modified Cells)
In some cases, a patient’s T cells either cannot recognize a tumor or are unable to “activate” and expand sufficiently, meaning they are incapable of mounting a response against the cancer cells. Engineered TCR therapy can be used to combat this problem. This approach involves taking T cells from a cancer patient, modifying them so that they are armed with a new T cell receptor that allows them to target specific tumor antigens. Both surface and intracellular proteins can be displayed as antigens attached to the major histocompatibility complex (MHC) on the surface of a cancer cell.
Whilst T cells have the ability to recognize many different antigens, distinct types of T cell can be genetically engineered to recognize specific antigen targets – meaning treatment can be personalized to individual patients.
Chimeric Antigen Receptor (CAR) T-cell Therapy (Modified Cells)
In this approach a patient’s T cells are genetically engineered to display a synthetic receptor called a chimeric antigen receptor or “CAR”. CARs display antigen-binding fragments of a specific antibody fused to an intracellular T-cell signaling domain. The CAR T cells are expanded and infused back in to the patient. CAR T cells are able to recognize a smaller range of potential antigen targets compared to TCRs.
Natural Killer (NK) Cell Therapy (Modified and Unmodified Cells)
Several natural killer cell-based immunotherapeutic strategies are currently being investigated. Whilst autologous NK cells expanded ex vivo have been tested in a range of clinical trials for various cancers, success has been limited. This is thought to be due to inhibitory receptors on autologous NK cells “matching” self MHC class I presented on tumor cells, and this “self” recognition consequently inhibited NK cell activation.
Genetic modification of NK cells is also being investigated – CAR-NK therapy is currently being clinically evaluated, for example. It is thought treatment with CAR-NK cells could offer several advantages over CAR-T cells:
- NK cells can be easily isolated and have a relatively short lifespan – risk of over expansion in patients is therefore fairly low.
- The cytokines released by NK cells are considered “safer” than those released by CAR T cells.
- CAR-NK cells have the ability to trigger lysis of cancer cells by both CAR-dependent and CAR-independent means.
- NK cells can be derived from peripheral blood mononuclear cells, NK cell lines and human pluripotent stem cells. In comparison, T cells that are used to create CAR T therapies have to be autologous.
2. Cancer Vaccines
Unlike bacteria and viruses, which are easily recognized by our immune system as “foreign”, cancer cells more closely resemble our “normal” cells – meaning it is much more challenging to generate vaccines against them. As a result, more sophisticated approaches are essential to develop effective cancer vaccines. Let’s take a closer look at the three types of cancer vaccine.
Types of cancer vaccine
Some types of cancer, such as cervical or liver, can be caused by viruses – these viruses are known as “oncoviruses”. Preventive or “prophylactic” vaccines are used to prevent viral infections that either cause cancer or contribute to the development of cancer. They are designed to alert the immune system to a specific virus so that it is able to recognize and attack the virus before it is able to cause an infection. This type of vaccine is administered to healthy individuals.
Specific “high-risk” types of the human papillomavirus (HPV) are linked to numerous types of cancer including; anal, cervical, vaginal, vulval, penile, and head and neck cancers. HPV vaccines are designed to protect against HPV-related cancers. In 2006 the US Food and Drug Administration (FDA) approved Gardasil, the first ever preventive vaccine for cervical cancer, precancerous genital lesions and genital warts, due to human papillomavirus (HPV) types 6, 11, 16 and 18.
Chronic hepatitis B virus (HBV) infection can result in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (liver cancer). Individuals chronically infected with HBV have a 25–40% lifetime risk of developing liver cancer and HBV is estimated to cause at least 54% of all liver cancer cases worldwide. The world's first universal HBV vaccination program was initiated in Taiwan in 1984. In the US, the hepatitis B vaccine is recommended for all infants, children and adults at high risk of infection.
Therapeutic cancer vaccines are administrated to patients diagnosed with cancer and are designed to eradicate cancer cells by strengthening a patient's own immune responses. Bacillus Calmette-Guérin (BCG) and sipuleucel-T (Provenge®) are two examples of therapeutic cancer vaccines. The BCG vaccine is approved for patients with early-stage bladder cancer and sipuleucel-T (Provenge®) is approved for prostate cancer. Sipuleucel-T is known as an autologous cellular immunotherapy, and works by inducing an immune response, targeting the prostatic acid phosphatase (PAP) antigen, which is overexpressed in the majority prostate cancers.
Personalized neoantigen cancer vaccines are just that – personalized. Tumors can display unique targets that result from specific mutations. This type of vaccine is designed to exploit the presence of these specific mutations, by targeting the resulting new antigens or “neoantigens”. Neoantigens are only displayed on cancerous cells, meaning the immune response can be directed towards the cancer, avoiding healthy tissue, thus reducing the risk of side effects.
Immunomodulators regulate or “modulate” the activity of the immune system. Immunomodulating agents can be used to adjust the level of activity by stimulating or suppressing the immune system to help fight cancer. Immunomodulators can be loosely separated into four groups; checkpoint inhibitors, cytokines, agonists and adjuvants.
Types of immunomodulator
Checkpoint inhibitors can block immune checkpoints. Tumors often manipulate these checkpoints to shield themselves from the immune system. By blocking access to other checkpoint molecules, checkpoint inhibitors can reduce immune suppressive mechanisms – increasing the immune system’s response to cancer and promoting the elimination of cancerous cells. The FDA approved the first checkpoint inhibitor, for the treatment of melanoma, in 2011.
These molecular “messengers” enable immune cells to communicate and mount a coordinated response to a target antigen. Drug development efforts have been directed towards characterizing cytokines so that we may take advantage of their role in vast signaling networks. Several cytokine therapies have already gained regulator approval; the first to be approved was a cytokine called interferon-alpha 2 (IFN-α2) back in 1986.
Agonists activate pathways that promote adaptive immune responses. They work in two ways:
- By triggering killer T cells to “activate”. Once activated Killer T’s can directly target and kill cancer cells.
- By stimulating the activity of innate immune cells. These cells can coordinate overall immune responses against cancer by displaying cancer markers and boosting T cell activity.
The term adjuvant originates from the Latin word “adjuvare” meaning “help”. Adjuvants work by activating innate immune pathways which in turn stimulate general immune responses and promote adaptive responses. Adjuvants can induce damage-associated molecular patterns (DAMPs) and/or pathogen-associated molecular patterns (PAMPs) that can activate various pattern recognition receptors (PRRs) on innate immune cells.
4. Targeted Antibodies
Types of antibody
An antibody is a protective protein produced by B cells in response to a specific antigen. Scientists can harness the power of antibodies to supplement a patient’s own immune system by synthesizing “customized” antibodies. These antibodies specifically target antigens that are typically found in greater numbers on the surface of cancer cells compared to “normal” cells. Some antibodies are classed as “passive” immunotherapies because they target cancer cells directly without involving immune cells. Bispecific and trispecific antibodies are examples of “active” immunotherapies because they require help from immune cells.
Monoclonal Antibodies (mAbs)
Monoclonal antibodies are monospecific bivalent molecules consisting of two key regions; an AKA variable region, which is designed to bind to the target antigen on the cancer cell and an AKA constant region which can bind to immune cells. In 1997, the FDA approved the first antibody for the treatment of cancer – the monoclonal antibody rituximab (Rituxan®) for the treatment of leukemia. Many monoclonal antibody therapies are now approved, targeting numerous cancers including; brain, breast, colorectal, head and neck, Hodgkin’s lymphoma, lung, melanoma, non-Hodgkin’s lymphoma, prostate, and stomach.
Antibody–Drug Conjugates (ADCs)
An antibody–drug conjugate is an antibody linked to an anti-cancer drug. The antibody targets and binds to cancer cells – delivering the “toxic” drug directly to the tumor. This approach to chemotherapeutic drug delivery “spares” healthy cells from the drug’s toxic effects as it is concentrated towards the disease tissue. Approved ADC therapies exist for breast cancer, leukemia and lymphoma.
Antibodies containing two different antigen-binding sites in one molecule are known as “bispecific”. This type of antibody was first described in the 1960’s and is created by combining the AKA variable regions from two separate antibodies. Some bispecific antibodies are designed to include a cancer antigen binding site and immune cell binding site – once bound to both antigens it acts as a “linker”, keeping the immune cell in close proximity of the tumor. The first bispecific antibody – blinatumomab (Blincyto®) – was approved by the FDA in 2014 for certain patients with leukemia.
5. Oncolytic Virus Therapy
Viruses are infectious agents that are capable of infecting living cells, hijacking their genetic machinery, which allows the viruses to replicate inside of them.
Modified versions of viruses can be created to target and attack cancer cells. These are termed “oncolytic viruses” as they are designed to target cancer specifically. The viruses can be engineered to decrease their ability to infect “normal” cells and they can also be used as delivery vehicles, transporting therapeutic payloads to cancer cells. The first oncolytic virus therapy was approved by the FDA in 2015 – T-VEC for treatment of melanoma.