What Is Immunotherapy?

Introduction

Are you suffering from chronic allergic reactions? Are you interested in learning more about the treatment options available to you? In this article, we will tackle one of these treatments, known as immunotherapy.

Immunotherapy, also known as desensitisation, is a unique treatment developed by St Mary’s Hospital London towards the end of the 19^th century.^{1, 2} Specific immunotherapy (referred to as SIT) often includes giving patients injections or sublingual (under the tongue) drops or tablets containing increasing dosages of allergen extracts over time.¹

As the name suggests, SIT implements the use of our immune system to battle diseases. Our immune system is a complicated network of biological processes that work together to keep us safe from infections and other diseases like cancer.³

Over time, SIT has developed in different centres and countries, resulting in new treatment plans and unique philosophical perspectives on the therapy. A large portion of the early SIT literature is notable for its clinical empiricism and absence of the kind of objective data that is necessary for the approach to be implemented in the modern day. However, clinical trials carried out following contemporary guidelines have validated several different regimens that have been tested throughout the years and established the efficacy of SIT in recent years.²

Basics of immunotherapy

Immune system overview 

The immune system is a complex network of cells, tissues, and organs that work together to defend the body against harmful invaders, such as bacteria, viruses, and other pathogens.⁴ It consists of two main components: the innate immune system and the adaptive immune system.

1. Innate immune system:⁵
   • Physical and chemical barriers: these include the skin, mucous membranes, stomach acid, and enzymes that help prevent pathogens from entering the body
   • Phagocytes: white blood cells such as neutrophils and macrophages that engulf and digest pathogens
   • Natural killer (NK) cells: these cells recognise and destroy infected or abnormal cells
   • Inflammatory response: triggered by tissue damage or infection, leading to increased blood flow, recruitment of immune cells, and other responses to eliminate the threat
2. Adaptive immune system:⁴
   • Lymphocytes: white blood cells that are key components of the adaptive immune system. There are two main types:
     • B cells: make antibodies that can recognise and neutralise specific pathogens
     • T cells: harmonise immune responses, which can directly kill infected cells
   • Antibodies (immunoglobulins): proteins produced by B cells that can bind to specific antigens and neutralise pathogens
   • Memory cells: B and T cells that "remember" specific pathogens, providing immunity upon subsequent exposure
   • Major histocompatibility complex (MHC): proteins that present pieces of antigens of the foreign body/pathogen to T cells, triggering immune responses

3. Complement system:⁵
   • A group of proteins that work with the immune system to enhance the ability of antibodies and phagocytic cells to clear microbes and damaged cells

4. Cytokines and chemokines:⁵
   • These are signalling molecules that regulate the immune response, including inflammation and the activation of immune cells.

5. Bone marrow and thymus:^{5, 6}
   • Bone marrow: is the site of production of blood cells, which include immune cells
   • Thymus: where T cells mature and develop their specific functions

6. Spleen and lymph nodes:⁶
   • Spleen: filters blood, removes damaged blood cells, and contains immune cells
   • Lymph nodes: small structures that filter and trap pathogens, facilitating immune responses

Purpose of immunotherapy 

SIT is a well-researched treatment used for specific severe allergies, such as severe allergic rhinitis that has not responded to treatment via anti-allergy medication or a severe allergic reaction to wasp or bee venom. Products for targeted immunotherapy are being developed and used to treat some food allergies, such as peanuts.¹ SIT enhances our body’s natural defences by subjecting it to increasing doses of the allergen over a period of time; this causes the body to reduce its reactivity towards the allergen.¹

Furthermore, immunotherapy has incorporated using monoclonal antibodies to target specific ligands on cancer cells or enhance the activity of the immune system and stimulate them to target pathogens.⁷

Additionally, immunotherapy has shown promise in the treatment of cancers and autoimmune disorders.^{7, 8}

Types of immunotherapy

Checkpoint inhibitors

Our immune responses are regulated by a sophisticated and complex system of checkpoints. These checkpoints are of 2 kinds: stimulatory and inhibitory.⁸ Stimulatory checkpoints promote cell activation, such as T cell activation, while inhibitory checkpoints limit this activation and duration of immune response and regulate tolerance, homeostasis and reduction of inflammation.⁸

In immunotherapy, two checkpoint inhibitors showed clinical significance:

1. CTLA-4 inhibitors:^{8, 9} CTLA-4 is a surface protein found on T-cells, which was shown to downregulate immune response. Studies have shown that the inhibition of this protein can promote T cell activation and thus protection against cancers. An example of this treatment is ipilimumab.
2. PD-1/PD-L1 inhibitors:^{8, 10} PD-1 is a surface protein found on T-cells, when it binds to PD-L1 (found in solid tumours) it can stimulate inhibitory signals and suppress the immune response. Hence, PD-1 inhibitors, such as pembrolizumab and nivolumab, disrupt this interaction thus allowing T cells to find and attack tumour cells.

With the success of checkpoint inhibitors, it is worth noting that this therapy worked on a subset of patients and may vary between individuals; not all patients were responsive to this treatment due to their different types and degrees of cancer.⁸

Monoclonal antibodies

A monoclonal antibody (mAb) is a synthetic molecule created in a lab to imitate the immune system's recognition and binding to specific molecules, most commonly infections. There are several medicinal, diagnostic, and research uses for monoclonal antibodies. As they are designed to specifically target a single type of antigen (which could be a protein on the surface of a virus, a cell, or another biological target), they are extremely specific.¹¹

These mAbs have shown to be useful in various disease treatments like cancers (including HER-2 breast cancer), autoimmune diseases (like rheumatoid arthritis) and COVID-19.^{12, 13, 14}

Adoptive cell therapy

Adoptive cell therapy (ACT) is an immunotherapy technique whereby anti-tumour lymphocytes are isolated, cultured outside of the body, and subsequently injected into the cancer patient. This process frequently involves the addition of growth factors or vaccinations that might enhance the in vivo effects of the transplanted cells.¹⁵

There are different types of ACT, some examples include:¹⁶

1. Tumour-infiltrating lymphocyte (TIL) therapy
2. T-cell receptor (TCR) therapy
3. Natural killer (NK) cell therapy
4. T-cell therapy with tumour vaccines
5. Chimeric antigen receptor T-cell (CAR-T) therapy

CAR-T therapy has shown great interest due to the ability of CAR-T cells to treat malignant tumours found in the blood. For this treatment, the T cells are isolated from the patient's blood and genetically modified to express T-cell receptors (TCRs) that recognise specific tumour antigens. Following this, the modified cells are expanded in the lab and then infused into the patient to target the tumour cells.¹⁷

Vaccines as immunotherapy

"Traditional vaccines" and "therapeutic vaccines" denote various vaccine kinds with different intended uses. The following are the main variations between the two:

1. Traditional vaccines:¹⁸
   • Preventive focus: traditional vaccines are primarily preventive. They aim to stimulate the immune system to recognise and attack specific pathogens (such as viruses or bacteria) before an infection occurs.
   • Prophylactic use: traditional vaccines are administered to healthy individuals to protect them from future infections. Examples include vaccines for measles, polio, smallpox, rabies, tetanus, and many others.
   • Induction of immune memory: these vaccines induce immunological memory, so if a vaccinated person is later exposed to the actual pathogen, their immune system can respond more effectively, preventing or reducing the severity of the infection
2. Therapeutic vaccines:¹⁸
   • Treatment focus: therapeutic vaccines are designed to treat existing diseases or conditions rather than prevent them. They aim to stimulate the immune system to target and eliminate specific cells, such as cancer cells or cells involved in autoimmune diseases.
   • Treatment of established conditions: therapeutic vaccines are typically administered to individuals who already have a disease or condition. Examples include cancer vaccines, which target tumour cells, and vaccines for chronic viral infections, such as human papillomavirus (HPV) in individuals with pre-existing infections.¹⁹ Additionally, Sipuleucel-T is an FDA-approved therapeutic cancer vaccine for advanced prostate cancer.²⁰
   • Stimulation of immune response against specific cells: these vaccines are intended to provoke an immune response against specific cells or antigens associated with the disease being treated

Conditions treated with immunotherapy

1. Cancer:²¹
   • Melanoma
   • Lung cancer
   • Lymphomas
   • Renal cell carcinoma
   • Colon cancer

2. Autoimmune Disorders:²²
   • Rheumatoid arthritis
   • Inflammatory bowel disease (IBD)
   • Psoriasis
   • Multiple sclerosis

3. Allergies¹
4. Infectious diseases¹⁸

Challenges and future directions

Similar to any technique, immunotherapy faces multiple challenges, including:

1. Limited efficacy in some patients as the response can vary between individuals.⁸
2. Toxicity and this can occur if the immune system starts to harm healthy cells/tissue.²³
3. Resistance to therapy can develop over time.²³
4. Cost and accessibility.²⁴

However, some future directions that should be considered in immunotherapy include:

1. Precision immunotherapy aims to understand the genetic and molecular aspects of the target/disease on a deeper level.
2. Next-generation CAR-T cell therapies
3. Overcoming resistance challenges
4. Innovative technologies such as using CRISPR-based gene editing
5. Global collaboration

Summary

Immunotherapy is a novel and revolutionary method in the medical sector that opens new treatment options for a wide range of illnesses. Because of its effectiveness, especially in the treatment of cancer, the field of treatments has changed. However, some challenges still arise with this treatment and require ongoing research to refine the current techniques and hopefully find new approaches. As researchers and clinicians continue to unlock the full potential of immunotherapy, it is poised to play a pivotal role in reshaping the way we approach and treat a wide range of medical conditions, ultimately improving patient outcomes and quality of life.