Immunotherapy uses the body’s natural defences (the immune system) to fight disease-causing pathogens, such as bacteria, viruses, parasites or fungi, and to recognize and neutralize many harmful substances encountered in the environment. The immune system is also able to recognize changes within the body that manifest themselves as a cancerous change or an autoimmune disease, such as lupus.
Under normal conditions, the immune system, including the lymph glands, spleen and white blood cells such as T-cell lymphocytes, recognizes and destroys faulty cells, stopping the cancer developing. However, if the immune system recognizes cancerous cells, but is not strong enough to kill them, is inhibited by signals produced by the cancerous cells or if the cells contain changes that enable them to ‘hide or escape’ the immune system, then cancer can still develop.
Cancer immunotherapies (also referred to as immuno-oncology) stimulate the immune system to recognize and attack cancer cells, allowing targeting of cancer cells while leaving the rest of the body unharmed. Although not suitable for all types of cancer, immunotherapy has become a standard treatment for many cancer types and the number of immunotherapeutic candidates in clinical trials continues to increase. These immunotherapies may be used on their own or in conjunction with other cancer treatments such as surgery, chemotherapy or radiotherapy.
Better understanding of the complexity of the immune system has resulted in a range of immunotherapeutic approaches working in different ways to influence the immune response and attack the cancerous cells.
Since the first report in 2012 of a successful immunotherapeutic treatment, the field of immuno-oncology has advanced rapidly. Immunotherapy has become a standard treatment for many cancer types. In 2017 the Pharmaceutical Manufacturers and Research of America reported that there were more than 240 immuno-oncology treatments under development. These numbers have continued to grow.
Although terminologies may overlap, immunotherapeutic treatments can be broadly divided into several main categories according to their method of action: therapeutic cancer vaccines, checkpoint inhibitors, CAR T-cell therapy and cytokine therapeutics.
Therapeutic cancer vaccines
Vaccines are designed to stimulate an immune response within the body to attack cancer cells and thereby strengthen the body’s natural defences. Unlike cancer prevention vaccines, therapeutic cancer vaccines work against existing cancer cells, not against agents that may cause cancer.
How it works: Therapeutic cancer vaccines ‘teach’ the immune system to recognize tumor-associated antigens (usually peptides or proteins) that are not found or are at very low levels in normal cells. The immune system can then react to these antigens and destroy the cancer cells.
Protein or peptide therapeutic vaccines
Based on the genetic codes of many cancer cell proteins, scientists are producing large quantities of synthetic tumor-associated antigens (proteins or peptides) with the aim of stimulating the immune system into attacking the cancerous cells that contain the antigen.
To date, peptide therapeutics have been used to stimulate de novo generation of the white blood cells (T-cells), but, so far, these therapies have lacked efficacy.
Antibody-based, therapeutic vaccines
Antibodies are found naturally in the blood, helping to fight infection by recognizing and eliminating or inhibiting foreign substances (antigens) including those associated with abnormal cancerous cells.
A monoclonal antibody (mAb) is a single type of antibody, targeting a specific antigen. Today, mAbs are used to create many human therapeutics. More than 40 mAbs are already approved to treat a variety of diseases including cancer, inflammation, autoimmune diseases and others. As with peptide therapeutics, mAbs have been used to stimulate de novo generation of white blood cells (T-cells). Currently, mAbs must be produced in large quantities to provide therapeutic, clinically effective doses such that significant improvements in efficacy would be advantageous.
Another group of antibody-based therapeutics are the so-called antibody-drug conjugates that comprise an antibody ‘carrier’ chemically linked to a cytotoxic drug ‘cargo’.
How it works: mAbs can be designed to recognize and attach to specific proteins (antigens) on the surface of cancer cells. This interaction may be used to trigger the immune system into attacking cancerous cells, to interrupt the signalling that instructs cancer cells to grow, divide and spread, or to help the immune system recognize and eliminate cancer cells from the body.
Antibody carrier and peptide cargo – ADAC technology
Combining a tumor-associated antigenic peptide with a preselected antibody carrier can create a vaccine that not only enables the immune system to recognize and attack tumor cells, but also generates a functional ‘immune surveillance’ system to destroy metastases and provide a lasting immune response.
Strike Pharma’s initial development focus uses proprietary ADAC technology to develop therapeutic vaccines that can significantly enhance the immune response when targeting solid tumors. Tumor-associated neoantigenic cargoes (peptides), previously identified in solid tumors, will be affinity-linked to well-characterized agonistic antibody carriers. Improvements in peptide stability and delivery efficiency will ensure efficient T-cell activation and an enhanced immune response.
- ADAC technology can ensure efficient T-cell activation (initiation of an immune response) by providing a stable affinity-link between an antibody carrier and a peptide cargo to improve stability and efficiency of delivery
- ADAC technology offers the design flexibility essential to facilitate development of individualized vaccines based on the genetic profile of each patient’s tumor
How it works: An agonistic antibody that stimulates a targeted immune response acts as a ‘carrier’ for a tumor-associated antigenic peptide ‘cargo’ to ensure efficient delivery and subsequent T-cell activation.
Viruses are modified so that they do not cause disease and are then typically used as viral vectors to deliver cancer antigens, usually proteins or peptides, into the body in order to stimulate the immune system into attacking cancerous cells containing the antigen.
DNA and RNA vaccines
Based on DNA or RNA sequences usually found in cancer cells, scientists are producing formulations containing synthetic DNA or RNA sequences for injection with the aim of stimulating the immune system to attack cancer cells.
Whole cell vaccines
A whole cell vaccine uses the entire cancer cell, not just a specific cell antigen. The vaccine is made from the patient’s, or another person’s, cancer cells or using cancer cells that have been grown in the laboratory.
The cancerous cells are modified to make them more easily recognized by the immune system and reinjected.
Dendritic cell vaccines
Dendritic cells help the immune system recognize and attack abnormal cells. These cells are grown alongside cancer cells in the laboratory and used as a vaccine to stimulate the immune system to attack cancerous cells.
When used as so-called checkpoint inhibitors mAbs enable the immune system to recognize ‘hidden’ cancerous cells. They include some of the most promising MAb therapies with several drugs already approved by the FDA and many more in clinical trials.
How it works: When immune checkpoint molecules, such as cytotoxic T lymphocyte antigen 4 (CTLA-4) or programmed cell death-1 (PD-1) and its ligands (PD-L1 and PD-L2) are expressed on a tumor site their presence allows cancer cells to evade immune responses. MAb checkpoint inhibitors block their effect enabling the immune system to recognize and attack cancerous cells.
CAR T-cell therapy
Chimeric antigen receptor T-cell therapy (CAR-T) is a genetically-modified immuno-oncology treatment. While showing significant success in stimulating the body’s immune system, the ex-vivo procedures involved are cumbersome and expensive.
How it works: The first CAR T-cell treatment was approved as recently as 2017 for treating a blood cancer, acute lymphoblastic leukaemia, in children. The patient’s white blood cells are removed and the T-cell lymphocytes are re-engineered to produce chimeric antigen receptors (CARS) on their surface enabling them to attack cancerous cells when re-infused into the body.
Cytokine-based therapeutics aim to stimulate or inhibit cytokine activity, either as single agents or in combination with other immunomodulatory drugs.
How it works: Cytokines, such as interferon and interleukin, are a group of proteins secreted by several immune system cells. Crucial in cell-to-cell communication, they play an important role in controlling the immune system. Most frequently, man-made (recombinant) immuno-stimulatory cytokines are used to boost existing anti-cancer immune responses when using treatments such as immune checkpoint-blocking antibodies and immunogenic chemotherapeutics