How to Overcome The Hurdle of Immunotherapy

For most people, only vaccines come to mind when they think of immunotherapy. But in fact, immunotherapy encompasses more than just vaccines – it refers to a disease treatment method that has health benefits or prioritises disease modification while working through the immune system (or taking effects through the immune system). Therefore, immunotherapies can be largely grouped into several categories including vaccines, antibodies, and other methods that take effect through the immune system.

Active immunotherapy, also called vaccines, refers to delivering an antigen into the body with or without an adjuvant to initiate an immune response. This approach needs the stimulation or activation of the immune system (antibody production and T cell activation) to occur in order to generate an immune response. It can be traced as far back as five centuries ago, but Jenner was the first man to test this method to protect against smallpox in a scientific manner in 1796, and he named this approach as a vaccine. However, it was William B. Coley, MD, who is recognised as the Father of Immunotherapy for his treatment of cancer patients by injecting bacteria into tumours in 1891. Though Coley was famous for having successfully treated different cancer patients using this method, no one knew the mechanism of the approach at that time, and hence it was not popularised. Bacteria injection as a cancer treatment was used again in 1976 by using dead BCGs. Since then, scientists and clinicians have noticed the value of immunotherapy and have been inspired to continuously work on it. As for the component of a vaccine, it contains the antigen (protein-based vaccine, such as viral protein or subunit of the viral protein or peptide, or a small molecule linked to a big protein, DNA based vaccine, such as  viral vector, plasmid DNA and RNA based vaccine) plus an adjuvant. The antigen will drive the antibody production, and the antibody will have specific binding  for the antigen (therapeutic target). The role of the adjuvant is to non-specifically prime the immune system to enhance the function of the antigen.

Passive immunotherapy refers to giving anti-sera or antibody to the patient to treat the disease. The most recent example is the use of monoclonal antibodies against COVID-19 that has saved many lives during COVID-19 pandemic. It is worth noting that antibodies exist in our body even before we are born because mothers can pass the antibodies through the umbilical blood to the foetus to protect the baby from diseases. Passive immunotherapy was first used in the 19th century for the treatment of infectious diseases, such as through the use of antisera to treat diphtheria and the use of horse anti-sera to treat rabies. Now, it has been used to treat both infectious diseases and noninfectious diseases such as cancer (anti-PD1/PDL1 antibody) and arthritis (anti-TNF alpha antibody). Now, most passive immunotherapies use recombinant human or humanised monoclonal antibody for disease treatment. Antibody therapy is highly specific, but the cost is much higher compared to that of vaccines.

The other type of immunotherapy treats diseases by using immune cells or cytokines, or small molecules that can regulate or activate immune function to fight diseases, such as NK cell, antigen-specific T cell or modified T cell therapy and IL2, G-CSF as a treatment for diseases. Cells can be isolated from patients or healthy individuals, and cytokine, growth factor that are produced as recombinant proteins. This approach may be expensive or very cost-effective depending on availability. The treatment is less specific compared to vaccine and antibody therapies.

With the advancement in knowledge and understanding of immunotherapy and the immune system, immunotherapies are now becoming a more popular therapeutic for different diseases since they are considered as safer and more specific treatments. The major advantage of immunotherapy is that most of the molecules used for the therapy are derived from our body or produced by the human body, so there is a smaller chance of rejection by our body compared to methods such as NK or T cell therapy. Another major feature of immunotherapy is due to less toxicity to the body since it is normally produced by our body to against diseases, such as cytokines and antibodies.

The benefits of immunotherapy to human health is clear, such as its potential for vaccines against infectious diseases and antibody treatments for cancer (PD1/ PDL1 antibody). The success and promise of immunotherapy have motivated many investors and pharmaceutical companies to jump into this field. However, recent progress in clinical trials has pushed most of them to hold their steps, because of the high investment and high failure rates. This situation has warded off many pharmaceutical companies and stirred up hesitation in making investments on immunotherapy. Many investors have begun to question the function of immunotherapy. The key factor causing this dilemma should not be attributed to technologies but rather to our understanding of the mechanism of immunotherapy. In other words, most immunotherapies should work if they were tested properly. Unfortunately, most are wrongly transferred into clinical settings and lead to failed outcomes.

Before moving forward, it is important to understand how our immune system works and the role the immune system plays in disease onset. In short, there is the innate immune system (also called the adopted immune system) that we adopt from our parents and the acquired immune system (also called the adapted immune system) that we gradually develop after birth. Both innate and acquired immunity are varied among people and change with ageing, so some people may be resistant to certain infectious reagents because they inherited sound innate immune systems from their parents, but this may change with ageing. Importantly, the genes passed down from our parents plays a very important role in immune responses and will determine the effects of immunotherapy.

As immunotherapy develops, we should identify the therapeutic target and targeted population. In other words, we should be familiar with the mechanism through which it works. Particularly, how our immune system will use the molecule, and even need to know whether our body could handle these molecules or is able to uptake and initiate proper immune response and how to manage the adverse response. Two popular terms, precision medicine and personalised medicine, are very important and critical to immunotherapy. They determine the success of immunotherapy if we can understand what immunotherapy is and how to use it properly. As introduced earlier, immunotherapy works through the immune system by modulating immune responses, such as through strengthening the hypo or minimising hypered immune response. The efficacy of immunotherapy will rely on the association of the root cause of the disease. However, most diseases are associated with multiple factors or determined by more than one factor, including infectious diseases like COVID-19. It is well known that the virus is the causative factor, but not everyone who is exposed to the virus under the same circumstances will be infected, even if they are all exposed to the same dose at the same time. This is mainly due to the soundness of the individual’s immune system which can prevent them from being infected. Hence, the status of our immunity is the critical factor to the success of viral infection. Another factor is that the level of receptor expression and the degree of affinity to viral protein are also important for viral entry. From this simple example, it is easy to understand the role of immunity and the multiple factors related to a disease.

However, since our innate immunity is inherited, we do not have total control over the strength of our immunity. Thus, the immunity of our parents partially decides the condition of our immune system. Intriguingly, our life span is also related to that of our parents because it is associated with our genes, thus our genes impact our immune system and our life span. We know that our age will impact our immune system, and the immune system will determine our response to immunotherapy. Therefore, when we apply immunotherapy to treat a disease, we should consider the following factors: the condition of the immune system, age, and genetic factors to reach the best therapeutic effects. Why these are determined factors for the successful immunotherapy, it will be very difficult or even impossible to have any treatment effect if the patient has impaired or poor immune system, or it can even cause life threatening issues if the immune system overreacts to the treatment. Both conditions can cause major problems for immunotherapy and may force the cessation of clinical trials.

What can help guide immunotherapy development? As introduced in the beginning, immunotherapy is a personalised medicine and precision medicine because the variety of immunotypes will determine the different responses to the same treatment, and the responses to treatments differ due to age and health conditions. How do we ensure immunotherapies are applied to the right subjects? We need to understand the target population of the therapy first, so this is the precision medicine aspect of the approach (selecting and assigning patients into different groups). This means that we should find a way to select the right population that will have the best responses to the treatment. Our group has tested different vaccines on people with different immunotypes and collected important information. Another major factor for the success of immunotherapy is the physical condition of the person who will receive the therapy, such as age and the health condition. For example, the treatment and the preventive therapy should not apply to the same person. The treatment should apply to a person with a good immune system for active immunotherapy, but the same dose may cause severe adverse effects if it is used on a patient who has a poor immune system. The preventive vaccine should only be applied to healthy people because they can tolerate a higher immune response, but it may be life-threatening to older people who cannot not tolerate any over response.

To summarise, immunotherapy is a very promising approach for disease treatment or prevention and is likely to dominate the future pharmaceutical market given our ageing society. However, e should understand that it is a precision medicine and a personalised medicine, thus we should preselect the right target populations before it is translated into clinic application. Meanwhile, immunotherapy is also a highly personalised medicine, therefore, we should bear this concept in mind while we apply the therapy to patients. Monitoring the drug levels (PK/PD) is very necessary to reach ideal treatment benefits. This will ensure the success of clinical trials if we can create a monitor or selection method for immunotherapy.

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