Best oncologist doctor for immunotherapy
Dr (Col) Ranga Rao Rangaraju, VSM MD, DM
Chairman, Paras Cancer Centres, Gurugram
Immunotherapy of cancer has been grabbing headlines all over the world of late. Patients, caregivers, oncologists, scientists are excited about it. It appears as if we found ‘panacea’ of cancers. Let us understand the insights we have developed thus far.
Basics of immunity
First, let us understand what immunity means and how it functions normally. For the defense of a country, there is air force, navy, military and paramilitary forces for external security, central and local police for internal security, intelligence systems for acquiring enemy information, a defense manufacturing unit for guns, ammunition, a transport, supply chain, an engineering forces to make, repair and maintain roads ,bridges, vehicles, remove the obstructions, waste, debris of war; a signals system to maintain effective and constant communication of all these forces and analyze the inputs, and finally a command system that takes decisions in the best interest of the country. Immune system has all components and is actually more complicated. It works to utmost perfection to maintain health for life, but occasionally when it fails, a cancer or an infection or auto-immune inflammation can be the result.
Immunity to infections is well known to human beings, commonly referred to as power of the body to prevent infections. This power of immunity is natural and inborn to all living beings. Though sounds simple, it is a very complex system, and because of these, living beings are able to survive and propagate, despite exposure to many harmful substances. Imagine, the animals drink the water and walk away which you and me will get infected with! When we have a food article from the same source, someone walks away satisfied, while another one gets a tummy upset. There are some cells and systems in the body that identify and eliminate the harmful substances immediately through some readily available or activated immune cells or develop antibodies to eliminate them. We must understand that these systems are highly individualized like our bodies are! The customization or individualization develops over period of time as the individual is exposed hence the reaction to each situation varies from one to another. There is a great variation in animals, species, and individuals.
The immune systems are under control of genes and there are some genes which suppress the immunity and some which activate the immunity. These immune related genes are usually inborn with individuals and some develop with evolution. The communication, coordination, understanding and thus the perfect balance between these two antagonizing forces is the most important to maintain the appropriate environment for the body to sustain and grow. Any minor disturbances are usually taken care by mutual adjustments, but major disturbances can lead to diseases, including cancer. Balance between these two systems is affected considerably by the environment, our lifestyle and quantum of the offending agent.
When exposed to a harmful substance, the immunity gets activated and leads to its elimination and avoids harm to the body. The system operates through a cascade of events and complex mechanisms. The antigen of the harmful substance is detected, carried, presented by the immune cells (T cells, dendritic cells, macrophages) to the immune cells (B cells) that manufacture the antibodies (humoral immunity). The antibodies are released to destroy the harmful substance. Memory cells of the humoral immunity memorize the details of the offender for future use. Once the offender is eliminated, the ongoing processes are ordered to rest by the controlling genes through chemical signals. These signals of immune suppression are important as an active immune system without a purpose can be dangerous to the body. The immune suppression is to prevent unnecessary activity of these systems that can damage our own systems through a power of recognition of ‘self’ and cells. When this power is defective or lost, our own systems get damaged and the results are ‘autoimmune disease.’
So, immunity is a very complex process and is very finely, precisely regulated through multiple mechanisms. There is a powerful system to recognize various dangerous substances which are eliminated and protect the normal cells. Also equally powerful system to check unnecessary activity to prevent damage to self. Balance of these two antagonizing systems is critical and is affected by environment, our lifestyle, offending agents as well as our inherited genes.
Immunity and cancer
The relationship between immunity and cancer is very complex and our understanding of it continues to grow with the ongoing enthusiastic work of the research community.
We know that for a normal cell to become a cancer cell, prolonged exposure to some cancer producing substance (carcinogen) like tobacco is required. On exposure, there will be series of chemical changes in the nucleus of the cells, (mutations) one after the other. Over period of time, more cells acquire these mutations and their normal functioning gets altered. They now look different, become disobedient to the chemical signaling processes, continue to proliferate, and travel to other parts of the body where it is not supposed to go (metastasis). They then grow in these new sites to form new tumours, spread from there to other organs and grow again. Thus, on exposure to an offending agent a normal group of cells have changed into a tumour. The tumour cells first secrete chemicals and make new vessels (angiogenesis) , that grow rapidly as a network and allow the cells to feed and grow. This process occurs through various chemical transmitters (cytokines).
Let us see if the immune system can prevent this evil and if yes how?
- The immune system is capable of identifying mutations, which are different than normal genes, repair these mutations, if beyond repair eliminate them. The identification is through the intricate mechanisms of the cells in the environment which send signals to immune cells to reach, proliferate and get activated. Tissue environmental cells release a variety of chemicals (cytokines) for each task.
- The mutated cells can also be identified and with the help of activated immune (T cells, macrophages, dendritic cells) cells they can be removed, through various cytokines.
- The circulating tumour cells can be trapped in nodes and can be destroyed before they reach the next organ.
- Pro-tumour cytokines can be antagonized through anti-tumour cytokines.
In short, there is a constant attempt through physical and chemical war fare between the cancer cells and the immune cells. Health or cancer will be decided by the victory of the concerned party. One thus wonders, as to how the cancer occurs and grows despite such a perfect immune system. In a cancer patient, obviously something has not worked!
- Immune system in part or whole, may not have developed well due to some acquired or inborn error.
- Immune system may be inefficient due to some defective genes, acquired or inherited. Sometimes the tumour suppressor genes may be lost, defective so the whole process is not initiated or inefficient or defective.
- The cancer cells, being smarter cells, may make the immune system inefficient at different levels in various manners. They identify the activating chemicals and block their action through the receptors. Check points (PDL1, CTLA 4) are such examples.
- The immune system may become fatigued or tired by an overwhelming offender (carcinogen, mutations, the cancer cells).
- The immune system may be inhibited by some drugs (steroids, immunosuppressive drugs; infections (HIV); medical conditions (diabetes, auto immune diseases)
- Failure of recognition of cancer cells as ‘non self’ or consideration of the cancer cells as ‘self’ or ‘harmless’ by the immune cells could be the reason for the cancer cell proliferation.
- Despite the powerful immune system, cancer cells antagonize most or all of the systems designed for its destruction. They may acquire resistance to these chemicals, inactivate or destroy the immune cells and their products.
- It is possible that the immune system is perfect, and cancer has developed with a different mechanism, bypassing the entire immunity.
Immunotherapy of cancer
It is clear that many cancers occur due to some problem with immunity against cancer. Rectifying this defect, in some way or the other is termed ‘immunotherapy’ or also ‘biological therapy’.
Logically speaking, one needs to understand if the defective immunity was the real reason for the cancer and the exact problem with the immunity. Probably with this information, we can design the treatment accordingly. Currently there is limited understanding of what went wrong in given patient and the immunotherapy is given in similar way to all of the patients. After many clinical trials, we know that immunotherapy helps in some cancers better than others. In order to estimate the efficacy of immunotherapy in a given patient, there are some tests (Tumour mutational burden, microsatellite stability, PDL 1) on tumours and more are being looked for.
Types of Immunotherapy
There are several types of immunotherapy, including:
- Monoclonal antibodies and tumour-agnostic therapies
- Non-specific immunotherapies
- Oncolytic virus therapy
- T-cell therapy
- Cancer vaccines
Monoclonal antibodies are made in a laboratory through complex processes and may be used in a variety of ways eg. targeted therapy, immunotherapy against autoimmune disease etc. Normal immune cells, possess ‘check points’ (immune switches) to activate the cascade of events that can lead to elimination of cancer cells. Cancer cells smartly block or ‘apply brake’ over these check points to inhibit the immune cells from getting activated. If these check points are counter blocked (brake is released) by the externally administered antibodies, the cancer cells will not be able to use them for inhibition of immune cells, thus immunity is intact to tackle cancer cells. The antibodies target the check points, hence called as check point inhibitors. The examples of immune checkpoint inhibitors are: Ipilimumab (Yervoy), Nivolumab (Opdivo), Pembrolizumab (Keytruda), Atezolizumab (Tecentriq), Avelumab (Bavencio), Durvalumab (Imfinzi). Clinical trials of monoclonal antibodies are ongoing for several types of cancers and list is ever expanding.
While many immune checkpoint inhibitors are approved for specific cancers, some are used to treat tumours anywhere in the body by focusing on a specific genetic change. These are called “tumour-agnostic treatments.” For example, pembrolizumab has been approved by the FDA to treat metastatic tumours with specific genetic changes called microsatellite instability-high (MSI-H) or DNA mismatch repair deficiency (dMMR). Tumours that have MSI-H or dMMR do not repair damage to their DNA very well. This means that they often develop many DNA mutations, or changes, in their DNA. These changes make it easier for immune cells to find and attack the tumour. Nivolumab is a similar drug that has been approved to treat metastatic colorectal cancer with MSI-H or dMMR when chemotherapy does not work.
Non specific immunotherapy
BCG Vaccine, interleukins, interferons are examples of non-specific immunotherapy. BCG is used in superficial bladder cancers. Interleukins and interferons were used in few cancers and are rarely used nowadays.
Oncolytic virus therapy
It is well known that virus can get into a cell and change the genes to damage the cell. Instead the virus can be genetically programmed to change the required mutation to normal one or bring about a desired change. The programming of virus, introduction of the cells into the body to the specific tumour etc are practical challenges. This is an interesting area for research. Some brain tumours are being evaluated in clinical trials.
T cell therapy
T cells are immune cells that can kill the cancer cells, but due to some reason do not do so. Enabling them to kill the cancer cells, inside or outside the body, is the newer method under clinical research. Chimeric antigen receptor T cell therapy (CAR-T ) is the new treatment that has made some headlines recently. been used in acute leukaemia, lymphoma resistant to all standard therapies and found to benefit many patients. In this therapy, T cells are taken out of body, enabled with a receptor that can identify the cancer cells and kill them, and reinjected. Many countries including India are developing their methods of this process.
Cancer preventive vaccines are hepatitis B vaccine, and HPV vaccine. Both prevent infections with respective viruses and thus prevent cancers of the liver and cervix, oropharynx, anal region and warts.
Cancer treatment vaccines boost the immune system’s ability to recognize and destroy antigens. cancer cells have certain cancer-specific antigens on their surface and when these molecules are given to a person, they stimulate the immune system to recognize and destroy cancer cells that have these molecules on their surface. Most cancer vaccines also contain adjuvants, which are substances that may help strengthen the immune response.
Some cancer vaccines are made for individual patients. These types of vaccines are produced from the person’s tumour sample obtained by surgery. Other cancer vaccines target specific cancer antigens and are given to people whose tumours have those antigens on the surface of the tumours cells. Most cancer treatment vaccines are only available through clinical trials. But for last few years, Sipuleucel-T is available for metastatic prostatic cancer customized for each person through a series of steps.
We are beginning to understand cancer immunotherapy, currently under considerable research and it has a lot to offer in future. Encouragingly, it offers the possibility for long-term cancer remission, in some patients.
- Immunotherapy can train the immune system to remember cancer cells. This “immunomemory” may result in longer-lasting remissions.
- Clinical studies on long-term survival have shown that the beneficial responses to cancer immunotherapy treatment are durable—that is, they may be maintained even after treatment is completed.
Cancer immunotherapy is generally well tolerated, without the same side effects as chemotherapy and radiation. The variety of side effects of immune checkpoint inhibitors may include side effects similar to an allergic reaction or auto immune disease.
Based on the experience from all clinical trials the following can be concluded about immunotherapy.
- Immunotherapy currently being understood through extensive research and many facts are being discovered almost on a daily basis.
- Current available methods are limited to check point inhibitors (PDL1, CTLA 4) ; cellular therapies (CAR-T cell therapy); dendritic cell therapy; cancer vaccines. 7uu
- Immunotherapy does not work in all cancers. It does show benefit in some cancers. The number of cancers is increasing day by day as the research findings are coming out.
- When administered it does not work in all patients. In general, it shows some beneficial effects in about 40 % of the patients.
- While the benefit lasts for few months, the beneficial effect last long (few years) in about 10 % patients.
- Some tests can indicate the possibility of benefit in a given patient. PDL 1, MSI, TMB are some such tests. Though they do indicate the possibility of benefit, they are not absolute and lot eeds to be understood.
- Currently most uses are in stage iv settings and research is being done to determine if it is going to work in early cancers to cure them.
- They can be administered in combination with chemotherapy, radiotherapy, anther immunotherapy, targeted therapy and so on.
- While most patients tolerate them well, some patients do have varying side effects. Very rarely it can be fatal.
- Side effects may be nothing much and may be allergic reactions, autoimmune reactions of any organ.
- With chemotherapy, the responses are usually measured as ‘complete response’ (CR), ‘partial response’ (PR), when tumour shrinks. When size does not change it is referred to as ‘stable disease’ (SD). When tumour does not shrink and continues to grow it is called as progressive disease (PD). Oncologists think the best way of response evaluation needs to be different from conventional manner.
- There are new phenomenon seen with immunotherapy such as -pseudo-progression or hyper-progression. Pseudo-progression refers to a state when the tumour initially is increasing in size with patient feeling better and later actually shrinks. Hyper-progression means tumour starts actually increasing in size when exposed to immunotherapy much rapidly than its natural speed and in future is does not shrink. The exact mechanism is currently not well understood.
Immunotherapy of cancer has become an important part of cancer therapy, come to stay and improve the long term outcome of treatment. Currently we have limited options and being used in stage IV cancer. A lot needs to be understood before we say there we are !!