By Bruno Rosset, Founder of the IASO-Cancer Initiative, Scientific Advisor and Medical Editor

Updated on 15 September 2022

My oncologist here said my cancer is not suitable for the immunotherapy.

This we hear from a lot of patients who are interested to come to us for a dendritic cell therapy.

I am writing this overview article to explain, that when oncologists talk about immune therapy, they talk about drug-based therapies such as Cytokines, Monoclonal antibodies, Check-Point- Inhibitors, and CAR-T Cell therapies. In all those therapies the patient must have some specific antigens, receptors, or mutations for them to work.   The Doctor will therefore search for them using profound diagnostic laboratory procedures.  If they are not available, he will say that the patient will not be responsive to the treatment.

Dendritic Cell vaccination is totally different – it will work in all cancer types, in all stages of the cancer maybe except for blood cancers.

I hope that this article will help to better understand the differences between the different cancer immune therapies.

The aim of cancer immunotherapy is to fight tumours with the help of the body’s own immune system. Unlike chemotherapy, for example, the drugs administered are not directly directed against the cancer. Instead, they usually cause the immune cells to recognize, attack and destroy the cancer cells. Ideally, healthy cells in the body are not damaged. Read here how exactly cancer immunotherapy works and what risks it entails.

What is immunotherapy?

Cancer immunotherapy comprises various procedures and active substances that help to direct the power of the body’s immune system against cancer. So-called immuno-oncology is a fourth pillar of cancer treatment – alongside surgery, radiotherapy, and chemotherapy.

The idea of using the immune system to fight cancer is not new. But to implement it, many obstacles had to be overcome. Simply activating the immune system as part of immunotherapy is tricky and could lead to significant side effects. Immunotherapy must always maintain a balance so that the immune response is not too violent. And an immunotherapy must ensure that the immune activity is directed as specifically as possible against the cancer cells

Not suitable for every patient

Most of the time, cancer immunotherapy is only used when conventional treatment has failed. Its effectiveness depends on many factors. One of these is the form of cancer. Here are two examples:

In the case of metastatic non-small cell lung cancer, immunotherapy prolongs the life of patients by an average of several months. In the case of advanced black skin cancer (malignant melanoma), patients who would otherwise most likely have died quickly even gain several years in some circumstances.

However, only a proportion of those treated respond to immunotherapy. In others, it does not work at all. Because even the same form of cancer varies from patient to patient – everyone has their ‘own’ cancer.

Immunotherapy: cell biology background  

Normally, diseased, and ageing cells in the body die of their own accord. Doctors call this programmed cell death “apoptosis”. This is not the case with cancer cells. They continue to divide and push away healthy tissue.

In immunotherapy, white blood cells (leukocytes) are stimulated to put the cancer cells out of action: T-cells and natural killer cells – two representatives of the lymphocyte subgroup – must fight the cancer in the same way as the pathogens that have invaded the body.

Cancer cells outwit the immune system

But it is not that simple. Pathogens have molecules (antigens) on their surface that mark them as foreign and make them vulnerable to the immune system. Cancer cells, on the other hand, are derived from the body’s own cells. Their antigens identify them as belonging to the body. They are therefore not detected by the immune system and multiply – a tumour forms.

Other cancer cells are recognized by the immune cells, but they manipulate or weaken the immune system – for example, by presenting inhibitory signaling molecules on their surface for T cells, so that the latter no longer attack.

Immunotherapy – balance between activation and moderation

Cancer cells therefore use very different regulatory mechanisms to evade immune defenses. Scientists refer to these different strategies as “immune escape mechanisms”. As a result, there are also different approaches to immunotherapy to make cancer cells vulnerable:

Cytokine-based immunotherapy

Cytokines are endogenous messengers that regulate, among other things, the activity of the immune system. Their artificial equivalents are not tailor-made for the treatment of specific tumours but act generally on the immune system.

Interleukin-2, for example, stimulates the activity of the immune system. Interferon slows down the growth and division of cells, including cancer cells.

Disadvantage: Compared to the new immunotherapy methods, cytokines do not act in a targeted manner. They are only effective for a few types of tumours.

Immunotherapy with monoclonal antibodies

Antibodies are Y-shaped protein molecules that bind precisely to specific antigens on a cell. In this way, they mark diseased cells and pathogens (such as bacteria) for the immune cells to eliminate. Perfectly matched antibodies can also be produced artificially.

On the one hand, such monoclonal antibodies can be used for cancer diagnosis: Equipped with fluorescent or radioactive particles, they help to visualize cancer cells in the blood or cancerous tumours and metastases in the body.

On the other hand, monoclonal antibodies are also used as immuno-oncological therapeutic agents: If they bind to a tumour cell, it is a signal for the immune system to attack that cell. In addition, monoclonal antibodies can be used to deliver cellular toxins or radioactive substances to cancer cells in a targeted manner to destroy them.

Another possible application is that monoclonal antibodies act as immunotherapy by inhibiting certain signaling pathways that are important for tumour growth. In addition, there are immunotherapeutic antibodies that prevent the formation of blood vessels supplying the tumour.

For some types of cancer, the development of immunotherapy with monoclonal antibodies has already been successful. Rituximab, for example, is used in the treatment of non-Hodgkin’s lymphoma.

Disadvantage:

Immunotherapy with monoclonal antibodies only works for tumours that have very specific surface characteristics that are not or only marginally present in healthy cells. Even if the tumour is poorly vascularized or very large, the treatment does not work well because there are not enough antibodies reaching the target

Immunotherapy with therapeutic cancer vaccines

In contrast to vaccines that protect against cancer preventively (e.g., the HPV vaccine), therapeutic cancer vaccines must act against already existing tumours. This is done by targeting immune cells against cancer cells. Such immunotherapy could in the long term revolutionize cancer treatment. It can be tailored to each tumour, so that each patient receives his or her own ‘cancer vaccine’.

For example, research is being carried out into anti-tumour vaccines that are designed to direct the immune system’s attention to certain tumour antigens in a targeted manner. For example, tumour antigens can be produced in large numbers in the laboratory and then injected into patients as a ‘cancer vaccine’ – in the hope that their immune system will then recognize these antigens on the tumour cells present and attack them.

Immunotherapy using dendritic cells

Another approach is not to administer tumour antigens directly as a therapeutic vaccine, but to administer so-called dendritic cells to which such antigens have been added beforehand. Dendritic cells are immune cells whose function in the body is to take up foreign substances and then present their typical antigens on their surface – so that other immune cells recognize which foreign antigens are to be attacked.

In dendritic cell therapy, dendritic cells are taken from the patient’s body or blood and equipped in the laboratory with antigens that are characteristic of cancer cells and are not found elsewhere in the body. These ‘armed’ immune cells can then be given to the patient to speed up the fight of their immune system against the cancer.

We have been doing this in Germany since 2002, and in our clinic alone we have successfully treated more than 11,000 patients. Dendritic cell therapy can be used for all types and stages of cancer and has no side effects, as it uses only the patient’s own material, the immune cells.

Another, fairly recent variant is called CAR-T cell therapy.

T-type immune cells are first taken from the patient’s body and genetically engineered in the laboratory to form a specific binding site on their surface – the CAR (= chimeric antigen receptor). They are then multiplied before being introduced into the patient’s body by infusion. There, the modified immune cells can bind to the cancer cells using the CAR and then destroy them.

In preparation for CAR-T cell therapy, patients receive mild chemotherapy. This eliminates not only some of the cancer cells, but also the T cells. This increases the effectiveness of the subsequent CAR-T cell therapy.

Disadvantage: so far, the results are mixed. CAR-T cell therapy is very complex and expensive and is so far only possible for selected patients with certain forms of cancer.

 No tumour vaccines have yet been approved for cancer treatment; however, some candidates are being used at least in clinical trials.

Dendritic cell therapy is also not yet a standard in cancer treatment. – except for Germany, China, Japan and other Asian countries  

Immunotherapy with immune checkpoint inhibitors

Immune checkpoint inhibitors are special antibodies that belong to the latest generation of active substances in immuno-oncology. They target certain immune checkpoints. These act as ‘brakes’ on the immune system – they normally prevent excessive immune responses in healthy tissue.

Some tumours can activate these immune checkpoints, i.e., trigger their brake function: They carry on their surface molecules that correspond to certain T-cell receptors, which function as stop buttons. On contact, the T cell is inactivated and does not attack the cancer cell.

Immune checkpoint inhibitors can remedy this – they unblock the “brakes” by occupying critical surface molecules of the cancer cells in turn. As a result, the cancer cells can no longer operate the T-cell deactivation buttons. Subsequently, the T cells can act against them.

Disadvantage:

this form of immunotherapy is not a “miracle weapon”. It may take several weeks before they are effective. In addition, not all patients respond to immune checkpoint inhibitors. And when they are used, the immune system may overreact.

When is immunotherapy performed with drugs

At present, there are only suitable immuno-oncology drugs for certain forms of cancer. Moreover, some of them are currently only being used in studies. The active substances developed so far for cancer immunotherapy and their areas of application include:

Monoclonal antibodies – This form of immunotherapy is used for the following forms of cancer

– Breast cancer

– Colon cancer

– Non-Hodgkin’s lymphoma (NHL)

– Non-small cell lung cancer (a form of lung cancer)

– Kidney cancer

– Leukemia (“blood cancer”)

– Multiple myeloma (plasmacytoma)

Checkpoint inhibitors – They are available, among others, for the treatment of the following tumour types

– Lung cancer (non-small cell lung carcinoma and small cell lung carcinoma)

– Malignant melanoma (black skin cancer)

– Renal cell cancer (renal cell carcinoma) 

Cytokines – l the areas of application are for example:

– Skin cancer

– leukemia

– Kidney cell cancer

CAR-T cell therapy can be used in some cases of non-Hodgkin’s lymphoma and leukemia.

Dendritic cell vaccination is used successfully for all types of cancer:

In adjuvant therapy, i.e., in patients whose primary tumour could be surgically removed without metastasis,

and in the prophylactic use of immunotherapy to prevent further metastases, the success rate is over 90%. A cure is possible here

In this situation, the aim is to cure and prevent a relapse.

A single course of treatment is sufficient here 

In the palliative care situation, i.e., when the tumour could not be removed and remains in the patient, when metastases have formed and other organs are affected, we have response rates of 60-65% according to WHO criteria, depending on the form of the cancer.

The aim here is to prevent the cancer from progressing and affecting other organs.

The cancer is then considered a kind of chronic disease, it may not disappear, but it is under control and life expectancy and quality of life are greatly improved.

In this case, more than one cycle of therapy may be required. Depending on the patient’s individual situation, another cycle may be repeated after 6 to 9 months. Note that a second cycle will cost less than the first.

What happens during immunotherapy?

In cancer immunotherapy, immuno-oncological substances are usually administered to the patient by infusion. In some forms of immunotherapy, such as dendritic cell therapy, immune cells are also taken from the patient’s blood, activated against the cancer, and reintroduced into the body. As a rule, immunotherapy is carried out in specialized immuno-oncology centers, which are also aware of the possible side effects.

What are the risks of using immunotherapy?

Fighting cancer gently is only possible with dendritic cells. The cancer vaccines used so far are accompanied by side effects such as chills, fever, and headaches

  Drug immunotherapy can also have side effects. However, they manifest themselves differently from the side effects caused by chemotherapy. For example, patients do not usually lose their hair.

If the body’s own defenses are activated during immunotherapy, there is a risk that they will then turn against the body’s own healthy cells – this is not possible with dendritic cell therapy.

Immunotherapy with immune checkpoint inhibitors can trigger inflammation in tissues and organs, especially in the skin and gastrointestinal tract. In some cases, the side effects do not appear until several months after the last dose.

The use of cytokines such as interferon can cause flu-like symptoms such as fever, fatigue, loss of appetite and vomiting. Interferon also acts on the nervous system. In this way, it can in some cases cause depression and confusion.

On the one hand, CAR-T cell therapy can trigger a whole-body (systemic) inflammatory reaction – cytokine release syndrome – with symptoms such as fever, increased heart rate, lowered blood pressure, rash, nausea, vomiting and possibly circulatory and respiratory problems. On the other hand, neurological side effects (e.g., headaches, confusion, fatigue, slurred speech, seizures) as well as an increased risk of infection may occur because of CAR-T-cell therapy.

What should I look out for after immunotherapy?

Although immunotherapies are specifically targeted at cancer cells, they can be accompanied by significant side effects. Therefore cancer immunotherapy should always be carried out in specialized centers.  If problems arise afterwards, always talk to your doctor. Especially if the immune system is too strongly activated, it is important to quickly rebalance the balance in the context of immunotherapy.

The IASO Cancer initiative was founded by Bruno Rosset in 2018 with the aim of improving the success rates and quality of life of cancer patients worldwide by giving them access to innovative and scientifically proven cancer therapies. These therapies are often not, or not yet, known and are currently only available in a few locations around the world. To date, our network includes 8 innovative clinics, all of which specialize in the integrated treatment of cancer. The doctors are pioneers in cancer immunotherapy, such as dendritic cell therapy.

Please note that all clinics are managed by us here in Switzerland. We are responsible for collecting patients’ medical data, informing patients about treatment options, organizing appointments at the respective clinics, assisting patients with travel and accommodation and managing all financial aspects. Treatment fees must be paid into our accounts in Switzerland.