Overview

Pancreatic cancer refers to any type of cancer which starts in the pancreas. This organ sits behind your stomach and it is responsible for making hormones which help you digest food. Cancer begins in the pancreas when its cells start to grow out of control, resulting in the formation of tumour masses. Pancreatic cancer is unfortunately a very aggressive disease. Although there are various treatments available such as surgery, chemotherapy and radiotherapy, the 5-year survival rate for this type of cancer is around only 10%.¹ In fact, it is predicted to be the second largest cause of cancer-related deaths worldwide by 2030.¹ A reason why this cancer is often fatal is because it is quite difficult to treat. This is because:

• Pancreatic cancer is known to grow outside of the pancreas and spread to different organs²
• A lack of screening methods which can accurately detect the early stages of this type of cancer²
• The only current curative therapy for pancreatic cancer is surgery. However, roughly 80% of all patients are diagnosed with late-stage cancer, which makes them non-eligible to undergo surgery as the cancer will have grown too big and likely spread around the body² 

In recent years, significant efforts have been made to develop new treatments for pancreatic cancer patients. One specific line of treatment which has received a lot of attention is immunotherapy. Immunotherapy is a treatment which involves manipulating your immune system to help it fight cancer. The immune system, composed of the lymph glands, spleen and white blood cells, is a natural bodily system which recognises any foreign substance in your body and seeks to eliminate it, protecting you from harm. Such foreign substances can include viruses, bacteria, and even cancer cells. However, when faced with cancer, sometimes your natural immune system is not enough to fight against it. This is because:

• The immune system is sometimes not strong enough to fight against the cancer, particularly when the cancer has spread wide across the whole body³
• Cancer cells can create signals which can stop the immune system from working entirely, allowing the cancer to grow uncontrollably³
• Cancer cells can also evolve to hide and escape from the immune system, meaning it cannot detect the cancer cells to kill them³

To counter these ‘attacks’ from the cancer cells towards the immune system, immunotherapy aims to aid your immune system in finding and killing cancer cells. This article will focus on the various immunotherapies that are currently being explored as options for new treatments for pancreatic cancer. 

Monoclonal antibodies

One important way that your immune system protects you from foreign substances is by producing antibodies. These are substances which circulate the body to recognise and attach to antigens, which are small proteins found on foreign substances. Once attached, the foreign substances are essentially ‘trapped’ by the antibodies - meaning they can no longer spread around the body or cause more harm. The antibodies can then signal other immune cells to come and eliminate the foreign substances.⁴ Medical research has explored this natural concept in the lab, and it is now possible to design antibodies which will attach to specific antigens, such as ones found on pancreatic cancer cells. This therapy is known as monoclonal antibodies - a large quantity of one specific type of antibody is injected into the patient’s vein.⁵ 

There are various monoclonal antibodies that are being assessed as potential therapeutics for pancreatic cancer therapy. A particularly promising class of these antibodies includes immune checkpoint inhibitors. 

Immune checkpoint inhibitors

Immune checkpoint inhibitors are a specific type of monoclonal antibodies which aim to block cancer cells from interfering with the immune system.⁶ 

An important type of white blood cell is the T-cell, and this cell has substances on its surface called checkpoint proteins, which have the fundamental role of telling the T-cell when to turn its immune response on or off. Cancer cells, such as pancreatic ones, can interact with such proteins, and signal these checkpoints to switch off their T-cell’s activity, stopping the immune cell and the immune system in general from killing the cancer cells. Hence, cancer stops the immune response via interacting with these checkpoint proteins.⁶

Immune checkpoint inhibitors are monoclonal antibodies which interact with these checkpoint proteins found on T-cells, blocking cancer cells from binding with them and turning off the immune response. This results in T-cells and the immune response remaining ‘switched on’, and they can continue to recognise and attack cancer cells, stopping the progression of the cancer.⁶ 

Pembrolizumab is an immune checkpoint inhibitor which has been FDA-approved as an immunotherapy for the most common type of pancreatic cancer - known as advanced pancreatic ductal adenocarcinoma.⁷

Adoptive cell therapy

Another type of immunotherapy showing promising results as a potential treatment for pancreatic cancer is adoptive cell therapy. This type of treatment involves giving patients specific modified white blood cells to help fight the cancer. There are various types of adoptive cell therapy being explored for pancreatic cancer. 

CAR T-cell therapy

Chimeric antigen receptor (CAR) T-cell therapy is a treatment which alters the T-cell genes to help them eliminate cancer cells more effectively. 

One of the essential roles of T-cells is to recognise antigens from foreign substances such as cancer cells. They do so by having proteins on their surfaces known as receptors, which have the specific role of finding and attaching to antigens. This process will then signal the rest of the immune system that a foreign substance is in the body, and an immune response will be created - antibodies will be produced, and immune cells will be activated to eliminate the harm. This interaction between the T-cell’s receptor and an antigen is very specific - each receptor can only interact with one specific type of antigen. This means that if the T-cells do not have any receptors which can attach to the specific antigens found on cancer cells, they cannot recognise such cells and the cancer can continue to grow uncontrollably.⁸ This is where CAR T-cell therapy can step in and solve the issue. 

In CAR T-cell therapy, T-cells are extracted from the blood of the patient and are modified in the lab through the addition of a gene for the receptor specific to that cancer’s antigens. These receptors are called chimeric antigen receptors. These CAR T-cells will then be given back to the patient through infusions in the vein, and these modified T-cells will be able to recognise the cancer cells’ antigens, and hence stimulate an immune response against the cancer.

CAR T-cell therapy has been shown in early trials to be able to stop pancreatic cancer progression and improve the survival of patients.⁹

NK cell therapy

Natural killer (NK) cells are another important specific type of white blood cell which are in charge of killing foreign substances, such as cancer cells, in the body. They are one of the groups of immune cells which are signalled by antibodies and T-cells to destroy the harm. Naturally, NK cells have a relatively short lifespan, and hence are not sufficient to be able to eliminate cancer. To solve this and harness the potential NK cells have, researchers have developed ways to enhance them in the lab. They do so by treating NK cells with substances called cytokines, which are also important immune proteins which act as stimulants for NK cells, improving their longevity. Also, sometimes NK cells can be genetically modified to have chimeric antigen receptors, to make them highly specific to cancer cells.¹⁰ 

NK cell therapy is very effective in stopping the growth of pancreatic cancer. This therapy is one of the most significant immunotherapies discovered for pancreatic cancer to date.¹¹

Tumour-infiltrating lymphocytes 

White blood cells, also known as lymphocytes, can sometimes penetrate into tumour masses and start to kill the cancer cells. If they manage to do so, they are termed tumour-infiltrating lymphocytes (TILs). These TILs have been explored therapeutically in recent years as an adoptive cell immunotherapy. An advantage that TILs provide as an immunotherapy is that, since they have already infiltrated into the specific tumour, they have been exposed to all its antigens, meaning that these lymphocytes can already recognise many targets on the specific cancer cells. They do not need much specific modification to be an effective therapy to target the cancer. A further advantage that TILs provide is that they can serve as an effective long-term therapy. Studies have shown TILs to still be present in the body several years after the first delivery of the treatment. This makes TILs an attractive therapy as it means that their long-term stay in the body can allow them to survey and eliminate any recurrences of the cancer. 

Clinical trials are currently being carried out to assess TILs as a pancreatic cancer therapy, and they are showing promising results.¹² 

Therapeutic cancer vaccines

Most people will be familiar with preventative vaccines, famous examples including those against the flu and COVID-19. These vaccines help boost your immune system’s ability to defend your body before a foreign substance has infected you. However, there are also vaccines which are made specifically for cancer patients, instead used to treat cancer after it has already occurred.¹³ 

Therapeutic cancer vaccines train the immune system to protect the body from cells that look abnormal, such as cancer cells. The goal of these vaccinations is to put a stop to tumour progression, kill the cancer that is already present, and keep the cancer from coming back after treatment is finished.¹³ 

There are various of these vaccines which are currently being assessed as pancreatic cancer immunotherapies. Examples include:

Neoantigen mRNA vaccine

Cancer cells typically change (also known as mutate) during the development of a tumour. These changes are known as neoantigens - “new antigens”. As they are mutations which have occurred as the cancer is growing, these neoantigens will only be found in tumour cells and not any of a patient’s healthy, normal cells. Therefore, this makes these neoantigens attractive targets for therapeutic cancer vaccines. In a recent clinical trial in pancreatic cancer patients, 20 of these neoantigens were identified after surgical removal of their tumours. A copy of the genetic code (the instructions needed to make these neoantigens) was made for these new targets, and such copies were made into vaccines - termed mRNA vaccines. When administered to the patients, these neoantigens were replicated in their body and they triggered a specific immune response against any remaining cancer cells which had them on their surface. These mRNA vaccines provided a highly personalised immunotherapy treatment to each patient - as the vaccine given was specific to which neoantigens were detected in each patient’s specific tumour.¹⁴ 

ELI-002 vaccine

A 2024 study is looking into a vaccine named ELI-002, which is a vaccine made to target any cancer cells which have a mutation in a gene called KRAS. This gene normally plays a role in controlling the life cycle of a cell - its growth, its maturation, and its death. Pancreatic cancer cells typically mutate this gene to keep the cell from dying, allowing the cancer to continue to grow uncontrollably. This vaccine consisted of giving pancreatic cancer patients these mutated versions of the KRAS gene. When administered to patients, their immune systems built a response against any cancer cells which had such mutations. This cancer vaccine shows very promising results, as the patients showed significant decreases in their cancer activity and a roughly 85% drop in the risk of their cancer coming back or being fatal.¹⁵

Combination therapies

One of the main challenges that comes with immunotherapies for pancreatic cancer is the dense tumour microenvironment. A tumour’s microenvironment is the space the cancer cells take up, as well as any surrounding healthy cells and blood vessels which help feed the tumour to grow. For pancreatic cancer, this microenvironment is typically quite difficult for immunotherapies to penetrate. Not only this but the pancreatic tumour’s microenvironment is known to be quite heterogeneous - meaning there are a wide variety of different cells involved in the growth and development of the cancer. Hence, this makes the cancer more difficult to kill as there are so many different targets.^5,16

One way to combat this challenge is through combining multiple therapies into the same treatment regime. This is known as combination therapies, and they have been shown to result in much more favourable outcomes compared to when one therapy is used by itself. 

Examples of how some immunotherapies mentioned above are being incorporated and assessed for combination therapies include the following:

• Monoclonal antibodies such as nimotuzumab, matuzumab and panitumumab have all been used alongside chemotherapy and radiotherapy for pancreatic cancer treatment plans. These combinations have shown significant improvement in the survival of patients⁵ 
• Chemotherapy has been incorporated into CAR T-cell therapy and TILs regimes. Prior to the immunotherapies being given to patients, small doses of chemotherapy have been administered, in order to kill some cancer cells. This means that once the adoptive cell therapies are in the body, they are not overwhelmed by the number of cancer cells
• Therapeutic cancer vaccines can be used after surgery or radiation, as a way to eliminate any remaining cancer cells and to prevent the cancer from coming back
• mRNA cancer vaccines can be used alongside chemotherapy¹⁴

Summary

To conclude, immunotherapy, which concerns the manipulation of the immune system to boost its role in protecting your body from any harm, is now being assessed as a treatment option to combat the aggressive pancreatic cancer. There are various immunotherapies which have shown significant results in eliminating pancreatic cancer and preventing it from coming back. Prime examples include monoclonal antibodies, adoptive cell therapies and therapeutic cancer vaccines. These immunotherapies show their best results in stopping the progression of pancreatic cancer when used in combination with other existing treatments, such as radiotherapy and chemotherapy. Hence, immunotherapy is an exciting new treatment approach which shows promise in tackling the debilitating cancer of the pancreas.