Immunotherapy for Pancreatic Cancer: For Patients

Our immune system fights germs and also fights cancer. Cancer immunotherapy enhances the ability of the immune system to fight cancer. An important function of the immune system is the ability to distinguish between our own body, “self”, and “non-self” foreign invaders such as disease-causing bacteria. Cancer cells are recognized as “non-self” by the immune system due to abnormal proteins on their surface, called tumor-specific antigens. The immune system frequently encounters cancer cells and eliminates them.

Pancreatic cancer cells are particularly good at escaping immune detection by looking like normal “self” cells to the immune system. Cancer immunotherapies help the immune system identify cancer cells as “non-self” or help the immune system attack cancer cells in other ways.

Pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, accounting for more than 90 percent of pancreatic cancer cases. Among cancers, PDAC has the lowest 5-year survival rate. PDAC tends to be diagnosed at later stages when cancer is harder to treat. PDAC aggressively invades surrounding tissues, spreads to other areas of the body, and develops resistance to therapies. Even patients who have had their pancreatic cancer surgically removed are likely to have disease recurrence.

Pancreatic cancer is more resistant to chemotherapy than other cancers. One of the reasons PDAC is difficult to treat with chemotherapy drugs is that other cells and tissues surrounding the PDAC tumor, the tumor microenvironment, create a barrier that prevents chemotherapy drugs from reaching the cancer cells. According to the Pancreatic Cancer Action Network pancreatic cancer patients who participate in clinical trials have better outcomes than those who do not. Immunotherapy is a type of cancer treatment that is, at the moment, mainly available through clinical trials.

How pancreatic cancer evades the immune system

Pancreatic tumors usually do not have a lot of genetic rearrangements, so they produce fewer abnormal proteins and produce less tumor-specific antigens on their surface for the immune system to recognize. This is why pancreatic cancer is often said to be non-immunogenic. It is thought that about 5 percent of pancreatic cancers have mutations that cause more abnormal proteins on their surface and these patients are more likely to respond to immunotherapy. Tumor genetic testing can determine which patients are more likely to respond to immunotherapy.

The immune system uses “checkpoints”, which are proteins on the surface of immune cells that act like keylock-activated switches that can be turned “on” or “off” by molecules that act like keys. Immune checkpoints can suppress the immune response to keep the immune system from overreacting and damaging normal tissues. Tumors produce lots of key molecules that activate checkpoint switches that keep the immune system more suppressed than normal. Immune checkpoint inhibitors are drugs that block certain immune checkpoints as a strategy to keep the immune system more active.

Pancreatic tumors have plenty of ways to avoid being attacked by the immune system. The tumor microenvironment surrounding the pancreatic tumor shields it from the immune system and makes it hard for T cells to get to the tumor. Macrophages are immune cells that eat damaged or abnormal cells. Cancer cells fool macrophages into leaving them alone by sending out a signal protein that says ‘don’t eat me’.

Pancreatic cancer immunotherapies

The two FDA-approved immunotherapies for pancreatic cancer are immune checkpoint inhibitors, appropriate for a small subset of pancreatic cancer patients. Most immunotherapy drugs are not yet approved for pancreatic cancer but are available to patients in clinical trials. Immunotherapies that have proved successful for other types of cancer are under investigation for pancreatic cancer.

Patients receive immunotherapy treatment by injection, IV, or pill. After immunotherapy patients may experience side effects due to the immune system attacking normal cells and tissues. Some possible side effects of immunotherapy include fever, headache, nausea, fatigue, muscle/joint aches, redness/itching/soreness at the injection site, and pancreatitis. Pancreatitis is a swelling of the pancreas. Patients should discuss the benefits and risks of immunotherapy and clinical trial participation with their healthcare team.

Unfortunately, the mechanisms that enable pancreatic cancer to avoid being seen and attacked by the immune system also tend to make it resistant to many immunotherapy approaches. That’s why most immunotherapy drugs used on their own have not been effective against pancreatic cancer. Immunotherapy is usually given along with other treatments in clinical trials. Researchers believe that to fight pancreatic cancer, combination therapies are needed that include immunotherapy along with targeted therapies, chemotherapy and/or radiotherapy, and agents that target the tumor microenvironment.

Targeting immune checkpoints

The two FDA-approved immunotherapy drugs for pancreatic cancer, target programmed death receptor (PD-1), an immune checkpoint protein on T cells. These checkpoint immunotherapies are used to treat a small percentage of patients who have inoperable pancreatic cancer. PD-1 acts like a switch that can turn the T cell “on” or “off”. In the “off” position the T cell won’t attack. Antibody-based immunotherapies stick to the PD-1 receptor and block it from engaging with proteins PD-L1 and PD-L2 which act as keys for the PD-1 switch. Since binding of PD-L1 and PD-2 normally turns the PD-1 switch “off”, blocking these proteins causes PD-1 to remain in the “on” position. Some cancer cells make large amounts of PD-L1, which they use to turn off the PD-1 switch on T cells, allowing them to hide from immune attack.

FDA-approved anti-PD-1 immunotherapies are used to treat advanced pancreatic cancer in patients whose tumors are known to be mismatch repair deficient (dMMR) or have high microsatellite instability (MSI-H) based on molecular profiling. The terms dMMR and MSI-H are used interchangeably to refer to a deficiency in the ability of the tumor cells to repair their DNA. Approximately 1 in 50 cases of advanced pancreatic cancer are mismatch repair deficient. Tumors that are mismatch repair deficient have a lot of abnormal proteins on their surface, making them more sensitive to targeting by T-cells that are switched “on” with anti-PD-1 immunotherapy.

An immunotherapy that targets the immune checkpoint protein CD40 to stimulate the immune system is being evaluated in pancreatic cancer clinical trials. Patients enrolled in clinical trials for immunotherapy often receive chemotherapy as well. Checkpoint immunotherapy and chemotherapy in a combined treatment (chemoimmunotherapy) have been shown to improve survival in pancreatic cancer patients compared to either treatment alone.

Cancer vaccines

Cancer vaccines, such as GVAX, hold promise for helping the immune system target pancreatic cancer. GVAX is made by genetically altering cultured pancreatic cancer cells to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). Before administering to patients, the cells are irradiated to prevent them from growing. Although the cells do not grow, they are alive and secrete GM-CSF which acts like a beacon to attract cells of the immune system to the vaccine. Immune cells go to the vaccine and encounter tumor-specific antigens on the vaccine, which are like wanted criminal posters, that help the immune system home in on the pancreatic tumor as well as cancer cells that may have spread elsewhere in the body. Researchers supported by the US non-profit organization, Cancer Research Institute (CRI), found that the GVAX vaccine can make pancreatic cancer more likely to be detected by the immune system.

Targeting inflammation

Another type of immunotherapy, that targets inflammation through the protein IRAK4, has shown promise in pre-clinical research and is part of the NCI Experimental Therapeutics Clinical Trials Network which includes more than 30 clinical sites in the US and Canada. In pancreatic tumors IRAK4 promotes inflammation, a process that exhausts T cells, diverting them away from their job of attacking harmful cancer cells. In animal studies, researchers found that an IRAK4 inhibitor reduced inflammation improved the ability of T cells to fight pancreatic cancer, and made tumors more susceptible to checkpoint immunotherapy.

As scientists and doctors learn more about how the immune system works to fight cancer and how pancreatic cancer evades the immune system, it is hoped that one day pancreatic cancer can be managed with immunotherapy drugs. For pancreatic cancer, immunotherapy appears to be most effective alongside other treatments. Patients with pancreatic cancer should discuss approved and clinical trial immunotherapy options with their healthcare provider.

myTomorrows is dedicated to helping patients with pancreatic cancer find pancreatic cancer clinical trials.