Immunotherapy involves harnessing the power of your own immune system to identify cancerous cells, and destroy them.

“In some ways your cancer is a part of you, but in other ways it’s different or foreign,” said Dr. Mahua Dey, a brain cancer researcher at the IU School of Medicine Department of Neurosurgery, IU Simon Cancer Center and Goodman Campbell Brain and Spine. Dey is investigating personalized brain cancer immunotherapies and how we can make them more effective. “Cancer cells are unlike the other cells in your body that are dividing and dying at a normal pace. Cancer cells in your body are proliferating abnormally, at a much higher rate than your other cells. The premise of immunotherapy is that your immune cells can identify these proliferating cancer cells and destroy them.”

Our immune system is very good at identifying foreign bodies like viruses. As we develop in utero, our body learns which cells belong to self and which are foreign. A robust immune system clears out viruses, bacteria and even damaged cells by recognizing abnormal antigens on their surfaces. An antigen is “any substance that causes the body to make an immune response against that substance,” such as toxins and virus particles. Cancer cells also have unique and often characteristic antigens present on their surfaces that can cause an immune response — but our immune cells often need training to mount this response.

“Cancer is also a part of who you are — the cells may look a little different than normal cells, but they still look like ‘you,’ so we have to train the immune system to identify these cells,” Dey said.

Cancer cells have ways to hide from immune surveillance, especially at first. However, as these cells continue to proliferate and divide with abandon, they may accumulate an increasing number of mutations and abnormal cell surface proteins, making them more prone to attack if we can train our immune system against them. This starts with learning, for any particular patient, what targetable mutations or abnormal cell surface proteins characterize their cancerous cells, through genomic sequencing. Tumor cells are stealthy, but by looking for mutations in tumor DNA we can start to identify changes that may lead a tumor cell to give itself away to an immune cell.

Macro Glioblastoma. Courtesy of Dr. Rodney D. McComb, Omaha, NE.

The potential success of immunotherapy approaches to cancer treatment also depends on the organ the cancer is affecting. Some organs, such as the skin, lungs, GI tract and circulatory system, see and are trained against diverse foreign antigens on a daily basis. Immunotherapies for cancers originating in these organs have been more successful, such as immunotherapies for melanoma and leukemia, than immunotherapies for more protected organs. The brain, for example, is extremely protected against foreign bodies and antigens, meaning it has a relatively “immature” immune environment.

“The T cells that live in the brain like to stay quiet, even when surrounded by brain cancer cells,” Dey said. “Normally, this is a good thing. As a T cell in the brain, you don’t want to get excited about everything, because you don’t want the brain to react to every single foreign-looking antigen. This makes it much more challenging to get the immune system to work against a brain tumor than against melanoma or lung cancer, for example.”

Commonly employed immunotherapeutic strategies enhance antitumor immunity by addressing different components of the immune response. Credit: Anna C. Filley, et al. Oncotarget. 2017 Oct 31;8(53):91779–91794.

“Immunotherapies are targeted towards activating and enhancing endogenous host immune responses. Among those being investigated are: 1) T-cell based therapies like chimeric antigen receptor (CAR) T-cells and adoptive transfer of immune cells to directly bolster antitumor immunity, 2) therapeutic vaccines that enhance antigen presentation and stimulate the generation of robust antitumor immune responses, 3) viruses engineered to selectively infect and destroy tumor cells, and 4) antibody inhibition of signaling through tumor-promoting pathways (VEGF, CTLA-4, PD-1 etc.).” — Oncotarget, 2017

It’s Personal.

Dey sees immunotherapy as the ultimate frontier of personalized medicine.

“Our immune systems are as diverse as we are,” Dey said. “Let’s say you grew up in Indiana. I grew up in India. Growing up, your immune system saw a completely different set of antigens than my immune system saw. Our immune systems are incredibly different; if we both get the same disease, to think that if we both receive the same immunotherapy agent our immune systems will react in the same way is naïve.”

T cell factsheet, from NIAID.

Dey says that she always jokes with her husband, who grew up in the United States, that she never gets as sick as he does because her body has seen every antigen out there.

“I never get sick!” Dey laughs. “Growing up, I had every single weird infection that you could imagine, but my immune system learned from these infections. The lesson here is that the same immunotherapy is never going to work for everybody, even if they have the same disease. Immunotherapy is going to be the ultimate personalized medicine for cancer.”

The future of immunotherapy, as Dey imagines it, involves taking your tumor tissue, sequencing its genetic information to find the mutations specific to your tumor, and using that information to train your T cells to identify the specific antigens revealed through genetic sequencing. Anyone else’s tumor cells, even if their diagnosis were the same, would have a completely different set of mutations and antigens and interact very differently with the immune system based on T cells that recognize a completely different set of antigens than yours.

“We have to teach each person’s immune system to react against their own tumor cells,” Dey said.

It’s not that much different from how a flu vaccine works or doesn’t work in some cases. The flu vaccine is typically only 60% effective because not everyone’s immune system reacts the same way to antigens from a particular flu virus. Our T cells recognize antigens based on T cell receptors and antibodies that are different for every individual based on our personal history of exposure to various foreign viruses, bacteria and other agents.

“To use the immune system against cancer is personalized medicine,” Dey said.

But how do we train our immune system against cancer cells in our bodies? One of the simplest ways is to look for common mutations in cancer cells that are expressed as proteins presented at the surface of cancer cells, where T cells can recognize them and mount an attack. For example, in 30% of glioblastoma cases, a type of brain cancer, many of the individual cancer cells express EGFRvIII, a variant or mutated form of the EGFR protein. EGFR or epidermal growth factor receptor is a transmembrane protein that is a receptor to the epidermal growth factors, which you may know of as the proteins found in milk that promote cellular proliferation and survival. (Why do you think your parents told you to drink your milk to grow big and strong?) Some brain cancer cells express a mutant form of the epidermal growth factor receptor, which immune cells can be trained to recognize and attack.