Wearing White: How To Prepare Your Immune System to Fight Cancer

June is the Cancer Research Institute’s (CRI) Cancer Immunotherapy Month. CRI recently hosted a #WearWhite day to raise awareness of immune-based therapies, with white symbolizing the immune system’s cancer-fighting white blood cells. To learn more about immunotherapy and how we can prepare our T cells to fight cancer, we interviewed Dr. Mahua Dey, a brain cancer researcher and surgeon at Indiana University School of Medicine with an interest in anti-glioma immunotherapy.

LifeOmic scientists wearing white for immunotherapy.

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.

Diagram of the epidermal growth factor receptor (EGFR). A mutant form of this protein is found in some cancers, including some glioblastomas. Credit: Boghog.

“We essentially tell the T cells, look, this is EGFRvIII, if you see it, kill all cells expressing it,” Dey said. “Rindopepimut, a vaccine targeting EGFRvIII, worked beautifully for our patients who were EGFRvIII-positive, at first. When you injected the peptide drug, T cells would recognize it as foreign and then go about killing everything that looked like it. The problem was that once a tumor recurred [grew back], it no longer expressed EGFRvIII. EGFRvIII was getting mutated out.”

In other words, cancer cells “learn” to down-regulate their mutated EGFRvIII to evade the immune system response. This way they can continue to live, grow and divide.

So how do we get around the issue of cancer cells surpassing immune system checks and evading, through further mutations, the T cells we train against the mutations or antigens they express? This is where precision medicine comes in, Dey says. In other words, our personalized immunotherapies need to be as dirty as the cancers we are fighting, by targeting a variety of antigens. One approach to immunotherapy that may be more successful is to use immunotherapy drug combinations lethal to cancer cells. We can generate these combinations by looking for tumor cell mutations across many patients to see how often and when different targetable mutations occur together.

“We have to create a dirty bomb of personalized medicines for a disease like glioblastoma,” Dey said.

By picking three or four different antigens to target, we can minimize a tumor’s ability to mutate and evade the immune system response. However, such combinations of antigens can be difficult to identify in individual patients.

In addition to variants like EGFRvIII, cancer cells also express neoantigens that form based on a tumor’s microenvironment. Every time one of the tumor’s cells divides (which tumor cells do rapidly and sloppily), it can make a mistake in replicating its DNA. This mistake can cause single amino-acid differences in proteins that the immune system recognizes as abnormal. Imagine these mistakes as single “point” differences along chains of amino acids that form proteins. When these single amino-acid differences show up in proteins at the surface of tumor cells, they can be recognized and targeted by T cells.

“A single base-pair change to a DNA sequence, and a single amino-acid difference in the resulting protein, can be enough to alert the immune system that something is amiss, and cause it to mount a response to the tumour.” — Nature News & Comment

“One option is target these neoantigens with immunotherapy drugs, and instead of picking one antigen like EGFRvIII to target, targeting a cluster of neoantigens all at the same time,” Dey said. “This way, you are killing more than just one group of cells.”

But identifying a cluster of neoantigens, let alone targeting them, is very difficult to do at the level of individual patients. To find effective immunotherapy drug combinations, clinicians may need to look across many different patients to identify neoantigens that often occur together or that are common for particular cancers.

For individual patients, researchers can compare somatic or non-cancerous cells to cells from tumor tissue to identify neoantigens targetable by immunotherapy drugs. In some cases, cancer cells make lots of mistakes while dividing and replicating their genetic material, leading to many potential neoantigens to target. These mistakes are known as the cancer cells’ mutational burden, which is typically high for cancers such as melanoma, a skin cancer. In the case of glioblastoma, the tumor cells’ mutational burden is often low. This, combined with the fact that glioblastoma is a rare form of cancer, makes it very difficult to find clusters of common targetable mutations or neoantigens.

“If a particular mutation occurs once in 10,000 patients, and you have 100,000 patients, you may find many patients with that mutation and successfully develop drugs that target that mutation,” Dey said. “But if your population of patients for that same mutation is only 20,000, you are only going to have two people with the mutation. It’s going to be more difficult to find common mutations. For glioblastoma, it often comes down to personalized medicine, training your own immune system against the mutations we can identify today.”

We Need More, More Data

For rare diseases like glioblastoma, it’s critical that patients and clinicians share insights across the patient population so that, for example, more mutations and neoantigens characteristic of that cancer can be identified and targeted. However, the healthcare system today makes it extremely difficult for researchers and patients to share data broadly, especially raw data such as genomic sequencing files. Just getting an MRI scan from one physician to another can take weeks and involve mailed hard copies of scans and PDF reports. Sharing genomic sequencing data or raw information about neoantigens across a patient population has been nearly impossible.

At LifeOmic we are changing that. Our Precision Health Cloud integrates any kind of patient data, such as tumor sequencing data, for analysis across patient populations. We envision a world where sharing the data necessary to inform immunotherapy treatments is easy, and patients can manage sharing and access permissions via mobile apps.

“The ability to easily integrate and share data with new technologies is what is really going to help us,” Dey said. “We are still doing research in silos. But with the incidence rate of glioblastoma being so low, we can’t afford to lose a single patient or miss out on the insights they can help provide. I’m only looking at mutations present in a hundred glioblastoma patients every year in my lab. But if we had data in one place for all the patients being diagnosed with glioblastoma in the United States, and all of their genomic sequencing data got uploaded to a single cloud platform, it could make a huge difference.”

What Can Cancer Patients Do to Help?

State-of-the-art healthcare organizations are already screening cancer patients for common mutations, like EGFRvIII in the case of glioblastoma. Patients can get the process started by requesting that pathology samples be sent for genomic profiling to Foundation Medicine.

FoundationCore™, is one of the world’s largest cancer genomic databases, with more than 180,000 anonymized patient records, designed to help researchers and biopharma companies advance precision medicine, develop new therapies, and design better trials.” — Foundation Medicine

For immunotherapy to be successful, however, especially for rare disease like glioblastoma, researchers and clinicians need to be able to share and learn from genomic sequencing, mutation and neoantigen insights across their own patients and patients at other institutions. They also need to be able to look at all of this data in the context of a patient’s medical history, clinical data and even lifestyle data. What we eat, what environmental factors we’ve been exposed to, how physically active and generally metabolically healthy we are — all of these factors can affect our immune systems and thus how well we will respond to a particular immunotherapy. Knowing what treatments will be effective for which patients and when is the basic premise of precision medicine. This knowledge depends on having lots of data for lots of patients with a particular disease.

What can people do to help accelerate this knowledge? Dey encourages everyone to support science, including basic science and cancer research. This may be as simple as donating tissue for genomic profiling and further analysis, or being an active participant if possible in clinical trials as well as your cancer care.

Find National Cancer Institute Supported Clinical Trials here. Find a clinical trial that is right for you with the American Cancer Society here. LifeOmic also plans to provide a clinical trial matching or recommendation service for interested LIFE Extend app users.

Colorized scanning electron micrograph of a T lymphocyte. Credit: NIAID.

Staving off Senescence for Immunotherapy

Researchers in Dey’s lab study various ways of training the immune system to attack glioblastoma cells. One of the struggles for immunotherapy as a treatment for this type of brain cancer is that most glioblastoma patients are older, around or above 50 years of age. As we age, our immune systems naturally get tired.

“The T cells in many of these patients are already exhausted,” Dey said. “So now we are talking about training the immune system first to surmount the age effect, and then to attack tumor cells. If we train young T cells the right way, they will attack the cancer very aggressively, but training aged T cells is like trying to teach an old dog new tricks.”

Unfortunately, glioblastoma presents even more hurdles for immunotherapy. Dey has recently found that the hypoxic or oxygen-poor, inflammatory environment that surrounds brain cancer tumors may lead T cells to age prematurely. An abnormally large percentage of T cells in the brain of a glioblastoma patient are in a state known as senescence, where they are blocked from dividing, are functioning poorly and spewing out toxic signals. These T cells are waiting in the wings, tricked by the cancer into paralysis, trying in vain to conserve energy resources by not fighting back, and sending out SOS inflammatory signals. Dey and her colleagues are studying this senescent state to see if they can reverse it. They are identifying senescent T cells by looking for loss of CD28 and expression of CD57, then sending these T cells off for RNA sequencing to see if they can identify patterns of gene activity that can be reversed.

“If we can change the microenvironment for these T cells, hopefully they will wake back up,” Dey said.

A robust immune system is a prerequisite of successful immunotherapy. Fortunately, living a healthy lifestyle can help our immune system stay strong as we age, better prepared to fight when trained to recognize cancer cells. Our metabolism plays an important role in the function of our tissues and the accumulation or clearance of senescent cells over time — even in our brains. By eating healthy, exercising, managing stress and perhaps even practicing intermittent fasting as we age, we can keep our immune systems younger, reduce tissue inflammation and help prevent an untimely accumulation of senescent cells that leave our bodies prone to cancer.

“What we eat absolutely has an effect on our immune system,” Dey said. “But if you’ve eaten poorly over the last 70 years and you try to change your diet once you’ve been diagnosed with cancer — will this really make a difference? I’m not sure. Maintaining a healthy immune system has to be a lifelong endeavor.”

Patient interaction (part of the Pet therapy Study, Dey Lab).

Dey believes that a lifelong healthy lifestyle and positive attitude will be an important component of any treatment’s success.

“Overall, leading a healthy lifestyle and having a positive attitude is important for every individual’s wellbeing, cancer patients being no exception. In my lab, we are even evaluating the efficacy of pet therapy for glioblastoma patients. Our preliminary data reveled a very important finding: spending as little as 15 minutes with a therapy dog improves patients’ feelings of overall wellbeing and decreases feelings of future uncertainty regarding their diagnosis.”

Learn more about LifeOmic’s Precision Health Cloud and LIFE Extend app for precision medicine at LifeOmic.com.

Learn more about immunotherapy with the Cancer Research Institute.