Ramping Up the Fight

Timothy Ratliff had no idea he had lung cancer, and neither did the doctor who did his hernia surgery in 2017. A complication after surgery – a blood clot in his leg – led the retired Navy veteran to the emergency room, where the ER physician ordered an X-ray to make sure the clot hadn’t traveled to his lung, which could be life-threatening.

More Effective Immune System: Dr. Melhem Solh, medical director for the cellular therapy program at Northside Hospital and a hematology oncologist: photo Daemon Baizan

“He came back and said, ‘Mr. Ratliff, the blood clot didn’t travel up your body,’” Ratliff recalls. “And then he said that key word – ‘but.’” But, the ER doctor said, I’m not a specialist, but I think you have lung cancer.

Six years later, Ratliff says, you wouldn’t have any idea that he was diagnosed with stage 4 lung cancer. “I walk around like I don’t even have it,” he says. “I get around just like everyone else,” only occasionally bothered by arthritis in his hip that flares up when it rains.

His cancer hasn’t been cured, but it’s been kept at bay so far by treatments that prompt his own immune system to attack and kill cancer cells. Immunotherapy has revolutionized cancer treatment and allowed people like Ratliff to go on living their lives with minimal disruption. Since being diagnosed, Ratliff – who had logged 20 years in the Navy and then worked as an international contractor for several years – decided to become a long-distance truck driver, making regular trips across the Southeast. “I just can’t sit at home,” he says.

“We used to have a really low, 2% to 3% survival in metastatic lung cancer at five years,” says
Ratliff’s oncologist, Dr. Steve McCune, who is medical director of clinical research for Wellstar Health System in Metro Atlanta. “Immunotherapy has really increased that dramatically, and with a lot less toxicity, usually.”

The concept of immunotherapy is simple, says Dr. Sharad Ghamande, associate director for clinical trials and research at the Georgia Cancer Center at Augusta University and a gynecological oncologist. “Why doesn’t every human being get cancer? Because your immune system is making rounds of your body like a policeman, trying to make sure no one misbehaves,” he says. Our cells, like everything in nature, have a propensity to “misbehave,” he says. In most people, the immune system recognizes this misbehavior and attacks abnormal cells to prevent them from multiplying. But in some people, the immune system loses the ability to recognize cells gone wild, allowing them to grow.

That’s where immunotherapy comes in.

Increased Survival: Dr. Steven McCune, medical director of clinical research for Wellstar Health System: photo contributed

Targeted Attack

Different kinds of immunotherapy work in different ways, but they all use the immune system to fight cancer. Some medications help the immune system do more to identify and destroy cancer cells. That’s the case with Ratliff’s treatment. He gets IV medications called checkpoint inhibitors, which target proteins on immune cells (T cells) that act like checkpoints to be turned off and on. It’s one way the body stops the immune system from attacking normal cells, but some cancer cells hijack those checkpoints to escape detection by the immune system. Checkpoint inhibitors stop the proteins from turning off the T cells, allowing them to attack cancer cells.

McCune calls checkpoint inhibitors the foundation of current immunotherapy, and there are different medications that work to stop different “checkpoint” proteins. Lung cancer, melanoma and kidney cancer are all now treated with this kind of immunotherapy alone or a combination of immunotherapy and chemo, he says. And these medications are approved to treat other cancers, among them bladder, colon and rectal, uterine, and head and neck cancer.

Living with Lung Cancer: Timothy Ratliff: photo contributed

Checkpoint inhibitors do have side effects. Because the medications stop T cells from turning off, the immune system can attack healthy cells as well as cancer cells. The most common side effects are gastrointestinal (diarrhea, colitis), skin rashes and itching, hypothyroidism and low adrenal function (when the adrenal glands don’t make enough of a hormone called cortisol), McCune says. But he adds that these side effects can be managed in most cases and that patients see them as much less intrusive than side effects from chemo. “It’s not just that their survival is longer – their quality of life is usually much better,” he says. And, he adds, immunotherapy can keep working even after people stop taking the medications. “The immune system basically keeps working,” he says. “If we’re not giving chemotherapy, people aren’t getting treatment. But immunotherapy can keep working for months or years after the last treatment is given.”

Ratliff says he was fortunate that he didn’t have the common side effects from chemotherapy, like nausea and hair loss. (Weight loss was the only real issue, he says). He’s had no side effects from immunotherapy.

But as much as these medications have transformed cancer treatment, they don’t work for everyone. “One of the realities is, while immunotherapy can be very effective for some patients, it’s only about 20% or so of the patients who get immunotherapy who have long-lasting results,” says Dr. Suresh Ramalingam, executive director of the Winship Cancer Institute of Emory University and a thoracic oncologist (thoracic oncologists treat cancers inside the chest). Winship is the only National Cancer Institute-designated Comprehensive Cancer Center in Georgia, which puts it in the top tier of cancer centers in the U.S.

Long-lasting Results: Dr. Suresh Ramalingam, executive director of the Winship Cancer Institute of Emory University and a thoracic oncologist: photo contributed

Ramalingam says there are many ongoing efforts, including clinical trials, lab research and studies, to improve immunotherapy. One approach that’s already approved by the Food and Drug Administration (FDA) is the kind of combination therapy Ratliff gets, where one drug targets one checkpoint protein while another drug acts on a different checkpoint. And researchers are trying to identify biomarkers that could help predict those patients who will get a benefit from immunotherapy and those who will not – and why not, so that they can look for more personalized treatment.

Researchers are also hoping to identify more kinds of cancer that respond to a combination of chemo and immunotherapy. Ghamande expects the results of one such clinical trial, called the RUBY trial, to change the standard of care for people who have advanced uterine cancer, so that treatment will include a combo of chemo and a checkpoint inhibitor.

Checkpoint inhibitors are one kind of immunotherapy that uses man-made antibodies (called monoclonal antibodies) to help the immune system find and kill cancer cells. Another kind, called antibody drug conjugates or ADC, uses man-made antibodies to bring chemotherapy directly to the cancer cells, so that when the antibody finds and attaches to a cancer cell, it delivers a drug that kills the cell. That gets the chemo right where it needs to go, while leaving other, healthy cells alone (meaning fewer chemo-type side effects).

A new kind of immunotherapy is called BITE, for bispecific T-cell engagers. These medications target both cancer cells and T cells, which are part of the immune system. As Dr. Melhem Solh, medical director for the cellular therapy program at Northside Hospital and a hematology oncologist (who treats blood cancers), explains it, one side of the drug attaches to a T cell while the other side attaches to a cancer cell. “It’s bringing the immune cell in proximity to the cancer cell, and that will activate the immune cell so it can kill the cancer cells,” Solh says. “It’s making the immune system more efficient.”

Engineering T cells

“One of the most cool things that has happened with immunotherapy.” That’s how Ghamande describes CAR T-cell therapy, which changes genes inside T cells to help them better fight cancer.

Seek and Destroy: Illustration of T cells attacking cancer cells: photo contributed

CAR T-cell therapy – which stands for chimeric antigen receptor (CAR) T-cell therapy – engineers a patient’s own T cells to do two things: “One, to be able to find the cancer in an easy and effective way,” says Solh. “We put a receptor on the surface of that immune cell that’s specific to the cancer. And the other thing we do when we engineer those cells, we make them more active. I usually tell my patients, [it’s] to the power of 10 compared to what your normal immune cell will do.”

CAR T-cell treatment involves taking T cells from the patient, then making these changes to them in the lab and putting them back in the patient’s body. It’s specific to each patient, and it takes a few weeks to engineer the cells in the lab. Once the new CAR T cells are back in the patient’s body, “they’re going to find the cancer,” says Solh. “Because we have given them the GPS signal to know where to go. Once they get in touch with the cancer, that activated molecule will turn the T cell on so it can kill the cancer cell.

Simple Concept: Dr. Sharad Ghamande, associate director for clinical trials and research at the Georgia Cancer Center at Augusta University and a gynecological oncologist: photo WoodieWilliamsPhoto.com

When the immune system kicks into high gear, some patients experience a reaction called cytokine release syndrome. It’s a relatively common side effect of CAR T-cell therapy and also BITE. Solh says it’s often like having a very bad flu, with fever, chills and sometimes drops in oxygen levels and blood pressure. Doctors monitor patients carefully for these symptoms. “Some patients require hospitalization to manage those symptoms,” says Ramalingam. “But it’s actually … a good sign that the immune system is now churning.” Some patients also have neurotoxic side effects, like problems with speech, tremors, headache, delirium and seizures. It’s called ICANS, for “immune effector cell-associated neurotoxicity syndrome,” and it’s another thing doctors watch for. In most cases ICANS gets better in a few days, and there are treatments to manage it.

Right now, CAR T-cell therapy is approved for some blood cancers, but researchers are trying to find ways to expand the types of cancer it can treat. The challenge, says Solh, is to find a receptor to put on the T cell that is only on the cancer and not on any healthy cells, because the engineered T cell will attack anything with the receptor, cancer or not. “With blood cancer, it’s easier because you can get rid of some blood cells without affecting the patient,” he says.

Another push in CAR T-cell research is figuring out how to use “off-the-shelf” CAR T-cells – T cells from donors that have already been engineered to fight a specific cancer and are ready to go. That would cut down on the time of treatment, lower the cost and make the therapy available to more patients.

Cellular immunotherapy is also expanding beyond T cells. Studies are examining how the immune system’s natural killer cells can be engineered to better attack and kill cancer cells, a therapy called CAR-NK or NK-cell therapy. Other studies involve TILs, or tumor infiltrating lymphocytes. TILs are a kind of immune cell that can be removed from a tumor, multiplied in a lab and then put back in the patient’s body to kill cancer cells. “Instead of having a million [TILs], probably expand them to 20 or 30 million,” says Solh. While these treatments are now only available in clinical trials, doctors say they represent continuing advances in cellular therapy; Solh says he expects TIL therapy will be approved by the FDA soon for treating melanoma.

In fact, while immunotherapy has become a first-line treatment for some cancers, it’s still relatively new and we’re just beginning to discover its potential. Solh believes major advances will come in treating solid-tumor cancers, like lung and breast cancer, with cellular therapies. Ramalingam says there is renewed interest in developing vaccines to treat cancer, and researchers are also trying to see if the immune system can be used to prevent cancer. “That’s the next frontier,” he says. “Can we intervene before cancer develops in a patient if we know who’s at risk?”

Personalized Treatment: Dr. Suresh Ramalingam, executive director of the Winship Cancer Institute of Emory University, explaining the findings of a CT scan that shows cancer in the right lung: photo contributed

“We’re still kind of in the early stages of learning how to use immunotherapy,” McCune says. “People will look back in 50 or 100 years and say, ‘Man, these people just got lucky and had a couple of drugs that happened to work, and they didn’t even really understand what they were doing.’ … People are living longer and with fewer side effects. This is really a novel time. We’re really just learning how to use these tools and use them with existing therapies to make them work better.”