Designer antibodies, like checkpoint inhibitors, have revolutionized cancer treatment.
by Anna C. Christensen, UA Cancer Center
Originally published in the Spring 2018 issue of Act Against Cancer
Your immune system never sleeps. Every moment of the day, immune cells monitor your body for disease, calling for backup when they detect a threat. It’s a system that works elegantly — most of the time. It’s not foolproof; if it were, we’d never get cancer in the first place.
“The immune system is supposed to fight tumors, but it doesn’t do it very effectively,” says Daruka Mahadevan, MD, PhD, director of the UA Cancer Center Early Phase Clinical Trials Program.
If the immune system can’t suppress their development early, abnormal cells can blossom into cancers, and cancers can spread throughout our bodies, eventually taking our lives.
“So many of my patients feel like cancer is a betrayal of their own immune system’s ability to survey and protect them,” says Julie Bauman, MD, MPH, UA Cancer Center division chief of hematology and oncology.
When tumors evade detection by the immune system, we turn to chemotherapy and radiation, which don’t exclusively target cancer cells and are notorious for the collateral damage rained upon healthy cells, often causing side effects like nausea and hair loss.
But what if we didn’t have to subject normal cells to the friendly fire sprayed haphazardly by chemo and radiation? Many cancer researchers are optimistic about immunotherapy, a treatment that harnesses the power of the immune system, teaching it to recognize — and destroy — cancer cells.
“It’s not the drugs that are killing the cancer,” says Emmanuel Katsanis, MD, division chief of pediatric hematology and oncology. “It’s the patient’s immune system, which has been activated to fight and kill cancer by itself.”
“I am amazed,” says Protul Shrikant, PhD, professor of immunobiology at the UA College of Medicine – Tucson. “An educated immune cell, like a guided missile, can specifically recognize and destroy the tumor target, sparing normal tissues.”
“It really appeals to people, the idea that their own immune system could do the job,” says Dr. Bauman. “There’s this notion that we’re restoring a natural process in the body, the ability to harness its wisdom to attack cancer.”
“The development of immunotherapy has revolutionized the way we treat cancer,” says Clara Curiel, MD, leader of the UA Cancer Center’s cutaneous oncology team. “It’s a paradigm shift.”
T cells: A crash course in immunity
The immune system evolved to distinguish between foreign invaders, like viruses and bacteria, and friendly faces, namely a person’s own “self” cells. The ability to recognize this difference is essential to keeping the system in balance.
A crucial component of the immune army, T cells cruise the bloodstream, on the lookout for “bad guys.” T cells can call in reinforcements by special-ordering customized proteins called antibodies, which are able to lock onto these “enemy” cells and tag them for destruction.
When T cells see a “non-self” invader, such as a virus, they mount an attack. But when they see a “self” cell, they need to know to leave it alone — otherwise, the immune system would be attacking its own body, a misfire that can lead to autoimmune diseases like rheumatoid arthritis and lupus. When all goes according to plan, the immune system’s foot soldiers patrol the body for enemies while leaving innocent civilians alone.
“Immune responses evolved to maintain a sense of self and distortion of self,” says Dr. Shrikant. “Mutations in normal cells are distortions that pose a threat, as in the case with most cancers. The capacity of immune cells to recognize these distortions of self is important.”
But recognizing a cancer cell isn’t as easy as it may seem.
“Cancer cells arise from our own cells, so they have a lot in common with our normal cells,” explains Dr. Bauman. “We have to exploit the things that are different about cancer and teach the immune system to recognize cancer as the enemy. Exploiting that difference is tricky.”
Cutting brakes and deploying supersoldiers: Boosting the immune response
If the immune system can’t detect the subtle differences between a cancer cell and a normal cell, it can’t manufacture the antibodies that are crucial in protecting us from cancer. Luckily, science can give the immune system a boost.
“We’ve learned how to turn antibodies that we engineer in the laboratory into proteins that fight cancer,” says Dr. Bauman. Scientists customize these so-called monoclonal antibodies to lock onto a specific cancer molecule, and physicians deploy these super-soldiers into the body.
One subtype of monoclonal antibody, called a checkpoint inhibitor, can tinker with a specific component of a T cell, which is akin to a “brake.”
Dr. Shrikant likens the immune process to driving a sports car. “A Ferrari owner needs to appreciate and understand the use of the accelerator and the brake to enjoy the car over the long haul,” he explains. “Otherwise, the Ferrari would be wrapped around a tree and produce injuries.”
While a normally functioning immune system needs those brakes to protect self cells from immune attack, some cancers can slam on the brakes to suppress the immune response. Checkpoint inhibitors cut that brake, a boon in an environment in which cancer cells, rather than autoimmune diseases, pose the most serious threat.
What’s more, educating the immune system to recognize cancer cells can lead to long-lasting immune responses well after a patient completes treatment.
“When you prime the immune system to recognize a target, it stays as a memory in your immune system,” explains Dr. Curiel. If, after treatment, a tumor cell starts replicating again, the immune system “will remember that it is a ‘foreign’ target and will attempt to eliminate it. Priming the immune system in combination with drugs that enhance the effect of T cells or decrease the immune escape mechanisms can lead to long-lasting responses.”
Possible side effects of using checkpoint inhibitors to take the brakes off of T cells, however, involve triggering autoimmune reactions in which immune cells attack healthy cells.
“If you were to disable all brakes in your Ferrari, your Ferrari would be out of control,” explains Dr. Shrikant. “When we unleash the capacity of the immune responses in an unregulated fashion, we may cause exuberant immunologic reactions that destroy healthy self cells.”
Immunotherapy joins forces with other treatments
Despite all the promise immunotherapy holds, most patients don’t experience the dramatic results that make headlines.
“It really depends on the disease and the drug, but I would say that 30 percent of the time, we see some efficacy,” estimates Hani Babiker, MD, associate director of the UA Cancer Center Early Phase Clinical Trials Program.
For her head-and-neck cancer patients, Dr. Bauman clocks immunotherapy’s efficacy at around 15 percent.
“I’ve seen patients achieve deep remission that we never thought possible,” says Dr. Bauman. “I wish this worked for everyone, because if 15 percent of people have meaningful responses to immunotherapy, that means 85 percent come to the table with that level of hope and are disappointed.”
To realize immunotherapy’s potential, it needs to work for more patients.
“I don’t know whose T cells will be awakened in the right way and attack the cancer, and whose T cells will be awakened in the wrong way and attack the patient,” says Dr. Bauman. “My hope is that I learn how to unlock the right T cells at the right time for the right cancer.”
While it’s tempting to imagine a future in which immunotherapy alone can vaporize tumors for good, chemotherapy and radiation aren’t going away any time soon, and in fact might increase the effectiveness of immunotherapy — leading to longer survival and less disappointment.
“I believe we can improve response rates to 70 to 80 percent with these rational combinations,” Dr. Mahadevan tells us. “A tumor that is resistant to one immune checkpoint therapy may be really sensitive [to] a combo.”
“I’m treating high-risk patients with a combination of chemotherapy, radiation and immunotherapy. And they really do work hand in hand,” Dr. Bauman says.
Radiation and chemotherapy directly kill tumor cells in a process that can release cellular debris into the body.
“Radiation breaks a cancer cell open and exposes all of its hidden guts to the immune system,” explains Dr. Bauman. “Chemotherapy directly poisons the cancer cell. It dies an immunogenic cell death, and also shows more of its abnormal contents.”
When immune cells are activated by immunotherapy drugs, this debris can help train the newly empowered immune system to recognize the enemy.
“An army of T cells is waiting to recognize some part of that cancer cell as foreign and, therefore, worthy of attack,” Dr. Bauman says. “Immunotherapy is there to prime that response and help those T cells become more active.”
Beyond the realm of chemotherapy and radiation, Dr. Babiker elaborates on other innovative combinations. “We’re combining checkpoint inhibitors with oncolytic viruses,” he explains. “This means not only adding the checkpoint inhibitor, but adding a virus that is genetically engineered to attack the cancer.”
“It’s almost a fiction story,” says Dr. Curiel of oncolytic viruses. “We inject a virus in the tumor, the virus goes inside cancer cells, destroys the tumor and presents the immune system with the target it needs to recognize. This process allows the immune system to selectively kill additional tumor cells and decreases the chance of recurrences.”
Hope for the future
Although the idea of immunotherapy is not new, in the clinic, it is still in its infancy. Most patients don’t respond, and those who do run the risk of potentially serious side effects. But it also has been responsible for remissions that were previously unimaginable, and patients exhausted by the harsh effects of chemotherapy and radiation may find immunotherapy to be a gentler experience.
“It’s a really exciting time in drug development,” Dr. Babiker tells us. “We’re discovering a [different] modality in cancer treatment, using our patients’ own immune system to target and fight the cancer.”
UA Cancer Center researchers are actively involved in laboratory research and clinical trials to delve deeper into the intricacies of the immune system, discover new immunotherapy drugs, find more effective treatment combinations and reduce side effects. Energized by the swift advances in the field over the last couple of decades, they look forward to what the near future holds.
“The future for immunotherapy is incredibly bright,” says Dr. Shrikant. “In the last 10 years we’ve come a long way.”
“My hope for the future is that cancer will not be a word we are afraid of,” says Dr. Curiel. “We have made huge progress in a very short period of time — it is encouraging, it is fascinating.”
“Twenty years ago, most oncologists would say, ‘Immunotherapy is never going to work.’ Now everybody is using it,” says Dr. Katsanis. “There’s a ways to go, but the whole field is evolving very, very quickly.”
Photo 1: Daruka Mahadevan, MD, PhD, and Eric Weterings, PhD (credit: Kris Hanning, UAHS BioCommunications)
Photo 2: Emmanuel Katsanis, MD, with patient Azayliah D. Perez (credit: www.csrichards.com)
Photo 3: Protul Shrikant, PhD (credit: Anna C. Christensen, UA Cancer Center)
Infographic 1: Types of Immunotherapy (credit: Gaius J. Augustus)
Photo 4: Julie Bauman, MD, MPH (credit: Kris Hanning, UAHS BioCommunications)
Infographic 2: Manipulating the Immune System (credit: Gaius J. Augustus)
Photo 5: Hani Babiker, MD (credit: Kris Hanning, UAHS BioCommunications)
Photo 6: Clara Curiel, MD (credit: Kris Hanning, UAHS BioCommunications)