Milestones in Medicine: How Immunotherapy Began in Cancer Care

Sharon Belvin was 23 and running out of options to treat her stage 4 melanoma in 2005 when her oncologist at Memorial Sloan Kettering Cancer Center in New York City offered to enter her in a clinical trial of a drug designed to empower her immune system to fight the cancer. By that point, she had progressed after several rounds of chemotherapy, plus radiosurgery to remove tumors that had spread to her brain.

The drug blocked CTLA-4, a protein “checkpoint” that prevents the immune system from recognizing and attacking cancer. After just four treatments, 60% of Belvin’s tumors were gone. Within months, they had all disappeared, and she has been cancer-free ever since. In 2011, that drug, Yervoy (ipilimumab), became the first checkpoint inhibitor to be approved by the Food and Drug Administration (FDA).

“To say I’m grateful is an understatement,” says Belvin, who lives in Williamsport, Pennsylvania, and works as a health coach for a hospital system. “I was 100% sure that if a new option didn’t come up, I was not going to be here. My children wouldn’t be here today. I feel privileged to have been in that clinical trial.”

The introduction of checkpoint-inhibiting drugs marked a new phase in the evolution of immunotherapy. Although they were not the first treatments designed to boost the immune response to cancer, these agents produced higher remission rates than did the prior generation of immunotherapy. Checkpoint inhibitors paved the way for a revolution in cancer research, leading to five additional approved checkpoint inhibitors, two personalized immune-cell therapies and clinical trials investigating nearly 1,300 innovative immuno-oncology approaches.

“Twenty years ago, we still had a very immature under- standing of immune regulation. The breakthroughs came by identifying completely new pathways and approaches (to activating the immune system),” says Dr. Robert Vonderheide, director of the University of Pennsylvania Abramson Cancer Center.

TAKING THE BRAKES OFF THE IMMUNE SYSTEM

Even though the role of the body’s immune system is to hunt down and eliminate pathogens, such as bacteria and viruses, cancer has always been a tricky foe. The immune system sees cancer cells as normal, even though they are dividing and growing at abnormal speeds.

The notion that the immune system could be tricked into attacking tumors emerged in the late 1800s, when physicians started publishing stories about patients with cancer who went into spontaneous remission after catching the flu or some other virus or infection. One physician, William Coley, was so devastated by the loss of a 17-year-old patient to sarcoma in 1890 that he set out to find a cure.

He reviewed 90 sarcoma cases that had occurred over 15 years and discovered a man who came down with the bacterial skin infection erysipelas while being treated for sarcoma tumors that had spread across his neck and face. His cancer disappeared. Coley attributed the remission to the activation of the immune system and spent years experimenting with injections of inactivated erysipelas. His managed to produce remissions in about half of his patients with soft tissue sarcoma.

Around the same time, two French researchers stumbled upon an immune-boosting treatment that is still used today to treat bladder cancer. Bacteriologist Albert Calmette and veterinarian Camille Guerin isolated a bacterium in cows that’s similar to the human strain of tuberculosis. They selected variants of these bacteria that were less virulent to create a vaccine against tuberculosis called bacillus Calmette-Guerin (BCG).

In 1929, researchers at Johns Hopkins began investigating BCG in oncology after noticing a low incidence of cancer among patients with tuberculosis. Several other researchers picked up the ball, proving that BCG slashed the risk of tumor recurrence in patients with noninvasive bladder cancer so significantly that the FDA approved the vaccine as a treatment in 1990.

Interferon alpha, a cytokine that helps regulate and activate the immune response, was approved in 1986 to treat hairy cell leukemia. It has since been approved to treat four other cancer types.

“Although the approaches we have now are completely different in their design, the early use of immunotherapy showed, every now and then, a remarkable patient with an amazing result,” Vonderheide says. “They were unusual, but it was very clear that something dramatic happened because of immune activation.”

It would take many more years of research to understand what was happening at detailed cellular and molecular levels in those patients who experienced positive outcomes, he says. As it became known that cancer cells can activate checkpoints to evade the immune system, one of the first advances to emerge was the idea of releasing the brakes on the immune system by inhibiting molecular checkpoints like CTLA-4.

The CTLA-4 inhibitor Yervoy was approved based on the results of a study in 676 patients with late-stage melanoma. Participants were randomly assigned to one of three treatment groups: Yervoy plus an experimental tumor vaccine called gp100, Yervoy alone or the vaccine alone. Those who received Yervoy, either with the vaccine or by itself, lived an average of 10 months, whereas those who got only the vaccine lived just 6.5 months. A fraction of the patients who responded to the CTLA-4 inhibitor became long-term disease-free survivors of what would have otherwise been a rapidly fatal disease. Yervoy has since been approved to treat some patients with renal cell and colorectal cancer, though it is far from perfect: Nearly 13% of patients in the original melanoma trial suffered severe autoimmune reactions, some of which were fatal, and trial results published in 2017 showed that Yervoy had a low response rate of 19%.

The discovery of new checkpoints — and novel ways to block them — has generated immunotherapies that work in broader groups of patients. Drugs that inhibit PD-1 and PD-L1, for example, have been approved to treat several cancer types. The PD-1 blocker Keytruda (pembrolizumab), first approved in 2014, is now used to treat at least nine cancers, including melanoma and Merkel cell carcinoma — both skin cancers — and cervical, gastric and non-small cell lung cancer. Opdivo (nivolumab) and Libtayo (cemiplimab) also block PD-1, and there are three PD-L1 inhibitors on the market, including Tecentriq (atezolizumab), Bavencio (avelumab) and Imfinzi (durvalumab).

Keytruda reached a milestone in 2017 when it became the first drug approved to treat cancer based on a genetic feature rather than the origin of the disease. The FDA added an approval to Keytruda for the treatment of any tumor that is microsatellite instability-high or mismatch repair deficient, meaning it is unable to properly repair its own DNA and therefore acquires many mutations that make them particularly vulnerable to an immune attack. In a trial that enrolled 149 patients with this deficiency in 15 different tumor types, nearly 40% of patients had a complete or partial response to the drug. The most common side effects included fatigue, itchiness and decreased appetite.

ENGINEERED IMMUNE CELLS

After Kristin Kleinhofer received an acute lymphoblastic leukemia (ALL) diagnosis in 2010 at age 36, she underwent two years of chemotherapy that put her in remission. Then her cancer relapsed in 2014, right around the time the stories of a miracle patient with ALL started appearing in magazines and newspapers. Emily Whitehead participated in one of the first clinical trials of a personalized treatment called chimeric antigen receptor (CAR)-T cell therapy, in which her immune cells were removed from her blood, engineered to be able to recognize and attack her cancer, and then put back into her body.

Kleinhofer, who was initially treated at Stanford University near her Northern California home, heard Whitehead’s story and immediately went looking for clinical trials of CAR-T treatments. She was accepted into a trial of a CAR-T therapy called JCAR014 at the Fred Hutchinson Cancer Research Center (Fred Hutch) in Seattle. Kleinhofer received her engineered cells in November 2014 and a stem cell transplant, which doctors thought would boost survival. A month later, she was declared disease-free.

Now Kleinhofer volunteers as a patient advocate for immuno-oncology. “My hope is that CAR-T will become a front-line treatment, so patients don’t have to go through the toxicity of chemotherapy,” she says.

In 2017, the CAR-T treatment that Whitehead received, Kymriah (tisagenlecleucel), was FDA approved to treat patients up to 25 years old with B-cell ALL that has relapsed. It was later approved to treat adult patients with large B-cell lymphoma, as was another CAR-T treatment, Yescarta (axicabtagene ciloleucel). Both therapies produced remission rates previously believed impossible in patients who had exhausted all other treatment options. In the trial leading to its approval, Yescarta produced a 51% complete remission rate and Kymriah produced an 83% remission rate. (JCAR014 is still in clinical trials in non-Hodgkin lymphoma.)

The first-generation CAR-Ts were engineered to recognize a specific antigen, a molecule on the surface of B cells called CD19. Now researchers around the world are studying other targets so they can expand the use of T-cell therapies to many more tumor types.

Researchers at Fred Hutch are developing T-cell therapies targeting a molecule called WT1, which is produced at high levels in some cancer cells but hardly at all in healthy cells.

The therapy works by taking T cells and modifying them so they can find and destroy the cells with WT1. These T-cell receptors are being tested in acute myeloid leukemia, and they may have the potential to treat other cancers, including non-small cell lung cancer and breast cancer. Preclinical studies on another T-cell receptor therapy targeting the protein mesothelin in pancreatic, lung and ovarian cancers are also underway, says Dr. Phil Greenberg, head of immunology at Fred Hutch.

“We can genetically modify only the cells that we’re giving, so they function differently from the other cells in the body,” Greenberg says. As the ability to do that improves, the cells could be engineered to directly target tumors, which will not only reduce the risk of autoimmune side effects but could also make it possible to target even more tumor antigens, he says.

FROM VACCINES TO COMBINATION TREATMENTS

Dendritic cells, another type of immune cell of interest in immuno-oncology, have a natural ability to present antigens to cancer-killing T cells. In 2010, the first dendritic cell vaccine, Provenge (sipuleucel-T), was approved by the FDA to treat advanced prostate cancer. The treatment involves isolating and removing dendritic cells from the blood, exposing them to a protein found in most prostate cancers and attaching them to an immune stimulator. The hope was that the cells would persist in the body, hunting down cancer cells and killing them before they could take hold in the body.

But in clinical trials, Provenge increased overall survival by just four months, a much weaker immune response than the oncology world had hoped to see, says Dr. William Decker, an associate professor at Baylor College of Medicine in Houston. He is one of the researchers working on a new generation of vaccines that has emerged since Provenge entered the market.

“We know so much more about dendritic cell biology now,” Decker says. One insight gained after Provenge’s approval, he says, is that when dendritic cells are immature, they actually suppress the immune response to cancer rather than stimulate it. Decker leads a research team that developed a vaccine using mature dendritic cells, which are more likely to generate an immune response. A phase 1 trial of a vaccine the Baylor researchers developed for the treatment of pancreatic cancer will start enrolling patients this year, and a similar vaccine approach is planned for glioblastoma.

Decker and many other immunooncology researchers see the field moving toward combination treatments that spur the immune system to fight cancer in several ways. If Baylor’s dendritic-cell vaccine advances to a phase 2 trial, Decker says, he hopes to combine the treatment with a checkpoint-inhibiting drug in one group of the study. “Taking the brakes off the immune system makes everything work better,” he says.

More than 1,700 clinical trials underway are combining PD-1 or PD-L1 inhibition with other cancer therapies and span every cancer type, including rare tumors, according to the Cancer Research Institute.

Many patients who got a second chance at life because of immuno-oncology research are excited to witness the evolution of the field. They include Stephanie Florence, who was treated in a CAR-T cell therapy trial at Fred Hutch in 2015 after chemotherapy and a stem cell transplant failed to prevent a relapse of her lymphoma. Florence, who was 34 at the time, has been cancer-free ever since she received the infusion of her CAR-T cells.

“From the time I was told I was incurable, I thought I would always be wondering when my next relapse would be. Thankfully, that is no longer part of my everyday life,” says Florence, a photographer who lives in Lewiston, Idaho. “I’m so encouraged by all the research. I am excited about the potential for immunotherapy to help all cancer patients.”