A Diagnosis

AROUND THANKSGIVING OF LAST YEAR, Patti Tautolo woke up with a sore shoulder. She’d been doing yardwork with her husband the day before, so she figured she had just overused it. A few months later, while working on projects in February, she started to feel similar pain in her right thigh. Thinking she’d pulled a muscle, she made an appointment with her doctor. X-rays revealed something a great deal more worrisome — large, erosive lesions — and a biopsy showed they were malignant. Cancer. Additional scans showed that the cancer had spread to her lungs, her kidney, her breast, her trachea, her pelvis, her skull: It was everywhere. The official diagnosis was stage 4 kidney cancer.

As a former pediatric nurse, Tautolo immediately understood the gravity of the diagnosis. She knew that even with the best care available, doctors would give her six months to two years to live. If she wanted to beat those odds, she’d need to take a chance on something else, and immediately she thought of a hospital where she had previously sent patients.

“I'm well one day and I'm stage 4 the next,” says Tautolo, who is 59. “And I just knew—I was going to need a clinical trial, and it had to be City of Hope.”

City of Hope is a world-renowned independent medical and research center located about 25 miles northeast of Los Angeles. Founded in 1913, it is now a comprehensive cancer center, one of 47 designated by the National Cancer Institute. It includes a clinical research hospital for patients as well as its own science labs and drug-manufacturing facilities, where researchers and doctors are investigating and treating cancer, diabetes, HIV-AIDs, and other serious diseases.

Tautolo’s instinct was right: Her doctor immediately sent a note to Dr. Sumanta “Monty” Pal, M.D., co-director of the Kidney Cancer Program at City of Hope. Less than a week later, Tautolo was sitting in one of Pal’s consultation rooms with her twin sister and both of their husbands, who had come along for support.

A lab technician works on the CAR-T process at City of Hope’s Beckman Research Institute.

An Experiment

WHEN PATIENTS ENROLL IN A CLINICAL TRIAL at City of Hope, they will receive one of two types of treatment: Some of the patients are given a new drug or combination of drugs in addition to the current best care available, and those who do not receive the new drugs receive only the current best care. For therapeutic trials, it means trying a novel approach. Trial results eventually determine whether these treatments gain approval for general use by the U.S. Food and Drug Administration (and thereby become the new best available care). Thus, trials offer patients the opportunity to receive advanced treatments years before they become the standard of care—and as Tautolo knew, coming to City of Hope offers the greatest chance of joining a trial. City of Hope has more than 6,200 patients enrolled in 500 trials each year.

Even in a center renowned for its participation in clinical trials, Pal’s practice stands out. He currently has patients in more than a dozen trials and is designing several more. He went to college at 13, started medical school at 17, and added a fellowship in medical oncology so that he could combine advanced research with patient treatment. When he’s not at City of Hope, he’s usually speaking at medical conferences, informing the work of specialists around the world.

Pal had reviewed Tautolo’s scans several times before this meeting. He knew that with standard care, patients in her situation might survive for six months, maybe two years if she responded well to treatment. Still, he managed to sound genuinely optimistic as he explained his plan. He grabbed a marker and drew a diagram on the thin paper that covered the hospital bench in the room. “You’re probably wondering about chemotherapy,” he said. “That was the standard in the 1970s.” He drew the cancer cell, with an arrow pointing to a protein receptor on the edge of the cell. “Today, treatment is much more targeted.”

Pal is a visual person. As he starts to explain the treatment plan to patient Patti Tautulo, he draws a diagram of how the investigational drugs will attack her cancer cells.

Targeting a Cure

“TARGETED” TREATMENT TAKES MANY FORMS at City of Hope. In Tautolo’s case, the trial will test the efficacy of two drugs that have never been combined before, a trial open only to patients with stage 4 kidney cancer. It will test whether this drug combination offers results better than the current standard, which is a single drug. Pal currently has patients in similar trials targeting other stages of kidney cancer, as well as patients with prostate or bladder cancer.

As extraordinary as his practice is, Pal is just one of many at City of Hope—one of hundreds of research scientists and physicians. The center has a history of scientific discoveries that have influenced the standard of care for a range of diseases and medical conditions. In the late 1970s, City of Hope researchers were the first to create technology that led to the development of synthetic human insulin, which has transformed the treatment of diabetes for millions of patients worldwide. Its breast cancer specialists recently identified a genetic abnormality that is associated with aggressive tumors and a higher risk of recurrence and are now working to slow or stop it. Another intense research project is working to eradicate the most common form of cancer in children.

Within the next six years, say Pal’s counterparts in the diabetes lab, they think they can actually develop a cure for type-1 diabetes.

In the six-story research building across the street from the hospital, immuno-oncologists are working to get the patient’s own immune system to target and fight cancer on its own. In other labs, molecular biologists are targeting specific genetic mutations in cancer cells, testing what happens when a drug used for breast cancers is applied to prostate cancers that show the same mutation.

Whatever the target and method under investigation, City of Hope scientists are in constant communication with the patients’ physicians, attempting to inspire still more clinical trials with their findings. Their close proximity means that surgeons can deliver tissue samples to researchers while a patient is still in surgery. In some cases, the surgeon herself is also the researcher and will immediately walk from the surgery to her lab to continue investigating a cure. This is a process that normally can take weeks when a hospital must send tissue samples to outside labs, then wait for results. As a result, City of Hope has nearly 30 drugs in the pipeline at any given time. Immuno-oncologist Marcin Kortylewski, Ph.D., has a simple explanation for this success: “Science moves faster here,” he says.

Pal often collaborates with Kortylewski, whose lab is directly across the street from the hospital.

An Immune Approach

KORTYLEWSKI AND FELLOW RESEARCHERS are breaking new ground in cancer treatment by targeting the immune system in two ways. Kortylewski’s team is developing novel drugs; one floor below his lab, another team is working in direct cell therapies. It’s the same target, approached through entirely different methods.

Many patients at City of Hope Helford Clinical Research Hospital can look out their windows and see the Beckman Research Institute building where researchers are developing the treatments that might extend their lives.

The immune system is designed to recognize and destroy all intruders, from conditions as innocuous as the common cold to those as serious as cancer cells. Its first line of defense are T cells, which are produced by the thymus gland to hunt down and kill foreign or damaged cells. Usually when they detect these cells, T cells attack, but cancer cells produce a protein that acts as a disguise, allowing them to proliferate undetected. Immunotherapy seeks to strip away the protein mask and so spark the natural immune response. The aim, as Kortylewski puts it, is to “put the immune system back on the proper track and then just watch it go to work.”

Scientists have been trying to find ways to stimulate T cells since the 1980s but until recently with little success. What worked in lab studies did not translate to human trial, explains Kortylewski, because in patients the tumors fought back and, more often than not, the tumors won. More recently, researchers started to succeed in undermining the tumor’s self-defense system by targeting it with a series of drugs called checkpoint inhibitors.

Now, clinical trials have started pairing checkpoint inhibitors with immune-stimulating drugs. This is the approach being tested in the trial that Pal prescribed for Tautolo. In the lab, Kortylewski’s team is testing what happens if these two approaches are combined into a single drug, simultaneously prompting a T cell attack while defeating the cancer cell’s defense. Based on successful results in animal tumor models, he has created an entirely new class of targeted immunotherapeutic drugs. His team is in the last stage of toxicology studies and a clinical trial could reach City of Hope patients as early as 2018.

There are dozens of scientists working in the 5th floor lab at the Beckman Research Institute.

Another approach to immunotherapy pioneered at City of Hope is already in clinical trials. This is the cell therapy approach, in which doctors take blood from a patient and bring it to the cell biologists in the labs, who then attach receptors (called CARs, for “chimeric antigen receptors”) to the T cells. The patient’s modified CAR-T cells, proliferated in the lab by the billions, are reinfused into the patient to attack the tumor. They lift the tumor cells’ protein mask and guide the immune system’s attack.

Early clinical trials at City of Hope have already shown that reengineered T cells are better able to fight brain tumors than both chemotherapy and radiation, and that patients treated with T cell therapy are less likely to see their cancer come back. Doctors at City of Hope are already experimenting with CAR-T in the treatment of some patients with leukemia, lymphoma, rare brain cancers, or prostate cancer, and plan to expand that list in the future.

CAR-T is a revolutionary cell therapy but hard to scale. Every single patient needs to have their cells extracted, reengineered, and reinfused. If the drug that Kortylewski’s team is developing proves successful, he says, it would introduce the next generation of personalized care, one that asks the immune system to personalize treatment for each patient without the need for any other interventions. If successful, the therapy could be mass-produced, allowing it to reach patients well beyond the City of Hope campus.

A Small Molecule Approach

ONE OF THE REASONS that Kortylewski can say science moves faster at City of Hope is the sheer amount of collaboration among doctors and researchers. There are days when Pal takes blood samples from prostate cancer patients straight to the lab of molecular biologist Jeremy Jones, Ph.D. The two are running a study together to determine the root of drug resistance in certain prostate cancer patients. Pal enrolls his patients, and he and Jones test their blood samples throughout their treatment for signs of genetic mutations. Thus far, they’ve detected a mutation that’s also often seen in breast cancer. Now, they’re preparing a clinical trial to see if a breast cancer drug might successfully attack the mutation in prostate cancer as well.

“Sitting down with Monty [Pal], understanding the problem, getting the clinical samples, looking at the data, and figuring out the new therapeutic options—all of this is coming together,” says Jones.

“I think we've hit on a real, possible, new treatment for these patients.”

Jones is also focusing on developing entirely new prostate cancer drugs. Prostate cancer develops when testosterone interacts with a specific protein in prostate cells. For decades the best treatment was castration, later chemical castration. Whether surgical or chemical, the reason for castration was that, Jones explains, “you basically stop the testes from producing testosterone and it shrinks the cancer.” Still, the cancer is not destroyed and eventually comes back, most often within a year.

Researchers next developed drugs that limited the interaction between testosterone and the receptor proteins, so that the cells could not turn cancerous and proliferate. The effectiveness was limited, because cancer cells often mutated and developed drug resistance.

“We needed a better drug that works in a different way,” says Jones, and his team set out to develop one. At first, they tested how different molecules could better block the receptor-testosterone connection. After several unsuccessful attempts, they shifted their focus to the way the receptors respond once they bind with testosterone. This led to what could prove to be the most targeted prostate cancer drug to date. It is currently in the last stage of animal testing. Jones will then present it to the FDA for permission to run a phase 1 clinical trial in humans.

The compound will be manufactured right on campus, in one of City of Hope’s three FDA-approved drug and cell therapy manufacturing facilities. From there, it will be walked across the street to the hospital, where City of Hope patients will be the first to gain access to the clinical trial.

A postdoc researcher prepares a DNA concentration in the 5th-floor lab at Beckman Research Institute.

The Next Phase

THIS ACCESS TO CLINICAL TRIALS is what drew Tautolo to City of Hope as soon as she heard her diagnosis of stage 4 kidney cancer. Tautolo didn’t know if she’d get into a trial. If she did get in, she didn’t know if she would be selected for the trial’s combination of drugs or instead be one of the participants selected to receive the standard of care. Even if she received the trial drug combination, no one knows whether that will be better than the standard of care. That’s what this study is designed to determine.

Tautolo does know, however, that without a trial, most doctors say she has about six months to live. She wants more time. If there’s a chance that a clinical trial can offer her that time, she’s willing to try, and she trusts that her best chance of getting into a trial is to be treated at City of Hope.

As Pal and fellow doctors enroll ever more patients, their counterparts in the lab continue to design the next generation of trials.

Long-term, Jones says, the hope in prostate cancer treatment is to put his progress in small molecule science together with Kortylewski’s advanced work in immuno-oncology, creating a combination of cell and drug therapies more powerful than either on its own.

Collaborations like these are happening across all departments at City of Hope, as molecular biologists, immunologists, geneticists, pathologists, pharmacologists, statisticians, and population scientists join with surgeons, clinicians, nurses, and patients to treat every form of cancer with every proven and potential approach. What they share is a common belief that they will deliver what Tautolo and so many others are coming to them for—something that can “if not cure them,” says Jones, “keep the cancers in remission for a long, long time.”

City of Hope patients and their family members often leave wishes hanging on the branches of the wishing trees located adjacent to the Rose Garden.