Philip Prichard’s clinical trial success story
Broadening the immunotherapy attack
A successful immune attack that began with melanoma is being extended to other cancers
The kidney tumor that snuck up on Philip Prichard was surprisingly large and aggressive by the time it clearly announced itself in the jarring voice of excruciating pain in his right side and leg during a 2012 business trip.
A physical exam and CT scan back home in Memphis revealed stage IV kidney cancer. Surgery removed a nearly 4-pound tumor, but by now the cancer had spread to other organs. Targeted therapy and an attempted second surgery didn’t slow its growth.
“When I opened my eyes after the second surgery, my doctor came in and said ‘we’ll talk later,’” recalls Prichard, 48. “He had that look in his eyes that said, ‘I don’t know what to say right now.’ Even on my morphine drip I could tell he was saddened by what was going on.”
Prichard’s wife, Susan, began researching where to turn next.
The couple arrived at MD Anderson in the spring of 2013 in search of hope and found it in a clinical trial for a drug that treats cancer by freeing the immune system to attack it.
At that time, the immunotherapy drug nivolumab was deep into clinical trials for melanoma, thought to be the cancer most vulnerable to immune approaches. However, newer studies had opened to test it against other cancers.
When doctors told Prichard he could join the trial, his response was, “Yeah, let’s do this!”
“Over the first three months, I began to feel a bit stronger and eat better,” Prichard recalls. “Then the CT scans started to come in and they showed my tumors decreasing in size every time.”
He didn’t notice side effects, but given the discomfort and fatigue caused by the disease, he’s not sure he would have noticed.
“I was pretty far down the path there,” he says.
After three years of coming to Houston every other Tuesday for treatment, Prichard stopped taking nivolumab in March. He’s back in good health and his fresh start inspired him to strike out from the family distillery business in a new venture with Susan: They’re opening a new whiskey bar back home in Memphis.
Prichard is among the 25% of metastatic kidney cancer patients who respond to nivolumab. About half of those have durable, long-term responses, says his oncologist, Nizar Tannir, M.D., professor and deputy chair of Genitourinary Medical Oncology.
“He’s done really well. Nivolumab is the least toxic therapy we have for metastatic disease, and it comes with the chance of cure, or at least durable remissions for many years,” Tannir notes. “That’s not something you get with any other therapy.”
Good news for metastatic cancer patients The approach that helped Prichard, called immune checkpoint blockade, continues to have an increasing impact on solid tumors that have metastasized, or spread, to other organs. These cancers are the hardest to treat.
Response rates to immonutherapy drugs on a variety of metastatic cancers range from 15 to 40% of patients, with many of these enjoying long-term remissions, some of which appear to be cures.
Not bad considering at one point many predicted these drugs might only work well for melanoma, the cancer with the highest rate of genetic mutations, thus providing the most targets for immune attack. It has long been thought to be the most “immunogenic” of cancers.
That’s not surprising to Jim Allison, Ph.D., chair of Immunology and executive director of the immunotherapy platform at MD Anderson.
Allison conceived checkpoint blockade out of his basic research on immune response.
“This approach treats the immune system, rather than focusing on the tumor, so there’s really no reason that it shouldn’t work in many human cancers,” he says.
The drug developed from his research, ipilimumab (Yervoy), was approved by the Food and Drug Administration (FDA) in 2011 to treat inoperable or metastatic melanoma. Follow-up research of 5,000 patients who had advanced melanoma and were treated with the drug showed 22% surviving to 10 years and beyond — unprecedented results.
While news accounts of these drugs often refer to them as “only helping a fraction of patients,” oncologists know that such results in metastatic cancers are incredibly rare.
“That immune checkpoint inhibitors work so well as single treatments against advanced, metastatic cancers is incredibly encouraging,” says Padmanee Sharma, M.D., Ph.D., scientific director of MD Anderson’s immunotherapy platform and a professor of Genitourinary Medical Oncology and Immunology.
“There’s great opportunity to improve these early results by more precisely identifying patients who will benefit from immunotherapy and by understanding how to best combine immunotherapy with other types of treatment,” Sharma says.
The immunotherapy platform addresses these issues by analyzing tumor biopsies before treatment, during treatment with immunotherapy, and then after treatment ends or the cancer worsens. It’s an important part of the Moon Shots Program and its goal to reduce cancer deaths by cutting down on the time it takes to turn scientific discoveries into progress against these diseases.
In addition to studying the presence and strength of T cells — the immune system’s targeted attack cells — in and around the tumor, the group looks for other immune cells, proteins and substances secreted by cells that foster or inhibit immune response.
Understanding the complex interplay of these factors might help identify biomarkers — proteins, cells or molecules whose presence indicates that a drug will or won’t work.
Since Philip Prichard entered the clinical trial in 2013, nivolumab (known as Opdivo), has been approved by the Food and Drug Administration for advanced melanoma, lung cancer, kidney cancer and Hodgkin’s lymphoma.
Another immunotherapy that hits a related target was recently the first approved for bladder cancer.
Immunotherapy drugs such as nivolumab works by blocking a protein called PD1 on T cells
— white blood cells that act as guided missiles against viruses, bacteria and abnormal cells identified by the immune
system. Cancer cells can “turn off” an attacking T cell because they bear a protein called PD-L1
that acts like a key, connecting with PD1 to lock down the T cell.
By blocking this connection, immunotherapy drugs allow the body’s immune system to fight cancer.
Working on prostate cancer
One such biopsy study has opened a new door in prostate cancer — a tumor type that so far has stoutly resisted treatment by checkpoint blockade.
Biopsy analyses by Sharma and her colleagues show that a particular combination of immunotherapy drugs might first draw T cells into these tumors, then free them to attack.
A national clinical trial of this concept, led by Sharma, will begin later this year.
“Companies with immunotherapy drugs had largely given up on prostate cancer, yet research has presented another opportunity,” Sharma says.
They’ve also identified a third immune checkpoint that might be hindering immunotherapy for the disease.
There are about 165 clinical trials of various immunotherapies underway at MD Anderson, most of which involve some type of checkpoint blockade or immune-stimulating molecule. These trials generally focus on:
- Extending immunotherapy to other types of cancer such as leukemia, colorectal, pancreas, lymphoma, glioblastoma and cancers caused by the human papilloma virus (HPV).
- Testing immunotherapy drugs in combinations with each other or with targeted therapies, radiation, and surgery to broaden and deepen patient response and survival.
- Comparing these treatments, which are approved for late-stage disease, with standard of care at earlier disease stages to see if immunotherapy might be used earlier.
Pharmaceutical companies are bringing new drugs to trials that seek to stimulate or protect immune response in new ways.
Allison and Sharma, who also are director and co-director of the Parker Institute for Cancer Immunotherapy at MD Anderson, wrote reviews last year in the journals Science and Cell outlining how research can advance the field.
Well-thought-out combinations, they wrote, are the key to “development of new, safe treatments that may prove to be curative for many patients with many types of cancer.”
Under an agreement reached this summer with Bristol-Myers Squibb, the developer of both nivolumab and ipilimumab, MD Anderson researchers will test new ways to treat lung cancer at all stages of the disease.
Currently, the standard of care for early-stage lung cancer is surgery. Clinical trials under the agreement will look at:
- Treating inoperable early-stage disease with immunotherapy, followed by targeted radiation.
- Giving patients whose disease is operable immunotherapy before and after surgery, seeking to cut the recurrence rate of lung cancer down from 50%.
- Providing immunotherapy followed by aggressive “consolidation therapy” — either surgery or radiation — for those with metastatic disease.
“These trials will allow us to integrate immunotherapy in innovative ways with other treatments, including surgery and radiation, to improve standard of care and expand treatment options for all patients, including those with early-stage disease,” says John Heymach, M.D., Ph.D., chair of Thoracic/Head and Neck Medical Oncology.