Mobilizing the Immune System
Shari Kienzle thought she had the flu. “I was very achy and my back really hurt,” remembers the 52-year-old wife, mother of three college-age daughters, and human relations director. Her symptoms got worse, and soon “even walking down the hall was an effort,” says the avid hiker.
She did not have the u. In September 2017, Ms. Kienzle was diagnosed with diffuse large B-cell lymphoma, the most common type of non-Hodgkin’s lymphoma. She was admitted to UPMC Shadyside for immediate treatment.
“At first we were hopeful,” says medical oncologist Rafic Farah, MD. “Most patients with her diagnosis respond to the aggressive chemotherapy combined with the antibody Rituxan that we were giving her. But Shari, sadly, did not. Even after a third line of chemotherapy, her disease continued to progress.”
By March 2018, “Shari was very, very sick,” says James Rossetti, DO, who specializes in hematological malignancy
at UPMC Hillman Cancer Center.“She had very advanced, widespread disease with bone marrow and organ involvement. She was critically ill with limited treatment choices.”
Ms. Kienzle’s oncology team had two options. One was to try allogeneic transplant, using stem cells from a donor. “However,” according to Dr. Rossetti, “the evidence has shown disappointing results for this treatment in refractory diffuse large B-cell lymphoma.
“But, thank God, we had an alternative option. CAR T-cells.
“And we had no time to waste.”
“An unbelievable time”
CAR T is a cancer immunotherapy, and immunotherapy is “the hottest area in cancer research and medical treat- ment today,” says Stanley Marks, MD, chairman of UPMC Hillman Cancer Center and chief of the Division of Hematology-Oncology at UPMC Shadyside.
Immunotherapy mobilizes the body’s immune system to fight and ultimately control or end cancer. With CAR T-cell therapy, white blood cells are removed from a patient’s blood and genetically engineered in a laboratory to become chimeric antigen receptor (CAR) T-cells, so they can target and destroy cancer cells when they are infused back into the patient. This highly specialized treatment requires a multidisciplinary team of experts working closely together at each step of the process.
“Until six to eight years ago, clinical efficacy of immunotherapy was mainly theoretical,” says Robert L. Ferris, MD, PhD, director of UPMC Hillman Cancer Center. “In fact, today, no one else in Pittsburgh is doing the breadth and depth of research into immunotherapy that we do at Hillman.”
The Cancer Center is among a select group in the United States to test new immunotherapy treatments in clinical trials. Because of this experience, Hillman and UPMC Shadyside became the only cancer center in western Pennsylvania and one of the first in the country to offer a CAR T-cell therapy approved by the FDA only in October 2017. It is one of the two FDA-approved CAR T-cell therapy products available at Hillman as of September 2018. (The second was approved in May 2018.)
“Even a couple of years ago, we never anticipated such advances in therapy,” says Kathleen Dorritie, MD, who with Alison Sehgal, MD, co-directs the numerous immunotherapy clinical trials underway at Hillman and Shadyside.
“It’s an unbelievable time to be part of this groundbreaking work.”
“Her course was not easy”
On April 2, 2018, Shari Kienzle, mortally ill, became the first person in Pittsburgh to receive the first FDA-approved CAR T product, Yescarta.TM
“I just kind of put it in God’s hands,” she recalls.
Side effects of immunotherapy can be severe, and Ms. Kienzle, already so sick, “had all the side effects that come along with CAR T to the nth degree,” she says.
According to Denise Winfield, CRNP, clinical director in the CAR T program, “These side effects included cytokine release syndrome, a systemic inflammatory response whereby people can get very high fevers, changes in their blood pressure, and neurotoxicity, which causes patients to become temporarily confused or develop difficulty speaking.”
“Her course was not easy,” says Dr. Rossetti, who stresses that “caring for immunotherapy patients requires training at an institutional level for virtually everybody. And the leadership here has made sure that everybody caring for these patients is adequately trained to deliver prompt care for the toxicities. Because, in general, patients get through these symptoms just fine if we manage them promptly and correctly.”
In addition to the expected side effects, the extensive bone involvement with her disease caused fractures of her hip and leg. “We had to manage her through surgery at a very vulnerable time,” recalls Dr. Rossetti. “It was very, very scary. The timing for surgery had to be just right in order to allow the area to heal and yet not complicate some of the side effects that we expect from CAR T therapy.
“But one of the benefits of being at UPMC Shadyside is that all of our specialists are used to dealing with oncology patients,” he continues. “Our orthopaedic surgeons understand how to think outside the box. So again, it was a team effort.” Richard McGough, MD, performed the surgery successfully.
“And Shari really had just a tremendous spirit, and a lot of family support,” Dr. Rossetti adds. “There were family members with her all the time, which I think is important for people considering CAR T therapy.”
“Then one day…”
“Then one day I woke up,” Shari says simply. “Pretty soon I kept going, ‘Please, you have to let me go home. I have to go to my youngest daughter’s high school graduation!’
“And I did.”
While her previous PET scans had shown extensive cancer virtually every-
where throughout Ms. Kienzle’s body, her 30-day post-infusion PET scan was completely clean, as was the bone marrow. The cancer was gone.
“It was amazing,” she says. “I didn’t believe it really for a couple of days.” Dr. Rossetti remembers that “when we presented the data on Shari at our weekly oncology team meeting, there was elation. And honestly, we were humbled by it.
“Nothing beats seeing a patient get back to their life before cancer. We always say, ‘We want you alive, but we want you living.’ And that’s what we see with Shari. She’s back to true living, and it’s a joy.”
“Shari truly is a miracle,” says Ms. Winfield.
“I feel so very fortunate,” Shari says. “I can’t thank everyone enough for getting me and my family through this. Now I want to help people that are going through CAR T or at least be a resource for them.
“I want to let people know there’s a lot of hope.”
“Although it’s too soon to know what the duration of this new modality is going to be for any of our patients, as we look ahead, we hope to be able to offer it to patients sooner in the course of their disease,” Dr. Rossetti states.
“I also suspect that we will see less severe toxicities, because we’re addressing them soon and acting quickly.
“This team is really dedicated to constantly fine-tuning the process. We are never satisfied with the current result.”
In addition to CAR T cell therapy, UPMC Hillman Cancer Center and UPMC Shadyside also are one of only a very few cancer centers in the country ramping up a TIL (tumor infiltrating lymphocytes) immunotherapy program.
TILs are white blood cells that have migrated into metastatic tumors. In TIL therapy, a patient’s tumor is surgically removed, and these white blood cells are collected and analyzed to isolate those with the most potent ability to attack the cancer. These “blue-chip” cells are cultured in the laboratory to activate and reinvigorate them, then reinfused to treat the tumors throughout the body.
While CAR T has been used most effectively against blood cancers, TIL therapy is aimed at harder-to- fight solid tumors.
“Solid tumors have been the holy grail of immunotherapy,” says Udai S. Kammula, MD, a scientist and surgical oncologist recently recruited from the National Cancer Institute (NCI) to direct Hillman’s Solid Tumor Cell Therapy Program. At the NCI, he conducted clinical trials that showed the first successful use of TIL therapy for uveal melanoma, a rare eye cancer previously thought resistant to immunotherapy.
At UPMC Shadyside, a follow-up TIL trial for uveal melanoma patients has started (it is the only one in the world), along with a trial for bile duct cancers. Dr. Kammula also plans to start a trial exploring TIL strategy in a variety of other cancers.
“Our goal is to make Shadyside the center of excellence for cell therapy,” Dr. Kammula says. “Now we want to see whether TIL therapy can work in other diseases. We also hope to come up with the next generation of cell therapies.”
No off-the-shelf products
“The advantage of the TIL approach is that we can pick and choose which T cells will work most effectively,” Dr. Kammula says. “We can then custom-make the immunotherapy product, and that allows us to cater the treatment to each patient. There are no two TIL products that are exactly the same. Thus, it is challenging to develop an off-the-shelf sort of strategy, like CAR T.
“This is both the beauty of it and the challenge of it. So what we have planned is to develop a large library of T cell receptor genes that target a broad array of tumor targets. We’d like to use these receptors to engineer T cells to treat a variety of patients. We are very much interested in expanding the cell-based immunotherapy in more targeted ways.”
“Cellular therapies are growing here, and it’s very exciting,” says UPMC Hillman Cancer Center director Robert Ferris, MD. “We are the only place in Pittsburgh with the capacity to make our own cellular cancer immunotherapies, thanks to our experience and leadership in basic and translational science and our Cancer Center. Making our own cells will allow us to have control over the quality and the process. Ultimately, that is good for patients.”
Still in infancy
Dr. Kammula emphasizes that, “although we’ve made progress, we are still in the infancy of these cell products. There is so much to learn. There’s so much that we have to develop. I love coming to work every day because every day is different.”