University of Minnesota Health Cancer Care locations now offer access to two recently approved autologous immunotherapies for patients with refractory or recurring acute lymphoblastic leukemia and diffuse large B-cell lymphoma.
Patients with diffuse large B-cell lymphoma (DLBCL) or pediatric acute lymphoblastic leukemia (ALL) do not typically have many treatment options if they relapse more than once or if their cancer fails to respond to multiple rounds of chemotherapy, radiation therapy or stem cell transplants. To better help patients whose cancer is not responsive to standard treatment, University of Minnesota Health physicians became part of two phase II multi-center clinical trials testing a chimeric antigen receptor (CAR) T-cell immunotherapy called Kymriah that, thus far, has shown remarkable results using patients’ immune systems to battle cancer.
“All of the patients enrolled in chimeric antigen receptor T-cell studies have failed standard chemotherapy or bone marrow transplantation,” says University of Minnesota Health hematologist/oncologist Veronika Bachanova, MD, PhD, who led a trial on adults with lymphoma and serves as Chair of the Interdisciplinary Committee for Lymphoma and member of the Division of Hematology, Oncology and Transplantation at the University of Minnesota Medical School. “Patients were considered incurable because they relapsed after several treatments or had refractory disease.”
An early flurry of positive results among participants helped lead to FDA approval of the new cell-based immunotherapy, bringing hope to individuals with recurring cancer. University of Minnesota Health physicians are just beginning to unlock the true potential of this innovative approach to treating cancer.
On the Fast Track to Approval
On-site participation in the Kymriah clinical trials began at University of Minnesota Health locations in 2015, and it quickly became apparent that this therapy is highly effective and can result in elimination of advanced cancer. One hundred patients with pediatric ALL and more than 90 patients with aggressive non-Hodgkin’s lymphoma were enrolled in the studies across multiple centers, and the results were so impressive that Kymriah obtained the Breakthrough Therapy distinction from the FDA. Both treatment protocols also received Priority Review designation, meaning that the FDA’s review process was shortened from 10 months to six months because of their effectiveness in the treatment of a serious medical condition.
In August 2017, the FDA approved Kymriah for use in patients age 25 or younger who have treatment-resistant or relapsed B-cell precursor ALL. The trial found that 83 percent of enrolled Kymriah patients exhibited leukemia remission within three months of treatment. The therapy’s approval was a historical milestone for cancer therapy in the United States — it was the first time the FDA cleared cell-based gene immunotherapy for use in this country. That success was quickly followed by the approval of Yescarta, a CAR T-cell based gene therapy, in October 2017.
Yescarta was approved to treat adults with DLBCL, primary mediastinal lymphoma or transformed follicular lymphoma whose condition becomes resistant to treatment, having failed to respond after at least two lines of therapy. Overall, 72 percent of patients who enrolled in the study examining Yescarta’s effectiveness had responded to the treatment, with 51 percent achieving complete remission. At a median follow-up time of 15.4 months, more than 40 percent of the study’s patients remained in complete remission, suggesting long-term benefits from the use of Yescarta. This medication is now offered to qualifying University of Minnesota Health patients.
“These results are truly remarkable and unprecedented for patients with refractory diseases,” Dr. Bachanova says. “Yescarta offers new hopes for long-term survival to patients with non-responding disease.”
A New Standard of Care
Both Kymriah and Yescarta are CD19-directed CAR T-cell gene therapies that use a patient’s own white blood cells (T-lymphocytes). Each patient’s T cells are separated and genetically engineered in the laboratory, using a disarmed virus, to produce proteins that bind to tumor-specific antigens on the cancer cells’ surface. The modified T cells are then expanded and empowered to grow and kill targets. After about 20 days, which includes a three-day regimen of lymphodepleting chemotherapy, the CAR T cells are infused into the patient. The CAR T cells persist in a patient’s body for many weeks to months and have been called a “living drug.” They also express co-stimulatory molecules that cause T cells to grow and become active, making them powerful cancer cell killers. A single infusion of Kymriah or Yescarta, preceded by a single course of lymphodepleting chemotherapy, is all that is needed to administer the CAR T-cell immunotherapy to patients.
“The CAR T-cell immunotherapy approval has revolutionized the way we approach cancer treatment and sets a precedent for cell therapies,” Dr. Bachanova says. “It’s the beginning of a new era, I believe, where immunotherapy treatments will supplement chemotherapy or perhaps even replace it in the future. We were in the first tier of institutions to offer Kymriah for ALL and Yescarta for lymphoma.”
Now that the FDA has approved Kymriah and Yescarta for use in certain cases of ALL and DLBCL, University of Minnesota Health has begun offering these treatments to non-trial patients. Only two dozen cancer centers across the nation are currently certified to offer Kymriah for pediatric ALL, and around 30 offer Yescarta for adults with lymphoma. University of Minnesota Masonic Children’s Hospital implemented Kymriah as a treatment option in the fall of 2017, under the leadership of Heather Stefanski, MD, PhD. University of Minnesota Health physicians began offering Yescarta to qualifying patients in May 2018.
“Currently, CAR T-cell immunotherapies are approved to be used after chemotherapy treatments have failed,” Dr. Bachanova says. “There are a number of novel, active clinical studies and investigations researching whether it would be beneficial to use CAR-T therapies earlier in the disease process or in combination with other therapies.”
“Often, patients with refractory acute lymphocytic leukemia or diffuse large B-cell lymphoma don’t have many options to treat their conditions. Certainly, very few of them would achieve remission. The refusal to give up and the desire to offer another chance to our patients are the main reasons we engage in the trials on chimeric antigen receptor T-cell immunotherapy.”
— Veronika Bachanova, MD, PhD, Associate Professor, Chair of the Interdisciplinary Committee for Lymphoma, and member of the Division of Hematology, Oncology and Transplantation at University of Minnesota Health
While the new CAR T-cell immunotherapies are promising, they are associated with unique and sometimes serious side effects, including cytokine release syndrome (CRS) and adverse neurological effects. These side effects are most likely to occur within the first few days or up to a month after CAR T-cell infusion.
CRS is an augmented response of the immune system caused by the release of a large amount of cytokines into the blood as a result of CAR T cell or other types of immunotherapy. The sharp accumulation of cytokines during CRS can cause high fever, drop in blood pressure, pulmonary edema and variable neurologic symptoms, such as lethargy, aphasia and seizure.
Because CAR T cells cannot distinguish between cancer cells and B-lymphocytes, which create antibodies, there is also risk for infection and weakened immune system for patients who undergo treatment.
“The majority of patients who underwent CAR T-cell immunotherapy in the clinical trials of Yescarta developed some side effects,” Dr. Bachanova says. “The side effects can range from mild to severe and, rarely, can become life threatening. The risk of severe, grade 4 CRS was 13 percent and for neurotoxicity 28 percent.”
Addressing these concerns requires vigilant clinical care and follow-up protocols. Alongside the approval of Kymriah, the FDA also approved the expanded use of tocilizumab — also called Actemra — for patients age 2 or older who experience severe or life-threatening side effects as a result of CRS.
During clinical trials on Kymriah for ALL, almost 70 percent of patients experienced CRS after undergoing CAR T-cell immunotherapy, and 48 percent required one or two doses of tocilizumab to completely resolve the effects of CRS.
“Tocilizumab doesn’t compromise the efficacy of CAR T-cell immunotherapy,” Dr. Bachanova says. “CRS may also require steroid treatment. It is important to know that these symptoms, although often dramatic, are reversible and manageable.”
Hospitals that offer CAR T-cell immunotherapy require special certification from the FDA as part of a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). University of Minnesota Health medical centers are able to offer Kymriah and Yescarta because they meet the REMS program and ETASU requirements.
“These types of treatments are typically limited to academic centers with bone marrow transplant expertise and the necessary regulatory accreditations to deliver cell therapies and particularly to centers that have been involved in CAR T-cell clinical trials,” Dr. Bachanova says.
University of Minnesota Health Cancer Care staff is trained to recognize and manage complications such as CRS, neurological events and neurological toxicities and to have tocilizumab immediately available in the case of CRS. Patients are also expected to stay in close proximity to the center for at least one month and are monitored almost daily for fever or other side effects from CAR T-cell immunotherapy.
“There’s a certain learning curve to using CAR T-cell immunotherapy because of side effects,” Dr. Bachanova says. “Comprehensive education takes place at all levels in outpatient and inpatient settings, and it is our priority to master the management of toxicities and have expert teams with skills to deliver CAR T-cell therapies to patients who need these treatments.”
University of Minnesota Health physicians continue researching potential applications for CAR T-cell immunotherapies. Researchers are also examining novel tumor targets to attack myeloma and solid-tumor cancer cells.
“Several groups are working on developing ‘tunable’ CAR T cells in the laboratory,” Dr. Bachanova says. “These are CAR T cells that can be tuned down or even switched off if the patient has excessive CRS.”
Another CAR T-cell trial currently open at University of Minnesota Health Bone and Blood Marrow Transplant Program for lymphoma investigates CAR T cells that express different antigens called CD16, which may benefit patients who are not eligible for Yescarta but wish to pursue alternative clinical trials to treat lymphoma.
“We want to offer patients a spectrum of therapies with diverse targets so we can tailor treatment to the individual patient’s needs, taking into consideration prior therapies and disease characteristics,” Dr. Bachanova says.
For a list of the University of Minnesota Health’s Masonic Cancer Center’s current clinical trials, visit cancer.umn.edu.