“Immunotherapy is moving at an accelerated pace, but just getting started for solid tumors.” So says Katie Albert, MD, Assistant Professor of Hematology-Oncology at Seattle Children's Hospital. The major difference between solid tumors and hematologic malignancies is a higher burden of circulating tumor cells. Bulk tumors have extra immunological barriers to T cells. It's harder for T cells to proliferate in this environment.
Kids Are Not Just Small Adults
Oncologists face unique challenges with a pediatric population. For one, the driver mutations are different. The same cancers in children and adults can be driven by different genes.
Michael Jensen, MD, Director of the Ben Towne Center for Childhood Cancer at Seattle Children's Research Institute, remarked, “Solid tumors have heterogeneity. Even within one child, some cancer cells don't express antigens necessary for T cells to kill it.”
In the lab, researchers must develop different types of T cells to kill all the cancer cells in the child. If patients are infants, there is the question if they will have enough T cells to extract for treatment.
“Relapsed tumors are a difficult area to adopt these therapies,” Jensen continued. Some patients don't have any healthy T cells to extract after chemo and/or radiation. New therapies need to balance the chance therapy won't work with the well-being of patient.
Another hurdle to new therapies is FDA regulations stipulating immunotherapies are tested in adults first. “Everyone wants studies in pediatric oncology, but if required to test in adults, children might get the short end of the stick,” said Stephen Gottschalk, MD, Chair of the Department of Bone Marrow Transplantation & Cellular Therapy at St. Jude's Children's Research Hospital. A good dataset that doesn't work in adults precludes testing in children. Gottschalk would prefer parallel studies.
Moderate Success in Glioblastoma
Gottschalk was part of a team that studied HER2-specific chimeric antigen receptor (CAR)–modified virus-specific T cells (VSTs) in patients with progressive glioblastoma at Baylor College of Medicine, Houston Methodist Hospital, and Texas Children's Hospital (JAMA Oncol 2017;3(8):1094-1101).
“There is some data that glioblastoma is virus-positive,” he noted. Virus-specific T cells can be activated outside the tumor by other cells that recognize the virus.
The 17-patient study included 10 patients under the age of 18. In this particular study, researchers found no differences between how the pediatric patients and the adult patients responded to the protocol.
Most glioblastomas progress and patients die within 12-15 months of diagnosis. Ultimately, researchers found HER2-CAR VSTs to be safe at the highest dose level. Study results showed some patients with disease stabilization who survived longer than average.
“Disease stabilization is meaningful criteria in solid tumors. If tumors don't grow for 4-5 months, there is meaningful benefit,” Gottschalk explained.
Beyond the Brain
Two current trials examine immunotherapy options for children and young adults with relapsed/refractory solid tumors. At Seattle Children's Hospital, Albert leads a team studying CAR T-cell therapy for 15 different types of solid non-CNS tumors in the STRIvE-01 trial.
“We decided it made sense to separate CNS and non-CNS tumors because there are different challenges getting to tumor site,” she explained.
STRIvE-01 is an experimental trial enrolling patients who failed standard therapies. The priority for the trial is to determine safety and feasibility. What is the safest dose? Are there unanticipated risks?
As of February 2019, researchers have screened about 30 patients, but have not treated anyone yet. They are looking for candidates with an overexpression of epidermal growth factor receptors on tumor cells, which occurs in approximately 15 percent of pediatric solid tumors. Treating oncologists can learn more about the trial at https://clinicaltrials.gov/ct2/show/NCT03618381.
New Approach for Liver Cancer
At Texas Children's Hospital, researchers drilled down and are examining CAR T-cell therapy for patients with relapsed/refractory liver tumors and Glypican-3 receptors.
Pediatric liver cancer is rare, with about 250 newly diagnosed cases in the U.S. each year. For those patients, there is an 80 percent cure rate. Patients with relapsed/refractory liver tumors are a different story.
“Coming from an immunotherapy lab, I thought, can we develop something new for these patients?” asked study lead Andras Heczey, MD, Assistant Professor, Department of Pediatrics, Section of Hematology-Oncology at Baylor College of Medicine and Director of the Liver Tumor Program at Texas Children's Hospital. The biology of pediatric and adult liver tumors is different. “The past 20-30 years haven't brought new drugs to the forefront, so we should make all the efforts to have more effective and less toxic drugs for the patients.” The drive for something new inspired the clinical trial.
Heczey and his team are currently enrolling patients in this phase I clinical trial. “We are relying on the community to refer patients to us since pediatric liver cancer is a rare cancer,” he explained. “We want to make sure the community understands the uniqueness of this approach.”
Patients will be injected with GAP T cells. Glypican-3 specific T cells are genetically engineered with a receptor made in the lab to recognize a receptor on cancer cells called Glypican-3. “In an ideal situation, they will expand and fight other cancer cells around them,” noted Heczey.
Researchers will evaluate how the GAP T cells interact in the tumor microenvironment. How are GAP T cells changing in patients' blood? How are GAP T cells changing the tumor? What counter mechanisms does the tumor mount to escape the immunotherapy?
This is the first time this approach for liver tumors is being tested in pediatric patients, so determining safety is the top priority. The FDA mandates the first enrolled patients be between ages 14 and 21. Once safety is established, the trial can open to a larger population.
The team hopes to emulate the success of immunotherapy for relapsed/refractory leukemia, considered the gold standard of immunotherapy for pediatric cancers. Pediatric oncologists can learn more at https://clinicaltrials.gov/ct2/show/NCT02932956.
Slow March From Bench to Bedside
“We're really just getting started in the solid tumor world,” Albert remarked. “How can we make CAR T-cell therapy better?”
Heczey cautioned it will take time to move therapies from the lab to the clinic. However, there are more exciting developments on the horizon for immunotherapy for pediatric solid tumors.
“I'm in the CAR-T business, so of course, I'm optimistic,” noted Gottschalk. He cautioned against the attitude these therapies won't work in solid tumors. Many current approaches have not been fully tested in clinical settings. “There's a continued need to discover new antigens that can be targeted. My hope is that over the next 1-2 years improved CAR T cells will come to the clinic.”
Meanwhile, progress continues in the lab. Research labs are creating molecules to protect T cells from the microenvironment on the tumor that rejects it. According to Jensen, Seattle Children's is doing safety studies over next 1-2 years before deploying these enhanced CAR T cells.
The next era will bring enhanced T cells that will have the ability to know where they are and what to do. Oncologists would like to one day combine CAR-T therapy with other immunotherapies like checkpoint inhibitor that are currently more advanced in adults.
A main goal for pediatric cancer is the ability to treat with just immunotherapy and not needing chemotherapy or radiation. “This is critically important for children with cancer because the long-term toxicities of chemotherapy and radiation are profound,” Jensen noted. He stressed the importance of academic trials supported by physicians as a way to move forward.
The initial success of immunotherapy in pediatric leukemia inspired the current research in immunotherapy approaches for pediatric solid tumors. All this work will have the impact to one day cure these rather devastating diseases.
Danielle Bullen Love is a contributing writer.