Fine-Tuning CAR T-cell Immunotherapy to Benefit More Kids

Madeline Boese was one of the patients in Seattle Children’s PLAT-03 trial.

Chimeric antigen receptor (CAR) T-cell immunotherapy, which reprograms a child’s white blood cells so they can seek out and destroy cancer cells, is making a difference in children’s lives. Currently, Seattle Children’s has multiple trials open that could benefit children and young adults with relapsed or refractory cancers. In October, Seattle Children’s opened a new pediatric research facility, Building Cure, to accelerate discoveries such as immunotherapy.

Seattle Children’s researchers are continuing to realize the promise of CAR T-cell immunotherapy and improve outcomes in difficult to treat pediatric cancers. They are applying knowledge gained from ongoing clinical trials to study effects on the youngest patients, develop new interventions to prevent side effects and boost T-cell persistence, and to better understand resistance to therapy.

Research recently published in major scientific journals and presented at the 2019 American Society of Hematology (ASH) Annual Meeting contributes new insight guiding the evolution of the experimental therapy. Here, On the Pulse summarizes their findings.

Limiting side effects with early treatment

CAR T-cell therapy can lead to side effects such as Cytokine Release Syndrome (CRS), a systemic inflammatory response that some experience after receiving the infusion of their altered T cells. It commonly presents as a fever and fluctuations in blood pressure. The reaction is usually mild, but it can be life-threatening. Previously, researchers were concerned that treating these side effects early would cause the CAR T cells to no longer be effective in fighting cancer cells. Thus, patients with CRS would get sick and stay in the intensive care unit (ICU) for several days before getting medication.

During phase 1 of the Pediatric Leukemia Adoptive Therapy trial (PLAT-02), an oncologist and her team thought they could intervene earlier to prevent patients from getting sick, while still maintaining the T cells’ effectiveness. They gave patients medication to calm the immune system down after the onset of mild symptoms of CRS to try to keep them from getting the more severe form.

The results, published in a new study, show that intervening when patients have mild CRS symptoms did not affect T cells’ persistence. This was previously a reason why many doctors waited to intervene with medications until patients had severe symptoms of CRS.

However, the CAR T cells were just as effective in the patients who received the early intervention, continuing to expand and get patients into remission. The study found that adding the medications reduced the rate of severe CRS from 30% to 15%. As a result, the medications were added as a standard of care in PLAT-02 for managing mild CRS. Researchers suspects the study will change practice at other centers using CAR T-cell immunotherapies in a pediatric population.

In addition, researchers learned that Seattle Children’s immunotherapy trials have significantly fewer cases of severe CRS compared to other contemporary studies.

“This is a big finding,” said Dr. Rebecca Gardner, the PLAT-02 principal investigator and the study’s lead author. “The low rates of CRS in the PLAT-02 trial could be a result of our intervention strategy or a combination of how we manufacture our T cells in addition to our early intervention strategy.”

Addressing concerns about CAR T cell therapy in resistant or relapsed infant ALL

Dr. Colleen Annesley, an oncologist and researcher at Seattle Children’s, shared research at ASH about the outcomes of the youngest patients enrolled in Seattle Children’s CAR T cell trials.

The abstract describes 18 patients with relapsed or refractory infant acute lymphoblastic leukemia (ALL) that received immunotherapy in the PLAT-02 or PLAT-05 trials.

“A significant portion of children with infant ALL tend to do poorly with chemotherapy and conventional therapy,” Annesley said. “Unfortunately, many will relapse and need to seek out additional therapies.”

There have been concerns in the field about infants undergoing CAR T cell therapy. However, researchers were able to manufacture CAR T cell products for all but one of the patients, and they saw no increase in toxicities compared to older patients. In addition, Annesley and her team found that experimental CAR T-cell therapies were as effective for younger patients as they were for older children, with more than 93% of treated patients achieving complete remission with no cancer cells detected after treatment.

“Despite theoretical concerns that these youngest patients with resistant infant ALL might not do well with CAR T therapy, so far our data has shown that their outcomes are comparable to older children,” Annesley said. “It’s great news.”

Re-activating T cells with booster infusions

In addition, Annesley presented early results with her research team’s experience so far with the “booster” infusions called T cell antigen-presenting cells (T-APCs) administered to 12 patients to date enrolled in the PLAT-03 trial.

CAR T cells are activated when they encounter a specific protein, such as CD19, on a leukemia cell. This causes them to expand in number. T-APCs are engineered with the CD19 protein. Researchers hope the booster infusions will re-activate the CAR T cells in patients so that the CAR T cells can continue to find and destroy cancer cells, protecting patients from future relapse.

“So far, we have been successful at manufacturing and giving T-APCs, and importantly the T-APCs have been very well tolerated,” Annesley said. “Excitingly, we have seen increases in the numbers of CAR T cells after doses of T-APCs in patients.”

Patients like Madeline Boese, who relapsed three times before entering PLAT-03, have received T-APC infusions and remain in remission. Patients receiving the infusions have not seen an increase in Cytokine Release Syndrome or neurotoxicity.

The study is a first of its kind.

“No one else is delivering T-APCs to ‘boost’ CAR T cells in this manner,” Annesley said. “In the future, we hope this approach might even be applied to other types of cancers.”

Working to predict immunotherapy resistance

Typically, patients relapse after receiving CAR T-cell immunotherapy if their disease has evolved over time or if the CAR T cells have stopped working. However, Dr. Rimas Orentas, PhD, and his team are studying the genetic profiles of a small number of patients who did not respond upfront to CAR T therapy. Orentas presented the research at ASH.

“Immunotherapy is a highly effective therapy that’s revolutionizing our field,” said Orentas, a researcher and co-director of Ben Towne Center for Childhood Cancer Research at Seattle Children’s Research Institute. “We need to understand why some cancers are inherently resistant to it.”

Currently, standard markers and tools of genetic analysis cannot predict whether a patient’s leukemia is resistant to standard CAR T therapy. Researchers hope to eventually predict how patients will respond to immunotherapy and alter treatment based on their disease, so that more children can benefit from CAR T therapy.

Using advanced genetic analysis techniques, researchers compared four bone marrow specimens that were resistant to CAR T therapy to five specimens that responded to the therapy from patients enrolled in phase 1 of the PLAT-02 clinical trial.

The analysis found shared genetic differences in samples with CAR-T resistant disease that could eventually help researchers predict responsiveness to CAR T-cell immunotherapy. Some mutations and fusions identified in the analyses have not been associated with CAR-T therapy resistance until now. Their findings suggest pre-existing genetic plasticity in leukemias that are unresponsive to immunotherapy, Orentas said.

“If we knew which patients have cancers that are resistant to immunotherapy before giving CAR T cells, it would tell us what genetic aspects we could change or block so that the CAR T cells can treat them effectively,” Orentas said. “For example, if the resistance has something to do with changes in DNA methylation patterns, we could introduce a methylene inhibitor.”

Seattle Children’s manages the specimens in the Immunotherapy Integration Hub laboratory.

“Because of our ability to look at these kinds of samples, we are going to figure out how to make this experimental therapy work for even more kids,” Orentas said.

Seattle Children’s is dedicated to improving CAR T-cell immunotherapy for a variety of childhood cancers to the point that it helps patients achieve long-term remission – and ultimately – a cure. For more information about these trials, please visit our current research studies page.

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