Trial provides first look at long-term outcomes of childhood immunotherapies

By reprogramming a patient’s own immune cells to recognize and destroy cancer, chimeric antigen receptor (CAR) T cells have significantly improved survival for children with refractory or relapsed B-cell acute lymphoblastic leukemia (B-ALL). However, decades of research and care have shown that treatment for pediatric cancers can affect survivors long into adulthood. So, learning from the past, a national group of physicians and scientists developing CAR T–cell therapies (the CARnation Consortium) decided to take an active approach to detecting any long-term side effects associated with these novel therapeutic agents. 

Instead of waiting for potential late effects to appear, the group co-designed a new kind of study: CONQUER.

“CONQUER is a feasibility study to proactively learn the best ways to perform follow-ups for patients who were treated with novel immunotherapies as children,” said principal investigator Aimee Talleur, MD, Department of Bone Marrow Transplantation & Cellular Therapy. “Survivors who were treated with experimental CAR T cells for B-ALL are coming to St. Jude so we can perform a comprehensive health assessment to find any long-term health impacts.”

In the past, long-term follow-up studies have focused on patients treated at a single institution. That approach is difficult for novel immunotherapies, where any one hospital may treat too few children to detect meaningful patterns of late effects quickly. CONQUER is designed to address that challenge through collaboration.

“CONQUER represents a large step forward for survivorship and St. Jude,” said Greg Armstrong, MD, MSCE, Department of Epidemiology and Cancer Control chair. “Instead of waiting for one institution to treat many children with novel immunotherapies and study their long-term side effects as we have classically done, many institutions are working together. As collaborators, we are finding the best ways to pool and screen our patients, creating the conditions where we can detect any late effects, if present, as early as possible, which may also lead to earlier and more durable interventions.”

St. Jude LIFE provides infrastructure head start for CONQUER

Once CARnation members decided CONQUER should be performed at a single host site, they needed an institution with the infrastructure to bring in survivors from across the country for comprehensive evaluation. St. Jude was a natural fit because of the St. Jude Lifetime Cohort Study (St. Jude LIFE).

St. Jude LIFE is a long-term follow-up study for survivors of childhood cancer who were treated at the institution. The study provides comprehensive health assessments designed to identify late effects and help researchers better understand the long-term side effects of pediatric treatments. These analyses include the typical blood tests performed for patients at any hospital, but also much more, such as physical ability testing in the Human Performance Lab, whole-genome sequencing and psychological assessments. The group determined that these pre-existing capabilities were enough of a head start for CONQUER that St. Jude was the most logical choice to host the study.

“It’s exciting to see that we’re the nexus of this research collaboration because we’re so unique in what we can do within the St. Jude LIFE infrastructure,” said Melissa Hudson, MD, Department of Oncology, who co-leads the trial with Talleur. “We can go beyond lab tests and imaging; we have the resources and expertise to correlate brain function and motor performance, study neurocognitive outcomes and see how these long-term side effects impact survivors’ daily activities and ability to live independently.” 

CONQUER will use that infrastructure to take a holistic look at each patient’s physical and psychological health, while the scientists will also assemble their health and treatment records. The study’s primary goal is to determine whether this kind of multi-institution survivorship assessment is feasible. A secondary goal is to generate early information about possible late effects that can guide future follow-up studies. 

“A big part of the ability for us to host CONQUER was the fact that the St. Jude LIFE infrastructure already existed,” Talleur explained. “Most of the testing and logistics are exactly what we do for current St. Jude LIFE participants, so we had to build very little, which, if we had needed to, would have taken a very, very long time.”

CONQUER casts a wide net to find late effects

One reason that CONQUER needs a comprehensive platform such as St. Jude LIFE is that it is unclear what kind of unique long-term toxicities survivors will experience from CAR T cells. The immunotherapy for B-ALL was the first of its kind in pediatric cancer, so there is no prior information to use as a guide. For that reason, CONQUER will not focus narrowly on one suspected late effect. Instead, investigators will use a broad array of assessments developed through decades of childhood cancer survivorship research, while adding measures tailored to CAR T–cell therapy.

“For CONQUER, we’ve had to make some modifications to the St. Jude LIFE assessment protocol, such as measuring immune system effects, which are not part of the St. Jude LIFE testing battery,” Hudson explained. “However, between our colleagues on campus and in CARnation, we have some of the best experts in the world supporting these additional analyses, providing the opportunity to advance understanding about the long-term effects of CAR T–cell therapy on immune system health.”

As a feasibility study, CONQUER is designed to identify possible late effects and demonstrate that they can be studied systematically. However, the children enrolled in CONQUER all had refractory or relapsed disease and complex, nonstandard treatment histories. Later studies will be needed to confirm which side effects are truly linked to immunotherapy and which may reflect previous treatments or disease history.

CONQUER will begin to answer survivors’ questions

Even as researchers search for unknown late effects, survivors and families already have practical questions about life after CAR T–cell therapy. One example is B-cell aplasia (the lack of a specific type of immune cell), which is a known consequence of CD19-targeted CAR T–cell therapy for B-ALL. Because the therapy targets CD19, a protein found on many B cells, it can eliminate both cancerous and healthy B cells. When survivors have B-cell aplasia, they often need regular intravenous antibody replacement to support immune function, which can be burdensome. Long-term health assessments may help determine when that support can safely stop, and which survivors may need it for longer.

“We have more and more patients who have gone through CAR T–cell therapy and are survivors, who are now asking questions about long-term follow-ups, how long to keep taking medicine, when to get vaccines and many others,” Talleur said. “We don’t yet have answers for them, but CONQUER is a first step to better study this population and inform future guidelines.”

Preparing for the next era of survivorship

CONQUER is designed to look for potential long-term risks of immunotherapy, but the reason so many institutions are investing in the study is the promise of CAR T–cell therapy itself. The treatment has already changed outcomes for some children whose disease did not respond to standard therapy, and its use is likely to expand. For now, CONQUER focuses on children treated with CD19-targeted CAR T cells for B-ALL. If successful, the study could become the gold-standard platform and model for identifying long-term outcomes after many kinds of novel pediatric immunotherapies.

“If we can define what the late effect profile looks like for this patient population, it will help us think about how to minimize toxicity in other disease settings too,” Talleur said. “CONQUER will be the proof-of-principle for how to evaluate new pediatric immunotherapies in a general way, educating us on the best ways to identify long-term side effects, and giving us a path towards creating guidelines to address them and help survivors as soon as possible.”

The CONQUER study is currently ongoing and actively enrolling patients.