Despite challenges, CAR-T may have ‘expanded role’ for children
Chimeric antigen receptor T-cell therapy has been heralded as a transformative addition to the cancer treatment armamentarium.
Adoption of these therapies for treatment of younger patients, however, has been much less widespread.
“There are far fewer centers that offer CAR-T for children,” Rebecca A. Gardner, MD, associate professor in the department of pediatrics at University of Washington and attending physician at Seattle Children’s Hospital, told Cell Therapy Next.
The first CAR T-cell therapy approved by the FDA — tisagenlecleucel (Kymriah, Novartis) — was indicated for children and young adults with B-cell acute lymphoblastic leukemia. However, subsequent indications have been limited to adults with hematologic malignancies.
CAR-T’s initial approval for a pediatric indication was a “unique” development, Gardner said.
“A lot of CAR-T research is first in human. A lot of first-in-human research is done in adults first [and] then in pediatrics, so there are a lot of regulatory hurdles that prevent us from moving straight into pediatric research,” Gardner said.
Funding is another obstacle, as few pharmaceutical companies look to partner on research for pediatric diseases.
“Often we need to rely on our own development funds and can’t really rely on industry to go after pediatric indications,” she said.
Cell Therapy Next spoke with pediatric oncologists about the pediatric CAR T-cell therapy landscape and the settings where this treatment modality may hold the most promise for younger patients with cancer.
CAR-T for Kids
Four key issues make developing CAR T-cell therapies for pediatric indications a unique challenge, according to Shannon L. Maude, MD, PhD, attending physician at Children’s Hospital of Philadelphia and assistant professor of pediatrics at Perelman School of Medicine at University of Pennsylvania.
The first applies to development of any oncology therapy for younger patients: Cancers in children don’t always act or respond to therapy the same way as cancers in adults. In addition, the spectrum of malignancies that affect children often is unique, and some are rarely seen in adults.
“An adult patient and a pediatric patient can have the same exact diagnosis, but the way that disease presents can often be quite different between the two,” Rayne H. Rouce, MD, physician at Texas Children’s Cancer Center and assistant professor in the department of pediatrics at Baylor College of Medicine, told Cell Therapy Next.
For example, children with cancer more often have aggressive and multifocal disease.
“The characteristics of the disease in pediatric patients makes it a separate challenge,” Rouce said.
Second, the small size of the pediatric population in need of treatment for some diseases make it unappealing as an economic model, Maude said.
“To be honest, there is not a huge market for some of these malignancies,” she said, adding that getting pharmaceutical companies to invest in technologies for pediatric malignancies can be difficult.
“We are doing everything we can in the academic research community to raise awareness of this unmet clinical need,” Patrick Brown, MD, director of the pediatric leukemia program at Sidney Kimmel Comprehensive Cancer Center and professor of oncology and pediatrics at Johns Hopkins University School of Medicine, told Cell Therapy Next.
Regulators such as the FDA could encourage pharmaceutical companies to sponsor studies that can help expand the labels for CAR T-cell therapies to include more pediatric indications, Brown said. He acknowledged the economic reasons why pharmaceutical companies might not support this type of work, which is why the answer may be to incentivize companies to conduct pediatric studies.
“We in the academic community have to take it upon ourselves to raise funds in other ways to support pediatric trials,” Brown said, citing philanthropic organizations as an example. “But it’s difficult to do so and a difficult challenge to address.”
A third challenge is that CAR T-cell therapies are labor-intensive and take a long time to develop, both in terms of research and subsequent manufacturing.
“In many cases, we can’t always use therapies that are being developed with adults in mind,” Maude said. “Instead, we have to develop something unique.”
Finally, a lack of target antigens can hinder development of CAR T-cell therapy for children.
“Many pediatric malignancies develop out of normal embryonic tissues and — in many cases — do not have a lot of mutations,” Maude said.
As a result, younger patients often lack antigens that are specific to tumor cells.
“Most of those antigens will be found on normal cells, as well, and that can be a problem when developing cellular therapies because that can cause cytotoxicity to normal tissue,” she said.
Promising Pediatric Research
Despite the challenges — including a lack of economic incentives — a number of clinical trials are examining CAR T-cell therapies for pediatric cancers.
Approaches range from targeting novel antigens to combination therapy. Researchers also are evaluating CAR T-cell therapy as a less toxic alternative to hematopoietic stem cell transplantation (HSCT).
“The field is exploring whether CAR-T can be a replacement for [bone marrow transplantation], or a bridge to it,” Brown said. “It’s a big question mark in our field and one for which we need better clinical trials to answer.”
One of the major questions he hopes will be answered is whether CAR T-cell therapy can be less toxic and more effective than HSCT for relapsed and refractory disease, or whether most patients will require HSCT after CAR T-cell therapy.
“Right now, we can’t predict outcomes,” he said. “At this point, it looks as if half of the patients can achieve long-term remissions without the need for [HSCT], but we are unable to predict which patients will not require [bone marrow transplantation], and that leaves oncologists and their patients with a major challenge to overcome.”
The following are a few examples of promising pediatric trials exploring the use of CAR T-cell therapy for high-risk or advanced hematologic malignancies:
An investigational CD123-directed CAR T-cell therapy is being evaluated at City of Hope for patients aged older than 12 years who have relapsed or refractory acute myeloid leukemia or persistent/recurrent blastic plasmacytoid dendritic cell neoplasm. The open-label, phase 1 dose-escalation study (NCT02159495) will evaluate the safety and best therapeutic dose of the therapy.
Primary outcomes include dose-limiting toxicity (grade 3 or higher), adverse events and response rates. Secondary outcomes include PFS, OS and DFS.
The therapy differs from currently approved CAR T-cell therapies that target the CD19 antigen, which is present on most ALL cells.
“Leukemia is smart, flexible and capable of downregulating — or silencing — its CD19, leading to relapse despite treatment with CAR T cell therapy,” Brown said. “It’s a major limitation of currently approved CAR-T.
Brown said that in addition to novel antigen targets, there is excitement around pediatric trials using CAR T-cell therapies that target multiple antigens, the most advanced of which are dual-targeting CD19 and CD22 therapies being investigated in NCI trials.
The CASSIOPEIA trial (NCT03876769) is examining CAR T-cell therapy as a potential solution to the problem of persistent minimal residual disease (MRD) after front-line chemotherapy.
The open-label, multicenter phase 2 trial aims to determine the efficacy and safety of tisagenlecleucel among children and young adults with newly diagnosed, high-risk B-cell ALL who are MRD-positive after first-line treatment.
The study’s primary outcome is 5-year DFS. Researchers also will assess the proportion of patients who are disease free without having to undergo allogeneic HSCT at 1 year after CAR T-cell infusion.
A direct comparison of CAR-T and HSCT has not been done and would be particularly challenging, according to Maude. However, the 5-year DFS rate for the population of children in the CASSIOPEIA trial is about 39%, so these children are at high risk for relapse, Maude said. The goal of the trial is to see whether CAR-T can improve the survival rate and avoid the use of HSCT, which typically would be the standard of care for these high-risk patients.
“Absent the option of CAR T-cell therapy, most of these patients would undergo HSCT,” Maude said.
The ability to avoid HSCT for children is appealing, she added.
HSCT for ALL typically includes whole-body radiation as preconditioning before therapy, which “in a young developing child can have significant long-term toxicities,” Maude said.
The BIANCA trial (NCT03610724) is evaluating CAR T-cell therapy for children with high-risk relapsed or refractory B-cell non-Hodgkin lymphoma who have poor survival and overall response rates after conventional salvage chemotherapy.
The open-label, multicenter phase 2 trial aims to determine the safety and efficacy of tisagenlecleucel among children and young adults with relapsed or refractory B-cell NHL.
ORR serves as the study’s primary outcome, with secondary outcomes that include OS, PFS, duration of response, percentage of participants who proceed to HSCT and safety.
“It’s a promising approach,” Rouce said. “It’s appealing to give a single dose of therapy that may have some immediate side effects but then allows the patient to live a relatively normal life — with a relatively normal immune system — rather than numerous courses of chemotherapy over a 2- to 3-year period, as is normal in this patient population.”
The Resilience of Youth
A promising area of research related to CAR T-cell therapy for pediatric malignancies involves use of the treatment as an earlier line of therapy for children, such as that being evaluated in the CASSIOPEIA trial. This is especially true for younger patients who are considered a high risk for disease relapse.
Despite the known short-term and unknown long-term effects of cellular therapy, experts consider CAR-T a less toxic and more convenient alternative to multiple lines of other therapies that can have long-term detrimental effects on quality of life.
Gardner said families who have endured multiple lines of therapy with their children have told her that the CAR T-cell therapy process is much easier. She said most patients who receive CAR T-cell therapy will experience adverse events, such as neurotoxicity or cytokine release syndrome (CRS), but these effects are manageable and typically range from mild to moderate.
“We still don’t know the long-term toxicities of CAR-T, but [they are] likely to be far less than standard therapies,” Gardner told Cell Therapy Next.
The adverse effects of CAR T-cell therapy are shorter and narrower in scope, which gives it “a much better safety profile than typical therapies,” she said.
Children experience CRS and neurotoxicity as frequently as adults when receiving CAR T-cell therapy, especially those who have a strong response to therapy as the body releases more cytokines, Rouce said. Nevertheless, children typically maintain strong organ function after CAR T-cell therapy despite having relapsed or refractory disease and undergoing many previous lines of therapy, she said.
“Their organs are resilient,” Rouce told Cell Therapy Next. “Many pediatric patients are actually easier to manage after receiving CAR T cells because they typically lack the number of comorbid conditions that adults may have.”
The toxicities associated with CAR T cells are not limiting, Brown said. Although he would like to see less toxic cellular therapies developed, those that are currently available compare favorably with standard therapies, he added.
“Immunotherapies like [CAR-T] are superior in safety and tolerability when compared with conventional therapies — including chemotherapy — for patients with relapsed or refractory disease,” Brown told Cell Therapy Next. “I am excited about the potential for CAR-T to move into an upfront treatment space to replace current therapies that have more toxic effects.”
Although treatment with CAR T cells as an earlier line of therapy is not current best practice, several clinical trials are exploring the possibility, Brown said.
As an example, a trial (NCT02315612) sponsored by NCI is evaluating a CD22-directed CAR T-cell therapy as second-line treatment for children and young adults with relapsed or refractory B-cell malignancies.
The consensus appears to be that CAR T cells present no additional risk over conventional therapies when used for younger patients, Maude said.
“We know of the numerous long-term toxicities associated with the multiagent chemotherapies we provide, plus there are additional toxicities associated with bone marrow transplant [for] high-risk patients,” she said. “CAR T-cell therapy seems to have fewer side effects than the cumulative side effects of other treatments.”
What remains uncertain are the possible long-term adverse effects of CAR T-cell therapy for children.
“CAR T-cell therapy is still in its relative infancy,” she told Cell Therapy Next. “We don’t yet know if there will be related toxicities 25 or 30 years from now.”
Maude pointed to the possible long-term effects of chronic B-cell aplasia as patients who undergo CAR T-cell therapy live longer.
“CAR-T’s role will hopefully evolve,” Maude said. “As we continue to study it — especially for high-risk populations — I hope we will see that there is an expanded role as an earlier line of therapy, with the potential to improve outcomes, minimize the number of therapies and limit the toxicities associated with treatment.”
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- Patrick Brown, MD, can be reached at email@example.com.
- Rebecca A. Gardner, MD, can be reached at firstname.lastname@example.org.
- Shannon L. Maude, MD, PhD, can be reached at email@example.com.
- Rayne H. Rouce, MD, can be reached at firstname.lastname@example.org.