Rethinking the Development of CAR T-Cell Products for Pediatric Cancer

The development of chimeric antigen receptor (CAR) T-cell therapy has been a significant breakthrough in the fight against pediatric leukemia. CAR-T-based treatments have proven to be highly successful in achieving complete remission for pediatric patients with refractory acute lymphoblastic leukemia (ALL).

The approval of tisagenlecleucel, the first CD19-specific CAR T-cell product, as a rescue therapy for previously incurable, refractory B-ALL in children and young adults, marked a major milestone in the field of pediatric oncology.

In a commentary published in the Journal of Clinical Oncology, Claudia Rossig, MD, of the department of pediatric hematology and oncology at the University Children’s Hospital Muenster in Muenster, Germany, and coauthors reviewed the challenges and opportunities in developing of CAR T-cell therapies for pediatric cancers. They also discussed alternative development pathways for CAR T-cell products.

The authors of the publication represent the European Society of Pediatric Oncology (SIOPE), the International Berlin Frankfurt and Muenster (I-BFM) Study Group, and the Innovative Therapies for Children with Cancer (ITCC) consortium.

Development Challenges

In academic settings, the prospective evaluation of CAR-T therapy in pediatric cancers is limited by the availability of CAR T-cell products. In addition, financial and regulatory hurdles limit new investigations.

Presently, the commercial sector has little incentive to develop these products for pediatric cancers due to a low potential for return on investment. Accordingly, it remains uncertain whether the standard developmental pathways will grant access to effective products.

As a result, experts from several pediatric oncology study groups are calling for change in hopes of addressing unmet needs and further developing the field. 

Alternative Models of Development

The European Medicines Agency (EMA) is pioneering an alternative approach to development by facilitating the licensing of CAR T-cells and other advanced therapy medicinal products (ATMPs) by academic researchers. Since the earliest days of progress in the field, the academic community has played a crucial role in driving innovation.

The first academic CD19-directed CAR T-cell product — ARI0001 — was granted eligibility to this scheme of the EMA.

“To allow the clinical development of a larger variety of cell products for rare indications, in adults and children with no or low commercial interest, an innovative regulatory approach is needed,” the authors wrote in their report.

Others have proposed a hybrid model, where a product is manufactured by academic institutions, for both in-house treatment and distribution to other sites. The manufacturing processes would require strict adherence to harmonized procedures and quality control, as specified by local manufacturing certificates. 

Although infrastructure challenges remain, researchers are building networks of academic manufacturing centers, which could overcome issues of cross-border trafficking of cell products and reduce gaps between needs and availability.

For example, a growing number of academic centers in Europe are equipping themselves with the necessary infrastructure and expertise to manufacture ATMPs. Further, proposals have been made to update EU legislation to acknowledge the importance of decentralization in manufacturing and to simplify oversight using risk-adapted and flexible approaches.

Reimbursement Strategies

As progress continues, experts stress the importance of new and innovative reimbursement strategies to ensure that patients can access products. As the researchers noted in their report, even if academia successfully takes over the capacities previously held by industry, new funding sources will need to be secured.

According to Dr Rossig and colleagues, one potential strategy could be to limit pharmaceutical licensing to the designated vector or CAR construct, as opposed to the individualized gene-modified patient-individual cell product. Currently, the high costs of CAR T-cell products make them inaccessible for many patients.

Looking to the future, the authors aspire to open a dialogue between industry, regulators, academia, and patient advocates to establish the most optimal strategy to reduce cost and extend access.

“Novel solutions will meet critical needs in children and also in adult patients, either with rare conditions or even with common cancers,” they concluded.

Reference

Rossig C, Pearson AD, Vassal G, et al. Chimeric antigen receptor (CAR) T-cell products for pediatric cancers: why alternative development paths are needed. J Clin Oncol.  Published online November 27, 2023. doi:10.1200/JCO.23.01314

This article originally appeared on Hematology Advisor