Conference Coverage

CAR-T in children branching out to solid tumors


 

FROM TCT 2021

Although the only pediatric indication for chimeric antigen receptor T-cell therapy currently approved by the Food and Drug Administration is B-lineage acute lymphoblastic leukemia (ALL) that is refractory to at least two frontline induction attempts or is in second or later relapse, clinical trials of CAR-T therapy for pediatric solid tumors are also currently in progress, said Gregory Yanik, MD, from the CS Mott Children’s Hospital at the University of Michigan, Ann Arbor, at the Transplant & Cellular Therapies Meetings.

In his presentation, Dr. Yanik discussed progress in solid tumor studies as well as some issues involving the current use of CAR-T therapy for ALL.

Solid tumor studies

Malignancies such as sarcomas, brain tumors, and neuroblastomas pose unique challenges, “In contrast to hematologic malignancies, the protein we’re targeting may not be present on the cell surface of all the tumor cells. There are lower-expression profiles, and this is a problem. In fact, many people have postulated that with CAR-T for pediatric solid tumors we’ll have to do repeated cycles, almost like we do with chemotherapy,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

There are currently 14 studies of CAR-T for central nervous system tumors in children, targeting either epidermal growth factor receptor (EGFR) in glioblastoma multiforme and high-grade gliomas, HER2 in a variety of CNS tumors, the GD2 antigen on pontine gliomas, and the checkpoint molecular B7H3 in medulloblastomas and pontine gliomas.

“In sarcomas in kids there are currently 12 trials in progress. Most of the targeting epitopes are targeting either HER2 or GD2. Repetitive CAR-T infusions are being used in several of these trials in sarcomas.

For neuroblastomas there are currently 13 studies in progress, nearly all of which target GD2. Some of the trials include combining CAR-T with immune checkpoint inhibitors or C7R, an engineered cytokine driver designed to prevent T-cell exhaustion.

In addition, several trials of tumor pulsed dendritic cell vaccines are underway for treatment of children with Wilms tumor, Dr. Yanik noted.

Unresolved procedural questions

It’s still early days in CAR-T therapy, and there are several still unanswered questions regarding optimal therapy for and management of patients undergoing CAR-T procedures, Dr. Yanik said.

For example, the optimal time to collect T cells during apheresis is still unclear, he said. Collecting prior to reinduction therapy raises the risk of transducing leukemic cells, while collecting after reinduction may result in inadequate quantity or quality of cells. Regardless of when cells are collected, apheresis should be performed only when the absolute lymphocyte count is above 500/mcL or the CD3 count is above 150/mcL at the time of apheresis.

In the case tisagenlecleucel (Kymriah), his center typically collects 1x109 CD3 cells regardless of age or weight.

The number of CAR T-cells infused also appears to matter, as responses are improved at CAR-T doses above 1.5x106/kg, while risk for higher-grade cytokine release syndrome (CRS) occurs at higher infusion doses.

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