HER2 Antigen–Specific T Cells Could Treat Sarcoma

HER2 chemical structure. Image © molekuul.be / Shutterstock.com.

T cells that express a HER2-specific chimeric antigen receptor (CAR) showed promise as a treatment for HER-2 positive sarcoma in a small phase I/II trial.

Local sarcomas tend to have good outcomes, but advanced-stage sarcomas yield generally poor prognoses. “Immunotherapy with antigen-specific T cells may benefit patients with sarcoma because immune-mediated killing does not rely on pathways used by conventional therapies to which such tumors are often resistant,” wrote study authors led by Stephen Gottschalk, MD, of Baylor College of Medicine in Houston. The use of adoptive transfer of T cells that have been genetically modified to express CARs has shown promise in certain malignancies.

In this study, researchers enrolled 19 patients with HER2-positive tumors-16 osteosarcomas, 1 Ewing sarcoma, 1 primitive neuroectodermal tumor, and 1 desmoplastic small round-cell tumor-to receive escalating doses of HER2-CAR T cells. The results were published online ahead of print in the Journal of Clinical Oncology.

The median age of study participants was 17 years at the time of T cell infusion. All patients included had metastatic or refractory disease, and had experienced treatment failure with at least one chemotherapy regime; 11 of 19 had undergone radiation therapy.

The study involved eight dose levels, between 1 × 10⁴/m² and 1 × 10⁸/m² HER2-CAR T cells. Thirteen patients received one infusion, four received two, one received four, and one received nine infusions. The only infusion-related adverse event was a fever in one patient, which resolved with ibuprofen. The study did not reach a dose-limited toxicity.

The researchers found that HER2-CAR T cells could be detected in vivo in 14 of 16 evaluable patients who received doses above level 3 (1 × 10⁵/m²). This dropped significantly after 3 hours beyond the infusion time, but a low-level T cell signal could still be detected 6 weeks after infusion in seven of nine evaluable patients who had received a dose greater than 1 × 10⁶/m². They also found evidence of the HER2-CAR T cells in some patients at 3, 6, 9, 12, and 18 months following infusion, suggesting that even without evidence of T cell expansion the cells apparently do persist long-term.

In terms of outcome, 4 of 17 evaluable patients had stable disease for 12 weeks to 14 months. The median overall survival in the study was 10.3 months.

“Targeting HER2 with antigen-specific T cells is an attractive strategy to expand HER2-targeted immunotherapies to malignancies that are HER2 positive but are insensitive to HER2 antibodies because they are not HER2 gene amplified,” the researchers wrote. They concluded that this study shows a safe dose of HER2-CAR T cells can be established, and that the cells can traffic to tumor sites and persist at low levels. “These data will facilitate subsequent clinical trials to further augment the expansion, function, and persistence of HER2-directed T cells.”