ATLANTA – A novel chimeric antigen receptor (CAR) T-cell construct centered on HER2 as the target antigen was safe and showed early promise in the treatment of advanced sarcomas of bone and soft tissues in a phase I trial.
One patient, a 16-year-old girl with advanced osteosarcoma metastatic to her lungs, had a complete response to the therapy that is ongoing out to nearly 3 years, reported, from Baylor College of Medicine in Houston.
A second patient, an 8-year-old boy with rhabdomyosarcoma metastatic to bone marrow, had a complete response lasting 12 months. Upon relapse he was re-enrolled, received additional CAR T-cell infusions, and had a second complete response that has been ongoing for 17 months.
“HER2 CAR T cells can induce objective clinical responses in some patients with sarcoma, and engagement of endogenous immunity may aid in generation of tumor responses. We are currently working to validate these findings in other patients who were treated,” she said at a briefing at the annual meeting of the American Association for Cancer Research.
HER2 is a member of the human epidermal growth factor receptor family that is primarily expressed on the surface of tumor cells but is largely absent from nonmalignant tissues. HER2 can be expressed in a variety of sarcomas, including osteosarcoma, and HER2 expression in osteosarcoma correlates with worse overall survival.
Unlike HER2-positive breast cancers, however, HER2 expression levels in osteosarcoma are too low to be effectively targeted by anti-HER2 agents such as trastuzumab (Hereceptin).
But as Dr. Navai and colleagues have found, HER2 appears to be a valid target for CAR T-cell therapy in otherwise antigenically “cold” tumors – that is, tumors with few targetable antigens.
Old target, new weapon
They have developed a CAR T-cell construct using a HER2-directed antibody coupled with CD28 as the costimulatory molecule. As with other CAR T therapies, the patient’s T cells or selected T cell subsets are collected, transfected to express the antigen, and are then expanded and returned to the patient following lymphodepletion with either fludarabine alone or with cyclophosphamide.
Each patient received up to three infusions of autologous CAR T cells at a dose of 1 x 108 cells/m2, and eligible patients received up to five additional infusions without additional lymphodepletion.
Dr. Navai presented data on 10 patients treated to date, including the two mentioned before; the boy with rhabdomyosarcoma was counted as two separate patients for the purpose of the efficacy analysis.
All patients had metastatic disease, including five with osteosarcoma, three with rhabdomyosarcoma, one with Ewing sarcoma, and one with synovial sarcoma.
The lymphodepletion regimens did their job, inducing neutropenia (defined as an absolute neutrophil count less than 500 per milliliter ) for up to 14 days.
Eight patients developed grade 1 or 2 cytokine release syndrome within 24 hours of CAR T-cell infusion, and all cases completely resolved with supportive care within 5 days of onset.
In nine patients, T cells were successfully expanded, with a median peak expansion on day 7.
In all 10 patients, CAR T cells were detected by quantitative polymerase chain reaction 6 weeks after infusion.
In addition to the two patients with complete remissions already described, three patients had stable disease. The remaining patients had disease progression. At the most recent analysis, five patients were still alive, and five had died.
The infusions were safe, with no dose-limiting toxicities reported. No patient required a transfusion, and there were no opportunistic, infections, no neurotoxicities, and no lasting pulmonary or cardiac toxicities, Dr. Navai reported.