HER2-targeted CAR T cells safely induce responses in advanced HER2-positive sarcoma
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ATLANTA — Adults and children with advanced HER2-positive sarcoma safely tolerated and derived clinical benefit from lymphodepletion chemotherapy followed by infusions of autologous HER2-targeted chimeric antigen receptor T cells, according to results of a phase 1 trial presented at American Association for Cancer Research Annual Meeting.
“HER2 is a protein in the epidermal growth factor receptor family which, unlike its family counterparts, has very limited natural expressions in the body,” Shoba Navai, MD, assistant professor of pediatrics at the Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, said during a press conference. “It is aberrantly expressed on the surface of cancer cells in a variety of tumors. By pairing it with itself or one of its partners on a tumor cell, it can activate signaling pathways that promote cancer cell growth.”
Although the percentage of sarcomas that express HER2 on the tumor surface is not known, one of the most common types of sarcoma, osteosarcoma, reportedly is HER2-positive in as many as 40% of patients.
"Unlike HER2-positive breast cancers, the amounts of HER2 to present on the surface of sarcomas is much less, and the lower level of expression is not sufficient for HER2-targeting drugs to show efficacy,” Navai said.
In the phase 1 dose-escalation trial, Navai and colleagues sought to determine whether the expansion of HER2-targeted CAR T cells could be safely improved by lymphodepleting chemotherapy.
The treatment group included 10 patients (median age, 14 years; range, 4-54) with recurrent/refractory HER2-positive sarcoma (osteosarcoma, n = 5; rhabdomyosarcoma, n = 3; Ewing sarcoma, n = 1; synovial sarcoma, n = 1). One patient with rhabdomyosarcoma was reenrolled in the trial and retreated.
After undergoing lymphodepletion with either fludarabine (n = 3) or fludarabine and cyclophosphamide (n = 8), each patient received up to three IV infusions of 1 x 108/m2 autologous HER2-targeted CAR T cells.
Patients who responded to this initial treatment subsequently received up to five additional infusions without lymphodepletion. Fludarabine and fludarabine/cyclophosphamide resulted in lymphopenia with an absolute lymphocyte count of less than 100/ml on the day of T-cell administration.
Fludarabine/cyclophosphamide led to neutropenia (absolute neutrophil count less than 500/ml) for up to 14 days.
Grade 1 to grade 2 cytokine release syndrome occurred in eight patients within 24 hours of CAR T-cell infusion; this was completely resolved within 5 days of onset.
Nine patients demonstrated expansion of T cells, with a median peak expansion on day 7 (range, 5-28).
“Importantly, no patients experienced decreased heart function, which has been reported with other types of HER2-targeted therapies,” Navai said in a press release. “We also did not observe any pulmonary toxicities in our patients despite expansion of the infused CAR T cells.”
Quantitative polymerase chain reaction detected CAR T cells in all patients 6 weeks after infusion. One pediatric patient with rhabdomyosarcoma metastasized to the bone marrow attained complete response for 12 months, but relapsed after 6 months off treatment. After retreatment, the patient again achieved complete response, which has been maintained for 17 months.
“We observed the appearance of new T-cell clones which were not present prior to treatment,” Navai said during the press conference. “We do not yet know the specificity of these clones and we are actively working to determine this. When we screened the patient’s serum for antibody responses against the large number of known human proteins, we identified new antibodies after treatment. These findings suggest that the patient’s own immune system may have engaged to elicit new immune responses after treatment with HER2 CAR T cells.”
One patient with osteosarcoma metastasized to the lungs has maintained complete response for 32 months. Three patients had stable disease and five had progressive disease. Navai and colleagues noted that their study is limited by the fact that it is a small phase 1 trial, and that additional testing of HER2-specific CAR T-cells in larger cohorts is needed.
“In summary, HER2 CAR T cells can safely be given in combination with lymphodepletion, and lymphodepletion enhances T-cell expansion and persistence,” Navai said. “HER2 CAR T cells can induce objective clinical responses in some patients with sarcoma, and engagement of endogenous immunity may aid in the generation of tumor responses.” – by Jennifer Byrne
Reference:
Navai S, et al. Abstract LB-147. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.
Disclosures: Navai reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.