Shoba Nabal, MD
Administration of HER2-targeted therapy CAR T cells and lymphodepletion chemotherapy have demonstrated antitumor activity and is recognized as safe in pediatric and adult patients with advanced HER2-positive sarcoma, according to findings of phase I, presented at the 2019 Annual Meeting of AACR.
In a small study (NCT00902044) of 10 patients with refractory / HER2-positive metastatic sarcoma treated product CAR HER2-directed T cells, T cell CAR expanded in all but 2 patients; expanding the average peak was 7 days (range 5-28), and CAR-T cells were detected using quantitative polymerase chain reaction in all patients 6 weeks after infusion.
«HER2 CAR T cells can safely be given in combination with lymphodepletion; lymphodepletion enhances the expansion of T-cells and perseverance, "said the study's lead author Shoba Nabal, MD, presenting the results at the AACR meeting. «HER2 CAR T cells can cause an & # 39; objective clinical responses in some patients with sarcoma, and involvement of endogenous immunity can help in the generation of tumor response."
One of the most common types of sarcoma, osteosarcoma, called HER2-positive in 40% of patients; Furthermore, the HER2-positive subtype associated with a higher likelihood of tumor metastasis. Preclinical data showed that HER2-targeted therapies, including trastuzumab (Herceptin) is significantly less effective in Surk compared with a HER2-positive breast cancer.
"Children and adults with relapsed or refractory sarcomas have limited treatment options," said Nawal, assistant professor of pediatrics at the Center for Cell and Gene Therapy at
Baylor College of Medicine, Texas Children's Hospital, and X & # 39; Euston Methodist Hospital. "Depending on the specific type of sarcoma, saving modes curative chemotherapy
available, but the success rate is low and the treatment can be very toxic. "
Nevertheless, HER2-directed CAR T-cells have the ability to target low levels of HER2 in tumor cells compared to trastuzumab, and also found in preclinical studies, Naval explained. CAR molecule T-cells were used in a phase I study consisting of HER2 connects domain from FRP5 antibodies produced bound to the signaling domain of the T-cell containing CD28 co-stimulation.
In the study, researchers enrolled 10 patients with osteosarcoma (n = 5), rhabdomyosarcoma (N = 3), Ewing sarcoma (n = 1), and synovial sarcoma (n = 1). One patient with rhabdomyosarcoma, received and relapses, and then re-entered and departed. The median age was 14 years (range 4-54) and up to 5 previous therapy garages were given.
Patients received 3 infusions of autologous target HER2-CAR T cells to 1 x 108/ m2 AMD lymphodepletion or fludarabine only at 25 mg / m2 daily (n = 3) or in combination with cyclophosphamide at 30 mg / kg daily (n = 8). Both schemes lymphodepletion induced lymphopenia with absolute lymphocyte count of <100 / ml on the day of infusion of T cells, and fludarabine / cyclophosphamide-induced neutropenia for 14 days. Patients were followed for safety period of 6 weeks, at which disease ratings were performed replay point.
Those who had initial answers to these procedures were then introduced another infusion 5 CAR T cells at the most, but without lymphodepletion.
The results further showed that at the end of the initial period of 6 weeks, 4 patients had progressive disease and 4 patients had stable disease, the latter of which lasted for 3.4 months and 9 months, said Naval during its presentation.
"Five of the 10 patients were alive last observation, and overall survival for all patients with lymphodepletion was 60% at 1 year," she added.
In particular, 1 pediatric patient with metastatic rhabdomyosarcoma, which has spread to the bone marrow, achieved a complete response (CR) for 1 year, but later relapse; Regeneration with CAR T cell constant CR is achieved within 17 months. Many patient blood samples showed the presence of antibody responses against several intracellular proteins involved in the cell cycle, cell growth, cell signaling, and also in invasion and metastasis.
In addition, the data showed that 1 pediatric patient with metastatic osteosarcoma that has spread to the lungs, has been ongoing CR 32 months.
With regard to safety, there were limited treatment-related toxicity, Nava said. Eight patients experienced grade 1/2 cytokine release syndrome in 24 hours infusion CAR T cells, which was completely eliminated after maintenance therapy during 5 days after the onset of the disease. After chemotherapy, all patients experienced decreased blood test is expected that later improved; None of the patients developed secondary infections lowest blood, and there was no neurological toxicity.