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ATLANTA – A Combination of Chemotherapy and Antigen Receptor Receptor T (AR) T Lines Designed to Target HER2 Protein Has Proved Safe and Showed Clinical Responses in Pediatric and Adult Patients with Sarcoma Advanced HER2-positive, according to the results of a Phase I clinical trial presented at the AACR Annual Meeting 2019, from March 29 to April 3.
"Children and adults with recurrent or refractory sarcomas have limited treatment options," said Shoba Navai, MD, badistant professor of pediatrics at the Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children & # 39; s Hospital and Houston Methodist Hospital Houston. "Depending on the type of sarcoma, treatment regimens for curative rescue chemotherapy are available, but the chances of success are low and the treatments can be quite toxic."
Although it is not known what percentage of sarcomas express HER2 on the surface of the tumor, osteosarcoma, one of the most common types of sarcoma, has been reported to be positive for HER2 in 40% of patients, and HER2 positivity is badociated with a higher probability of tumor metastasis, Navai explained. Previous clinical studies have shown that HER2-targeting antibodies such as trastuzumab are not effective for these patients. "Our group has already shown in the lab that HER2-directed CAR T cells are more effective in targeting low levels of HER2 on tumor cells than trastuzumab, so these T CAR cells may have antitumor activity in patients with sarcoma even when treatment with HER2-antibodies do not do it, "she added.
"Our study shows that HER2-centric T-cell therapy, administered in combination with lymphodifusion chemotherapy, is safe and demonstrates early promising antitumor activity in some patients with advanced HER2-based sarcomas. positive, "said Navai.
As part of this trial, Navai and colleagues treated a refractory / metastatic HER2-positive sarcoma in 10 patients aged 4 to 54 years (five with osteosarcoma, three with rhabdomyosarcoma and one sarcoma). Ewing and synovial sarcoma). Patients had already received up to five life-saving therapies.
Patients received up to three infusions of HER2-targeting T CAR cells after lymphodepletion with fludarabine or fludarabine and cyclophosphamide; those who responded to this initial treatment received up to five additional injections of CAR T cells without lymphodepletion.
The investigators found that CAR T cells increased in all but two patients, with a median peak on the seventh day, and that they could detect CAR T cells in all patients six weeks after infusion.
A pediatric patient whose rhabdomyosarcoma had metastasized in the bone marrow presented a complete response (CR) for 12 months, but then recurred; reprocessing with CAR T cells resulted in a CR that has lasted 17 months. The blood test of this patient at several times showed antibody responses against several intracellular proteins involved in the cell cycle, cell growth, cell signaling and in tumor processes such as invasion and metastasis said Navai.
"Some antibodies in this patient's blood have recently been detected and maintained after CAR T cell infusions, suggesting that in addition to the expected direct effect of HER2-targeting CAR T cells on the tumor, they could have activated the patient's immune system, "she added. "Further studies are needed to identify the specificities and functional significance of these responses."
A pediatric patient with metastatic osteosarcoma to the lungs has continuous CPR for 32 months. Three patients had stable disease and five had progressive disease.
Navai noted that overall, patients in this study had limited treatment-related toxicities. All patients expected a decrease in their blood count after chemotherapy, but no infection to develop following a low blood count, she added.
"Significantly, no patient has presented with decreased cardiac function, which has been reported with other types of HER2-targeting therapies." We have also observed no pulmonary toxicity in our patients. patients despite the expansion of CAR T cells infused, "Navai said.
One limitation of the study lies in the fact that it is a small phase I trial and that additional tests of HER2-specific T CAR cells in larger cohorts of patients Important are needed to define the optimal efficacy and dosage, Navai said.
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This study was funded by a Dream Team translational research grant from the St Baldrick & # 39; s Stand Up to Cancer Association (SU2C) (AACR is SU2C's scientific partner), Cookies for Kids & # 39; Cancer and the Texas Institute of Cancer Research & Prevention. Alex's Lemonade Stand Foundation provided travel and accommodation expenses to patients enrolled in the study. Navai does not declare any conflict of interest.
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