A woman diagnosed with neuroblastoma in childhood has remained in remission for more than 18 years after being treated with an engineered CAR-T cell therapy at four years of age, according to follow-up of a phase I trial.
Among 19 neuroblastoma patients treated with CAR-T cell therapy, eight survived more than five years after infusion, including five with follow-up of more than 13 years, reported Helen Heslop, MD, of the Baylor College of Medicine in Houston, and colleagues.
“Despite using first-generation vectors that are no longer employed because of the lack of co-stimulatory domains, patients with relapsed/refractory neuroblastoma achieved long-term disease control after receiving GD2 CAR-T cell therapy, including the one patient now in remission of relapsed disease for more than 18 years,” they wrote in Nature Medicine.
“This study described, to our knowledge, is the longest reported survival after CAR-T therapy for active malignancy.”
Medpage Today reports that participants in the study, which enrolled from 2004 to 2009, were infused with two immune effector cell products – activated T cells expanded with OKT3 antibody and Epstein-Barr virus (EBV)-specific T cells generated by stimulation with autologous EBV-transformed lymphoblastoid cell lines.
These were each transduced with first-generation CARs recognising GD2 expressed on neuroblastoma.
Regarding the woman in remission for longer than 18 years, dubbed “patient 1 144”, Heslop and colleagues pointed out that she had bone lesions before receiving the CAR-T cell therapy infusion and attained a complete remission.
“She has never required any other therapy and is likely to be the longest-surviving patient with cancer who received CAR-T therapy,” the researchers observed.
“Encouragingly, she has subsequently had two full-term pregnancies with normal infants. The overall toxicities observed during this long-term follow-up were attributable to previous chemotherapy, with sensorineural hearing loss as the most common adverse event.”
Eleven of the 19 patients in the phase I trial had active relapsed diseases at the time of infusion, while the remaining eight had no evidence of active disease. Of those eight, five had a history of relapsed disease, and three were infused after completing therapy for high-risk disease.
At enrolment, participants were between the ages of three and 20 years, and just more than half were male.
Of the 11 patients with active disease at the time of infusion, three had complete responses and one had a partial response. One of the patients with a complete response subsequently relapsed, but two had sustained responses: patient 1 144 and another with a response lasting eight years before being lost to follow-up.
Of the eight patients with no evidence of active disease at the time of infusion, five were disease free at their last follow-up between 10 and 15 years’ post-infusion.
However, Heslop and colleagues acknowledged that since these patients had no evidence of active disease before their CAR-T cell therapy, “they may have already been cured”.
Event-free survival at 15 years was 31.6% for the entire cohort, including 18.2% for patients with active disease and 50% for patients with no evidence of active disease at the time of infusion. Overall survival at 15 years was 36.8% – 18.2% and 62.5% for patients with active or no active disease, respectively, prior to their CAR T-cell therapy infusion.
Twelve patients died between two months and seven years after infusion, due to relapsed neuroblastoma. Seven patients are alive at the last follow-up.
The authors noted that one patient developed invasive ductal carcinoma of the breast at 32, more than a decade after infusion.
They attributed this secondary malignancy to extensive chemotherapy and thoracic spinal radiation therapy before infusion, “both of which are well-documented risk factors”.
Study details
Long-term outcomes of GD2-directed CAR-T cell therapy in patients with neuroblastoma
Che-Hsing Li, Sandhya Sharma, Andras A. Heczey et al.
Published in Nature Medicine on 17 February 2025
Abstract
In a phase 1 clinical trial open to accrual from 2004 to 2009, we treated children with neuroblastoma with Epstein–Barr virus (EBV)-specific T lymphocytes and CD3-activated T cells—each expressing chimeric antigen receptors (CARs) targeting GD2 but without an embedded co-stimulatory sequence (first-generation CARs). These CARs incorporated barcoded sequences to track each infused population. We previously reported outcomes up to 5 years and now report long-term outcomes up to 18 years. Of 11 patients with active disease at infusion, three achieved a complete response that was sustained in two patients, one for 8 years until lost to follow-up and one for more than 18 years. Of eight patients with no evidence of disease at the time of CAR-T administration, five are disease free at their last follow-up between 10 years and 15 years after infusion. Intermittent low levels of transgene were detected during the follow-up period with significantly greater persistence in those who were long-term survivors. Despite using first-generation vectors that are no longer employed because of the lack of co-stimulatory domains, patients with relapsed/refractory neuroblastoma achieved long-term disease control after receiving GD2 CAR-T cell therapy, including one patient now in remission of relapsed disease for more than 18 years.
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