Cancer-free for 18 years: CAR-T therapy sets new milestone in the treatment of neuroblastoma

Cancer-free for 18 years: CAR-T therapy sets new milestone in the treatment of neuroblastoma

New research shows GD2 CAR T cell therapy offers a potential cure for neuroblastoma, with some patients achieving long-term remission for over a decade, marking a major milestone in solid tumor treatment.

In a recently published study innatural medicine,Researchers report the successful treatment of a neuroblastoma patient with chimeric antigen receptor (CAR) T cell therapy.

What is CAR T-cell therapy?

CAR T-cell therapy involves isolating T cells from the patient's blood and genetically engineering them to express cars on their surface. When CAR-T cells are administered to the patient, they recognize and facilitate the clearance of cancer cells by binding to specific proteins on their surface.

To date, six CAR T-cell therapies have been approved by the United States Food and Drug Administration (FDA) for the treatment of lymphoma, leukemia and multiple myeloma. These FDA-approved therapies target CD19 or B-cell maturation antigen (BMCA) B cells, both of which are markers often restricted to B cells, reducing the potential toxicity of this therapy to other tissues.

Although CAR T-cell therapy has been widely successful in treating hematologic cancers, this treatment approach is limited in its ability to target solid tumors. Some of these limitations include antigen selection, tolerability, and safety concerns, which require additional studies to improve the design of CAR-T cells to achieve improved therapeutic efficacy and safety.

CAR T-cell therapy and neuroblastoma

Neuroblastoma is a rare solid tumor that develops in immature nerve cells. This type of cancer primarily affects children five years old and younger and is associated with high recurrence rates.

Between 2004 and 2009, the researchers in the current study conducted a Phase I clinical trial. During this study, activated T cells were designed to target disialoganglioside 2 (GD2), a protein that was commonly overexpressed in neuroblastoma cells. This therapy included both activated T cells (ATCs) and Epstein-Barr virus (EBV)-specific T cells (VSTs), which were trained to recognize and attack tumor cells.

After the infusion, the auto-transgene remained detectable in the patient's blood for 192 weeks. To extend these findings, investigators in the current study are providing long-term follow-up data 13-18 years after the initial infusion of clinical outcomes of treated patients and the biological effects of this treatment approach.

Experimental results

First-generation CAR T cells demonstrated unexpected longevity—despite lacking modern co-stimulatory molecules, GD2 CAR T cells persisted for over 5 years in some patients and played a key role in long-term remission.

The study included a total of 19 children, 11 of whom had active relapsed neuroblastoma. Of eight patients without active disease, five had a history of relapsed disease and three were infused with GD2 CAR T-cell therapy after completing therapy for high-risk disease.

Of eleven patients with active disease at the time of infusion, three had complete responses and one had a partial response. One of the three patients with complete responses subsequently experienced disease relapse. However, the remaining two patients had persistent reactions. One experienced beneficial effects for eight years until lost to follow-up, while the other reported positive results for more than 18 years.

In eight patients with no evidence of active disease at the time of infusion, five remained disease-free for up to 15 years after infusion. At the 15-year follow-up visit, event-free survival was 32%, while overall survival was 37%.

Of 19 enrolled patients, 12 died between two months and seven years after infusion due to relapsed neuroblastoma.

The patient, who achieved complete remission for more than 18 years, never required the infusion of any other cancer treatment. In fact, this patient completed two successful pregnancies with healthy infants. Nevertheless, this patient experienced some health adversities, including sensorineural hearing loss, which was due to previous chemotherapy.

Low levels of the GD2-CAR transgene were detected in patient blood samples, likely representing CAR T cells, that persisted for at least five years. The presence of long-persisting CAR-T cells was significantly higher in long-term survivors.

Conclusions

Immune profiling revealed distinct cell behavior - single-cell RNA sequencing showed that CAR T cells in long-term survivors had a mix of effector and memory-like T cell properties, likely contributing to their expanded therapeutic effects.

The current study provides evidence for the long-term survival of children with neuroblastoma who received GD2 CAR T cell therapy. Notably, researchers reported a patient's complete cancer remission for more than 18 years, which is likely the longest remission reported in a patient with a solid tumor treated with CAR T-cell therapy.

The study used first-generation CAR-T cells, which lack the costimulatory molecules currently found in advanced CAR-T cells. Therefore, the intermittent low granular gene levels detected during the follow-up period of experimental observation periods may be due to the absence of these co-stimulatory molecules. The significantly greater persistence of transgenes observed in long-term survivors highlights the importance of CAR-T cells in long-term disease control.

Study results suggest that GD2 CAR T cell therapy is safe and has the potential to deliver more than 18 years of complete remission in children with recurrent neuroblastoma without causing long-term complications.

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