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22 februari 2025: Bron: Nature d.d. 17 februari 2025

19 jaar geleden kregen kinderen met neuroblastoma, een vorm van een hersentumor die alleen bij kinderen in de leeftijd van 1 tot 5 jaar optreedt, in een gerandomiseerde fase I studie of een CAR-T cel behandeling (Chimere antigeen recepter T-cel therapie) of een behandeling met een anti lichaam 14g2a nadat de ziekte progressie had laten zien ondanks eerdere behandelingen.  

Uit een follow-up analyse van deze NESTLES studie blijkt dat meerdere kinderen van toen nog steeds in leven zijn. En nog belangrijker nog steeds kankervrij zijn zonder aanwizjingen dat er een recidief op zal treden. Zo wordt 1 kind van 4 jaar jaar eruit gelicht die nu in 2025 al 19 jaar kankervrij is en een gezond leven leidt. Zij had in de botten uitgezaaide neuroblastoom, maar reageerde dus zeer goed op de CAR-T cel behandeling. Het bijzondere aan haar genezing is dat een CAR-T cel behandeling dus ook bij solide tumoren effectieve behandeling kan zijn met duurzame genezingen.

Hier achtereenvolgens het studieverslag van de fase I studie en een toelichtend artikel uit Nature d.d. 17 fgebruari 2025:

Long-term outcomes of GD2-directed CAR-T cell therapy in patients with neuroblastoma

Nature Medicine (2025)Cite this article

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.

ClinicalTrials.gov identifier: NCT00085930.


Het toelichtende artikel uit Nature:

Woman in cancer remission for record 19 years after CAR-T immune treatment

CAR-T-cell therapy treated a girl with a rare childhood cancer, raising hopes for future recipients of the approach.

The girl was four years old when she arrived at Texas Children’s Hospital in Houston to receive a highly experimental therapy for nerve-cell cancer. Standard treatments had been unable to hold the cancer back. It had spread to her bones, and the prognosis was poor.

Nineteen years later, she is cancer-free and the mother of two children. The remarkable success story, published on 17 February in Nature Medicine1, is the longest reported cancer remission following treatment with engineered immune cells called CAR T cells.

In the years since the girl’s treatment in 2006, CAR T cells have produced stunning results in some blood cancers such as leukaemia. Seven CAR-T-cell therapies have been approved by the US Food and Drug Administration since 2017, and some early recipients of CAR-T therapy have been cancer-free for more than a decade.

But researchers have struggled to repeat that success against solid tumours such as those caused by neuroblastoma, a nerve-cell cancer that is typically diagnosed in young children. That makes the latest results particularly good news, says Sneha Ramakrishna, a paediatric oncologist and cancer researcher at Stanford University School of Medicine in California, who was not involved in the study.

“This provides me with a lot of hope,” she says. “We’re going to unlock CAR T cells for people with solid tumours.”

Cell target

CAR T cells are immune cells that have been engineered to make a protein called a chimeric antigen receptor (CAR). This protein is designed to latch onto a target found on a cancer cell, triggering the immune cell to attack and destroy it.

When the Texas neuroblastoma study began in 2004, CAR-T-cell therapy was still a bit of a wild idea, says Helen Heslop, an immunotherapy researcher at Baylor College of Medicine in Houston, and a member of the team that ran the trial. “This is some kind of weird synthetic biology,” she remembers thinking. “Will it actually work?”

The CAR-T-cell therapies Heslop and her colleagues tested then are now considered first-generation editions of the molecules. Later versions, including those that are now approved medicines, contain extra modifications to bolster their power. Heslop calls her first CAR-T-cell study “a vintage trial”.

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Data availability

All requests for raw and analyzed data and materials will be promptly reviewed by the Baylor College of Medicine Licensing Group to verify if the request is subject to any intellectual property or confidentiality obligations. Patient-related data not included in the paper were generated as part of the clinical trial and may be subject to patient confidentiality. Any data and materials that can be shared will be released via a material transfer agreement within 2 weeks. After removal of all human research participant identifiers, raw data for single-cell sequencing were deposited in the Gene Expression Omnibus under accession number GSE284343, which is now publicly available. Source data are provided with this paper.

Code availability

R scripts to reproduce single-cell analysis can be downloaded from https://doi.org/10.5281/zenodo.14544634.

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Acknowledgements

The initial trial was supported by National Cancer Institute (NCI) grant PO1 CA094237 (H.E.H., C.M.R. and M.K.B.), and the GMP facility was supported by P30CA125123. Support was also provided by the National Gene Vector Biorepository at Indiana University, which is funded under NCI contract HSN261201500003I, Task Order number HHSN26100077. We would like to thank the Genomic, Transcriptomic, Epigenomic and Single Cell Shared Resource of the Dan L. Duncan Comprehensive Cancer Center, NCI Cancer Center Support Grant (P30CA125123), for assistance with the single-cell analyses, and J. C. Crawford at St. Jude Children’s Research Hospital for attempting spatial transcriptomics on stained slides.

Author information

Authors and Affiliations

  1. Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, USA

    Che-Hsing Li, Sandhya Sharma, Andras A. Heczey, Mae L. Woods, David H. M. Steffin, Chrystal U. Louis, Bambi J. Grilley, Sachin G. Thakkar, Cliona M. Rooney, Malcolm K. Brenner & Helen E. Heslop

  2. Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA

    Che-Hsing Li & Andras A. Heczey

  3. Program in Immunology and Microbiology, Baylor College of Medicine, Houston, TX, USA

    Che-Hsing Li

  4. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Andras A. Heczey, David H. M. Steffin, Bambi J. Grilley, Mengfen Wu, Tao Wang, Cliona M. Rooney, Malcolm K. Brenner & Helen E. Heslop

Contributions

C.M.R., M.K.B. and H.E.H. conceptualized the project. C.-H.L. collected patients’ medical records from the original charts stored at Texas Children’s Hospital in Houston, Texas; thawed CAR-T products for single-cell analysis; analyzed the data; interpreted the results; and drafted the paper. C.-H.L., S.S. and S.G.T. analyzed the transgene results. S.S. thawed and expanded post-infusion samples and ran flow cytometry to analyze the CAR+ populations. M.L.W. analyzed the single-cell data. C.U.L. was the principal investigator while the trial was accruing, and A.A.H. took over for long-term follow-up. D.H.M.S. also followed patients in the trial. M.W. and T.W. provided statistical support for the clinical trial, and B.J.G., M.K.B. and H.E.H. served as Investigational New Drug (IND) sponsors. C.M.R., M.K.B. and H.E.H. edited the paper, and all authors reviewed and approved the paper.

Corresponding author

Correspondence to Helen E. Heslop.

Ethics declarations

Competing interests

C.M.R., M.K.B. and H.E.H. are cofounders of and equity holders in AlloVir, Inc. and Marker Therapeutics. M.K.B. and C.M.R. have equity in March Biosciences and serve on advisory boards for March Biosciences, Marker Therapeutics, Allogene, Walking Fish, Abintus, Tessa Therapeutics, Athenex, Onk Therapeutics, Coya Therapeutics, Triumvira, Adaptimmune, Vor Therapeutics and TScan. H.E.H. has served on advisory boards for GlaxoSmithKline, Fresh Wind Biotechnologies, March Biosciences, Marker Therapeutics and Tessa Therapeutics and has share options in Co-Regen, Fresh Wind Biotechnologies and March Biosciences. B.J.G. owns QBRegulatory Consulting, which has agreements with March Biosciences. C.U.L. has equity in and is an employee of TScan. A.A.H. has consultancy/scientific advisory roles with Waypoint Bio, Dispatch Bio and Cargo Therapeutics. The other authors declare no competing financial interests.

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Peer review information

Nature Medicine thanks Joseph Fraietta, Franco Locatelli and Julie Park for their contribution to the peer review of this work. Primary Handling Editors: Ulrike Harjes and Saheli Sadanand, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Graphical summary of the study design.

NB, neuroblastoma.

Extended Data Fig. 2 Survival estimates for all patients (n = 19).

(a) Event-free survival. (b) Overall survival.

Extended Data Fig. 3 Detection of chimeric antigen receptor (CAR) in mRNA and protein levels in the expanded T cells from three long-term survivors’ post infusion peripheral blood mononuclear cells (PBMCs).

(a) Schematic of activated T cell (ATC) expansion and virus-specific T cell (VST) protocols and strategies to detect CAR. lymphoblastoid B-cell line (LCL) is an EBV-transformed immortal cell line presenting EBV antigens. They were irradiated before co-culturing with PBMCs to expand VSTs. Transgene levels of CAR-ATCs and CAR-VSTs in cells expanded through ATC protocol (b) and VST protocol (c) were measured by qPCR. (d) CAR protein expression levels of patient 1,089’s expanded T cells (week 2, week 6, and month 19 post infusion) were detected by flow cytometry. (e) Quantification of CAR+ percentage (gated from live CD3+ cells) of patient 1,144, 1,089, and 1,632’s post infusion expanded T cells at multiple time points. Non-transduced and positive control T cells were generated from a healthy donor’s PBMCs.

Source data

Extended Data Fig. 4 Gating strategy for Extended Data Fig. 3d and e.

The live CD3+ CAR+ cells were gated based on the provided strategy.

Extended Data Table 1 Patient demographics
Full size table

Supplementary information

Source data

Source Data Fig. 1

The raw transgene copy numbers of each individual’s post-infusion samples, including blood, bone marrow and other tissues.

Source Data Fig. 2

The raw UMAP, proportion comparison, specific gene expression matrix and Shannon entropy data of single-cell RNA sequencing and single-cell TCR sequencing.

Source Data Extended Data Fig./Table 3

The raw transgene copy number and CAR protein percentage of the post-infusion expanded T cells from the three patients (1,144, 1,089 and 1,632).

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Li, CH., Sharma, S., Heczey, A.A. et al. Long-term outcomes of GD2-directed CAR-T cell therapy in patients with neuroblastoma. Nat Med (2025). https://doi.org/10.1038/s41591-025-03513-0

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