Antitumor activity without on-target off-tumor toxicity of GD2–chimeric antigen receptor T cells in patients with neuroblastoma
CARs to drive off neuroblastoma
Neuroblastoma is one of the most common types of pediatric cancer, and it can be difficult to treat. This tumor typically has high expression of the ganglioside GD2, and there have been previous attempts at targeting these tumors via GD2. Unfortunately, these have not been entirely successful, in part, because some GD2 is also present on nonmalignant nervous tissue. Straathof et al. report the results of a clinical trial in 12 pediatric patients with neuroblastoma, treated with chimeric antigen receptor (CAR) T cells against GD2. The treatment was well tolerated without on-target off-tumor toxicity but did not achieve objective clinical responses.
Abstract
The reprogramming of a patient’s immune system through genetic modification of the T cell compartment with chimeric antigen receptors (CARs) has led to durable remissions in chemotherapy-refractory B cell cancers. Targeting of solid cancers by CAR-T cells is dependent on their infiltration and expansion within the tumor microenvironment, and thus far, fewer clinical responses have been reported. Here, we report a phase 1 study (NCT02761915) in which we treated 12 children with relapsed/refractory neuroblastoma with escalating doses of second-generation GD2-directed CAR-T cells and increasing intensity of preparative lymphodepletion. Overall, no patients had objective clinical response at the evaluation point +28 days after CAR-T cell infusion using standard radiological response criteria. However, of the six patients receiving ≥108/meter2 CAR-T cells after fludarabine/cyclophosphamide conditioning, two experienced grade 2 to 3 cytokine release syndrome, and three demonstrated regression of soft tissue and bone marrow disease. This clinical activity was achieved without on-target off-tumor toxicity. Targeting neuroblastoma with GD2 CAR-T cells appears to be a valid and safe strategy but requires further modification to promote CAR-T cell longevity.
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Supplementary Material
Summary
Fig. S1. Generation of high-titer retroviral clone.
Fig. S2. Preclinical validation of 1RG-CART cell product.
Fig. S3. Recruitment and treatment on study.
Fig. S4. Count recovery after lymphodepletion and 1RG-CART administration.
Fig. S5. Assessment of response to 1RG-CART in bone marrow trephines for patient 25/010.
Fig. S6. Assessment of intensity scores in isolated regions of interest by normalization to liver uptake on 123I-mIBG scans before and after 1RG-CART.
Fig. S7. PD-L1 expression and T cell infiltration in tumor biopsies before and after 1RG-CART treatment.
Fig. S8. GD2 expression in tumor cells in bone marrow and biopsies after 1RG-CART.
Fig. S9. 1RG-CART cell product characteristics in patients with and without immune activation and antitumor activity.
Table S1. Eligibility criteria.
Table S2. Characteristics of patients recruited on study.
Table S3. 1RG-CART cell product dose and phenotype.
Table S4. Serum cytokine measurements.
Tables S5. Scoring of 123I-mIBG scans before and after 1RG-CART treatment.
Table S6. Scoring of PD-L1 expression in the tumor microenvironment before and after 1RG-CART treatment.
Table S7. GD2 expression in tumor samples at baseline and after 1RG-CART.
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Information
Published In
Science Translational Medicine
Volume 12 | Issue 571
November 2020
November 2020
Copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
This is an article distributed under the terms of the Science Journals Default License.
Submission history
Received: 7 July 2020
Accepted: 23 September 2020
Acknowledgments
We thank the parents and children who participated in this study, the clinical and manufacturing teams, and staff in the hematology and immunology laboratories at Great Ormond Street Hospital. We thank BioVec Pharma for supplying the packaging lines. Funding: This work was funded and sponsored by Cancer Research UK (CRUK). Additional funding sources are Action Medical Research, Neuroblastoma UK and Great Ormond Street Hospital Charity (Anstey fund), Children with Cancer UK, and Research into Childhood Cancer (RICC). Clinical trial work at GOSH is supported by the NIHR/CRUK Experimental Cancer Medicine Centre (ECMC) funding. This work is partly funded by the NIHR GOSH BRC. The original preclinical work was funded by Neuroblastoma UK. K.S. is the recipient of a Wellcome Trust Clinician Scientist Fellowship. M.P. is supported by the University College London Hospital BRC. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Author contributions: K.S., M.P., and J.A. designed and led the study and wrote the manuscript. M.P. generated the high-titer producer clone. B.F., R.W., S.S., T.G., S.T., G.W.-K.C., N.W., and J.S. led product development and manufacture. J.A., K.S., M.P., D.E., C.B., N.W., J.S., L.R., L.E., S.B., and K.D. managed the trial and regulatory submission. K.S., B.F., R.W., S.T., N.J., J.B., K.G., E.K., C.M., G.W.-K.C., S.I., G.W., D.R., A.U.A., O.O., T.M., M.A.-H., and W.D. generated and analyzed the data. J.A., G.B., C.D., T.L., N.J., S.D., A. Bedi, K.H., and A. Barry consented and managed the patients and collected the clinical data. K.S., T.L., N.J., K.M., L.B., N.S., C.B., D.E., L.R., J.S., S.T., L.E., S.B., and I.D. analyzed the clinical and laboratory data. Competing interests: M.P. receives a salary contribution from Autolus Ltd. S.T., M.A.-H., W.D., and E.K. are employees of Autolus Ltd. M.P., S.T., M.A-H., W.D., E.K., and J.A. own stock in Autolus Ltd. M.P., S.T., and J.A. are inventors on a patent describing the GD2-CAR (WO2015132604). M.P. is an inventor on a patent describing RQR8 (WO2013153391). C.B. is a freelance pharmaceutical physician; has undertaken paid consultancy work with Barton Oncology Ltd. for numerous companies, charitable groups, and other organizations; and owns shares in GlaxoSmithKline. All other authors declare that they have no competing interests. Data and materials availability: All data associated with this study are present in the paper or the Supplementary Materials. Plasmid encoding RQR8_2A_GD2-CAR (MP10413) is available from M.P. under a material transfer agreement with UCL.
Authors
Funding Information
Wellcome: 102803/Z/13/Z
Cancer Research UK: Trial, manufacturer and pharmacodynamic assay agreements
Action Medical Research: GN2400
Neuroblastoma UK: N/A
Research in Childhood Cancer (RICC): One off donation
NIHR Great Ormond Street Biomedical Research Centre: N/A
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