Human cancer-targeted immunity via transgenic hematopoietic stem cell progeny

Abstract

Copyright and License

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Acknowledgement

This study was funded by the California Institute for Regenerative Medicine (CIRM) grant CLIN2-11380. T.S.N. was further supported by NIH grant K08 CA241088, Hyundai Hope on Wheels, the Tower Cancer Research Foundation. This study was additionally funded in part by the Parker Institute for Cancer Immunotherapy (PICI), NIH grant R35 CA197633 and the Ressler Family Fund (to A.R.). N.N.A. is supported by the Alan Ghitis Fellowship for Melanoma Research. N.F. is supported by the National Center for Advancing Translational Science (NCATS) of the National Institutes of Health under the UCLA Clinical and Translational Science Institute grant number UL1TR001881 and California Institute for Regenerative Medicine (CIRM) INFR4 Alpha Clinic Network Expansion Award. D.B.K. is supported by endowment funds from the UCLA Eli and Edyth Broad Stem Cell Research Center. The authors gratefully acknowledge the NHLBI National Gene Vector Biorepository at Indiana University (PI Cornetta, P40HL116212) for assistance in the generation and maintenance of the NY-ESO-1 TCR retrovirus and NY-ESO-1 TCR/sr39TK lentivirus vectors. Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research Flow Cytometry Core Facility that is supported by National Institutes of Health awards P30 CA016042 and 5P30 AI028697, and by the JCCC, the UCLA AIDS Institute, the UCLA Technology Center for Genomics and Bioinformatics (TCGB) core lab, and the David Geffen School of Medicine at UCLA. The authors wish to acknowledge the participation of patients and their caregivers, and the patient care at the Hematology-Oncology Stem Cell Transplantation Unit at UCLA.

Funding

This study was funded by the California Institute for Regenerative Medicine (CIRM) grant CLIN2-11380. T.S.N. was further supported by NIH grant K08 CA241088, Hyundai Hope on Wheels, the Tower Cancer Research Foundation. This study was additionally funded in part by the Parker Institute for Cancer Immunotherapy (PICI), NIH grant R35 CA197633 and the Ressler Family Fund (to A.R.). N.N.A. is supported by the Alan Ghitis Fellowship for Melanoma Research. N.F. is supported by the National Center for Advancing Translational Science (NCATS) of the National Institutes of Health under the UCLA Clinical and Translational Science Institute grant number UL1TR001881 and California Institute for Regenerative Medicine (CIRM) INFR4 Alpha Clinic Network Expansion Award. D.B.K. is supported by endowment funds from the UCLA Eli and Edyth Broad Stem Cell Research Center. The authors gratefully acknowledge the NHLBI National Gene Vector Biorepository at Indiana University (PI Cornetta, P40HL116212) for assistance in the generation and maintenance of the NY-ESO-1 TCR retrovirus and NY-ESO-1 TCR/sr39TK lentivirus vectors. Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research Flow Cytometry Core Facility that is supported by National Institutes of Health awards P30 CA016042 and 5P30 AI028697, and by the JCCC, the UCLA AIDS Institute, the UCLA Technology Center for Genomics and Bioinformatics (TCGB) core lab, and the David Geffen School of Medicine at UCLA.

Contributions

T.S.N. and A.R. served as principal investigators for the clinical trial and its design/execution. C.P-S., J.Z., D.B., L.Y., D.B.K., O.N.W., and A.R. conceived and developed the lentiviral vector and its implementation within the clinical protocol. T.S.N., N.N.A., C.W.P., and A.R. wrote the manuscript. I.B.C. and P.K-L. supervised clinical trial regulatory and compliance regulations. B.C-A, M.M., C.W.P., B.B-M., I.P.G., J.P., J.R., A.C., and A.V-C. conducted transgenic cell product manufacturing. T.S.N., A.S., B.C., N.F., G.M.S., S.J.L., and A.R. screened, enrolled, treated, and/or cared for patients on the clinical study protocol. B.C-A. and S.H. conducted flow cytometry analysis. N.N.A., C.W.P., M.K., and C.K. performed single-cell sequencing assays. N.N.A., E.M., and D.C. conducted the bioinformatics analysis. G.C. and M.A-A. designed, conducted, and interpreted the [18 F]-FHBG PET scans. C.W.P., M.K., and C.K. performed the antigen-dependent stimulation assays and ELISAs. A.M.K. assisted with statistical analysis and test design. All authors reviewed and edited the manuscript.

Data Availability

Raw sequencing data are available via dbGaP (accession number phs003898.v1; https://www.ncbi.nlm.nih.gov/gap/advanced_search/?TERM=phs003898.v1). Source data for other figures are provided as a Source Data file. All other data (PET/CT images) are available upon request from the corresponding author only due to patient confidentiality laws. Source data are provided with this paper.

Conflict of Interest

TSN reports consulting honoraria from Allogene Therapeutics, PACT Pharma, Adaptive Biotechnologies, and Medidata Solutions. NF has received honoraria for speaker’s bureaus and advisory boards from Bayer AG, Fennec Pharmaceuticals, and Springworks Therapeutics, and holds stock ownership in Moderna, Bolt Biotherapeutics, Regulus, Bluebird Bio, and 2seventy Bio. BC has received honoraria for consulting and advisory boards from Novartis, Delcath Systems, Instil Bio, Replimune, Atreca, Regeneron, Treeline Biosciences, and SpringWorks Therapeutics, and has received research funding from Bristol-Myers Squibb, Macrogenics, Karyopharm Therapeutics, Infinity Pharmaceuticals, Advenchen Laboratories, Xencor, Compugen, Iovance Biotherapeutics, RAPT Therapeutics, IDEAYA Biosciences, Ascentage Pharma, Atreca. Replimune, Instil Bio, Adagene, TriSalus Life Sciences, Kinnate Biopharma, PTC Therapeutics, Xilio Therapeutics, Kezar Life Sciences, Immunocore, AskGene Pharma. O.N.W. currently has consulting, equity, and/or board relationships with Trethera Corporation, Kronos Biosciences, Sofie Biosciences, Breakthrough Properties, Vida Ventures, Nammi Therapeutics, Two River, Iconovir, Appia BioSciences, Neogene Therapeutics, 76Bio, and Allogene Therapeutics. A.R. has received honoraria from consulting with Amgen and Roche-Genentech, is or has been a member of the scientific advisory board, and holds stock in Appia, Apricity, Arcus, Compugen, CytomX, ImaginAb, ImmPact, Inspirna, Kite-Gilead, Larkspur, Lutris, MapKure, Merus, Synthekine, and Tango, has received research funding from Agilent and from Bristol-Myers Squibb through Stand Up to Cancer (SU2C), and patent royalties from Arsenal Bio. None of these companies contributed to or directed any of the research reported in this article. D.B. and L.Y. are inventors on patents related to this study filed by California Institute of Technology. All other authors have no competing interests to declare.

Supplemental Material

Description of Additional Supplementary Files

Supplementary Data 1

Supplementary Data 2

Supplementary Data 3

Supplementary Data 4

Supplementary Data 5

Supplementary Data 6

Reporting Summary