Inducible Apoptosis as a Safety Switch for Adoptive Cell Therapy
Open accessAbstract
BACKGROUND: Cellular therapies could play a role in cancer treatment and regenerative medicine if it were possible to quickly eliminate the infused cells in case of adverse events. We devised an inducible T-cell safety switch that is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization. When exposed to a synthetic dimerizing drug, the inducible caspase 9 (iCasp9) becomes activated and leads to the rapid death of cells expressing this construct. METHODS: We tested the activity of our safety switch by introducing the gene into donor T cells given to enhance immune reconstitution in recipients of haploidentical stem-cell transplants. Patients received AP1903, an otherwise bioinert small-molecule dimerizing drug, if graft-versus-host disease (GVHD) developed. We measured the effects of AP1903 on GVHD and on the function and persistence of the cells containing the iCasp9 safety switch. RESULTS: Five patients between the ages of 3 and 17 years who had undergone stem-cell transplantation for relapsed acute leukemia were treated with the genetically modified T cells. The cells were detected in peripheral blood from all five patients and increased in number over time, despite their constitutive transgene expression. A single dose of dimerizing drug, given to four patients in whom GVHD developed, eliminated more than 90% of the modified T cells within 30 minutes after administration and ended the GVHD without recurrence. CONCLUSIONS: The iCasp9 cell-suicide system may increase the safety of cellular therapies and expand their clinical applications. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00710892.).
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Multiple chemical-genetic systems have been devised to enable tunable regulation of protein stability using small molecules, including FKBP12-based destabilization domains, auxin-inducible degrons and SMASh.
“Multiple chemical–genetic systems have been devised to enable tunable regulation of protein stability using small molecules194, including FKBP12-based destabilization domains195, auxin-inducible degrons196 and small-molecule-assisted shutoff (SMASh)197.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [195]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Morgan, R. A., Yang, J. C.-H., Kitano, M., Dudley, M. E., Laurençot, C. M., & Rosenberg, S. A. (2010) · Molecular Therapy · doi:10.1038/mt.2010.24 · Cited by 2,542 · see citing works
HSV-TK Gene Transfer into Donor Lymphocytes for Control of Allogeneic Graft-Versus-Leukemia
Bonini, C., Ferrari, G., Verzeletti, S., Servida, P., Zappone, E., Ruggieri, L., Ponzoni, M., Rossini, S., Mavilio, F., Traversari, C., et al. (1997) · Science · doi:10.1126/science.276.5319.1719 · Cited by 1,158 · see citing works
Controlling Signal Transduction with Synthetic Ligands
Spencer, D. M., Wandless, T. J., Schreiber, S. L., & Crabtree, G. R. (1993) · Science · doi:10.1126/science.7694365 · Cited by 845 · see citing works
Self-citationDonnelly, M. L. L., Luke, G. A., Mehrotra, A. P., Li, X., Hughes, L. E., Gani, D., & Ryan, M. D. (2001) · Journal of General Virology · doi:10.1099/0022-1317-82-5-1013 · Cited by 798 · see citing works
Heslop, H. E., Slobod, K. S., Pulè, M. A., Hale, G. A., Rousseau, A., Smith, C. A., Bollard, C. M., Liu, H., Wu, M.-F., Rochester, R., et al. (2009) · Blood · doi:10.1182/blood-2009-08-239186 · Cited by 780 · see citing works
Self-citationAn inducible caspase 9 safety switch for T-cell therapy
Straathof, K. C. M., Pulè, M. A., Yotnda, P., Dotti, G., Vanin, E. F., Brenner, M. K., Heslop, H. E., Spencer, D. M., & Rooney, C. M. (2005) · Blood · doi:10.1182/blood-2004-11-4564 · Cited by 745 · see citing works
Self-citationGraft-versus-leukemia effects of transplantation and donor lymphocytes
Kolb, H. (2008) · Blood · doi:10.1182/blood-2008-03-077974 · Cited by 587 · see citing works
Riddell, S. R., Elliott, M., Lewinsohn, D. A., Gilbert, M. J., Wilson, L., Manley, S. A., Lupton, S. D., Overell, R. W., Reynolds, T. C., Corey, L., et al. (1996) · Nature Medicine · doi:10.1038/nm0296-216 · Cited by 564 · see citing works
Redesigning an FKBP–ligand interface to generate chemical dimerizers with novel specificity
Clackson, T., Yang, W., Rozamus, L. W., Hatada, M., Amara, J. F., Rollins, C. T., Stevenson, L. F., Magari, S. R., Wood, S. A., Courage, N. L., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.18.10437 · Cited by 558 · see citing works
Stem-Cell Gene Therapy for the Wiskott–Aldrich Syndrome
Boztug, K., Schmidt, M., Schwarzer, A., Banerjee, P. P., Díez, I. A., Dewey, R. A., Böhm, M., Nowrouzi, A., Ball, C. R., Glimm, H., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1003548 · Cited by 532 · see citing works
Ciceri, F., Bonini, C., Stanghellini, M. T. L., Bondanza, A., Traversari, C., Salomoni, M., Turchetto, L., Colombi, S., Bernardi, M., Peccatori, J., et al. (2009) · The Lancet Oncology · doi:10.1016/s1470-2045(09)70074-9 · Cited by 485 · see citing works
Haematopoietic cell transplantation as immunotherapy
Appelbaum, F. R. (2001) · Nature · doi:10.1038/35077251 · Cited by 414 · see citing works
Brentjens, R. J., Yeh, R., Bernal, Y. J., et al. (2010) · Molecular Therapy · doi:10.1038/mt.2010.31 · Cited by 380 · see citing works
Prospects for Stem Cell-Based Therapy
Daley, G. Q., & Scadden, D. T. (2008) · Cell · doi:10.1016/j.cell.2008.02.009 · Cited by 302 · see citing works
Tiberghien, P. (2001) · Blood · doi:10.1182/blood.v97.1.63 · Cited by 289 · see citing works
Amrolia, P. J. (2006) · Blood · doi:10.1182/blood-2006-02-001909 · Cited by 239 · see citing works
Tiberghien, P., Reynolds, C., Keller, J. R., et al. (1994) · Blood · doi:10.1182/blood.v84.4.1333.1333 · Cited by 216 · see citing works
Traversari, C., Marktel, S., Magnani, Z. I., Mangia, P., Russo, V. E. A., Ciceri, F., Bonini, C., & Bordignon, C. (2007) · Blood · doi:10.1182/blood-2006-04-015230 · Cited by 206 · see citing works
Tey, S., Dotti, G., Rooney, C. M., et al. (2007) · Transplantation and Cellular Therapy · doi:10.1016/j.bbmt.2007.04.005 · Cited by 204 · see citing works
Self-citationAntitumor effects of HSV-TK–engineered donor lymphocytes after allogeneic stem-cell transplantation
Ciceri, F., Bonini, C., Marktel, S., et al. (2007) · Blood · doi:10.1182/blood-2006-05-023416 · Cited by 172 · see citing works
Practical implementation of a modified continual reassessment method for dose-finding trials
Piantadosi, S., Fisher, J. D., & Grossman, S. A. (1998) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s002800050763 · Cited by 165 · see citing works
Quintarelli, C., Vera, J., Savoldo, B., Giordano-Attianese, G., Pule, M., Foster, A., Heslop, H., Rooney, C., Brenner, M., & Dotti, G. (2007) · Blood · doi:10.1182/blood-2007-02-072843 · Cited by 164 · see citing works
Self-citationAmrolia, P. J., Casadei, G. M., Yvon, E. S., Huls, H. M., Sili, U., Wieder, E., Bollard, C. M., Michálek, J., Ghetie, V. F., Heslop, H. E., et al. (2003) · Blood · doi:10.1182/blood-2002-11-3516 · Cited by 146 · see citing works
Self-citationIntravenous Safety and Pharmacokinetics of a Novel Dimerizer Drug, AP1903, in Healthy Volunteers
Iuliucci, J. D., Oliver, S. D., Morley, S. K., et al. (2001) · The Journal of Clinical Pharmacology · doi:10.1177/00912700122010771 · Cited by 126 · see citing works
Improved Artificial Death Switches Based on Caspases and FADD
Fan, L.-W., Freeman, K. W., Khan, T. M., Pham, E., & Spencer, D. M. (1999) · Human Gene Therapy · doi:10.1089/10430349950016924 · Cited by 108 · see citing works
Self-citationZhou, L., Ord, D., Hughes, A. L., & Tedder, T. F. (1991) · The Journal of Immunology · doi:10.4049/jimmunol.147.4.1424 · Cited by 90 · see citing works
An Inducible Caspase 9 Suicide Gene to Improve the Safety of Mesenchymal Stromal Cell Therapies
Ramos, C. A., Asgari, Z., Liu, E., Yvon, E. S., Heslop, H. E., Rooney, C. M., Brenner, M. K., & Dotti, G. (2010) · Stem Cells · doi:10.1002/stem.433 · Cited by 86 · see citing works
Self-citationAkatsuka, Y., Martin, E., Madonik, A. M., Barsoukov, A., & Hansen, J. A. (1999) · Tissue Antigens · doi:10.1034/j.1399-0039.1999.530202.x · Cited by 56 · see citing works
Pollok, K. E., van der Loo, J. C. M., Cooper, R. J., et al. (1999) · Human Gene Therapy · doi:10.1089/10430349950017202 · Cited by 55 · see citing works
Mercier‐Letondal, P., Deschamps, M., Sauce, D., Certoux, J. M., Milpied, N. J., Lioure, B., Cahn, J.-Y. Y., Deconinck, É., Ferrand, C., Tiberghien, P., et al. (2008) · Human Gene Therapy · doi:10.1089/hum.2007.156 · Cited by 25 · see citing works
Enhancing research in regenerative medicine
Williams, D. A., & Keating, A. (2010) · Blood · doi:10.1182/blood-2010-05-282723 · Cited by 7 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Car t cell immunotherapy for human cancer
June, C. H., O’Connor, R. S., Kawalekar, O. U., Ghassemi, S., & Milone, M. C. (2018) · Science · doi:10.1126/science.aar6711 · Cited by 3,207 · see citing works
CAR-T cell therapy: current limitations and potential strategies
Sterner, R. C., & Sterner, R. M. (2021) · Blood Cancer Journal · doi:10.1038/s41408-021-00459-7 · Cited by 2,926 · see citing works
Adoptive immunotherapy for cancer: harnessing the T cell response
Restifo, N. P., Dudley, M. E., & Rosenberg, S. A. (2012) · Nature Reviews Immunology · doi:10.1038/nri3191 · Cited by 1,688 · see citing works
The evolution of commercial drug delivery technologies
Vargason, A. M., Anselmo, A. C., & Mitragotri, S. (2021) · Nature Biomedical Engineering · doi:10.1038/s41551-021-00698-w · Cited by 1,361 · see citing works
Engineered T cells: the promise and challenges of cancer immunotherapy
Fesnak, A. D., June, C. H., & Levine, B. L. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.97 · Cited by 1,074 · see citing works
Ahmed, N., Brawley, V. S., Hegde, M., Robertson, C., Ghazi, A., Gerken, C., Liu, E., Dakhova, O., Ashoori, A., Corder, A., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.58.0225 · Cited by 1,004 · see citing works
Self-citationGlobal Manufacturing of CAR T Cell Therapy
Levine, B. L., Miskin, J., Wonnacott, K., & Keir, C. (2017) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2016.12.006 · Cited by 765 · see citing works
Jackson, H. J., Rafiq, S., & Brentjens, R. J. (2016) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.36 · Cited by 613 · see citing works
Schreiber, S. L. (2021) · Cell · doi:10.1016/j.cell.2020.12.020 · Cited by 598 · see citing works
Adusumilli, P. S., Zauderer, M. G., Rivière, I., Solomon, S. B., Rusch, V. W., O'Cearbhaill, R. E., Zhu, A., Cheema, W., Chintala, N. K., Halton, E., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0407 · Cited by 605 · see citing works
Chemically induced proximity in biology and medicine
Stanton, B. Z., Chory, E. J., & Crabtree, G. R. (2018) · Science · doi:10.1126/science.aao5902 · Cited by 475 · see citing works
Is autoimmunity the Achilles' heel of cancer immunotherapy?
June, C. H., Warshauer, J. T., & Bluestone, J. A. (2017) · Nature Medicine · doi:10.1038/nm.4321 · Cited by 445 · see citing works
CAR T cells: Continuation in a revolution of immunotherapy
Singh, A. K., & McGuirk, J. P. (2020) · The Lancet Oncology · doi:10.1016/s1470-2045(19)30823-x · Cited by 303 · see citing works
HLA engineering of human pluripotent stem cells
Riolobos, L., Hirata, R. K., Turtle, C. J., Wang, P.-R., Gornalusse, G. G., Zavajlevski, M., Riddell, S. R., & Russell, D. W. (2013) · Molecular Therapy · doi:10.1038/mt.2013.59 · Cited by 253 · see citing works
CAR-NK for tumor immunotherapy: Clinical transformation and future prospects
Wang, W., Jiang, J., & Wu, C. (2020) · Cancer Letters · doi:10.1016/j.canlet.2019.11.033 · Cited by 221 · see citing works
CAR T‐Cell‐Based gene therapy for cancers: new perspectives, challenges, and clinical developments
Jogalekar, M. P., Rajendran, R. L., Khan, F., Dmello, C., Gangadaran, P., & Ahn, B.-C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.925985 · Cited by 214 · see citing works
Unifying principles of bifunctional, proximity-inducing small molecules
Gerry, C. J., & Schreiber, S. L. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0469-1 · Cited by 199 · see citing works
Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide
Jan, M., Sperling, A. S., & Ebert, B. L. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00479-z · Cited by 137 · see citing works
Synthetic Immunology: Hacking Immune Cells to Expand Their Therapeutic Capabilities
Roybal, K. T., & Lim, W. A. (2017) · Annual Review of Immunology · doi:10.1146/annurev-immunol-051116-052302 · Cited by 124 · see citing works
Fail-Safe System against Potential Tumorigenicity after Transplantation of iPSC Derivatives
Itakura, G., Kawabata, S., Ando, M., Nishiyama, Y., Sugai, K., Ozaki, M., Iida, T., Ookubo, T., Kojima, K., Kashiwagi, R., et al. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.02.003 · Cited by 115 · see citing works
Molecular glues and bifunctional compounds: Therapeutic modalities based on induced proximity
Schreiber, S. L. (2024) · Cell Chemical Biology · doi:10.1016/j.chembiol.2024.05.004 · Cited by 112 · see citing works
The Cellular Immunotherapy Revolution: Arming the Immune System for Precision Therapy
Paucek, R. D., Baltimore, D., & Li, G. (2019) · Trends in Immunology · doi:10.1016/j.it.2019.02.002 · Cited by 104 · see citing works
Engineering chimeric antigen receptor-T cells for cancer treatment
Ye, B., Stary, C. M., Li, X., Gao, Q., Kang, C., & Xiong, X. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0814-0 · Cited by 95 · see citing works
Adoptive T-cell therapy for cancer: the era of engineered T cells
Bonini, C., & Mondino, A. (2015) · European Journal of Immunology · doi:10.1002/eji.201545552 · Cited by 93 · see citing works
Virus-Specific T Cells for the Immunocompromised Patient
Houghtelin, A., & Bollard, C. M. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01272 · Cited by 90 · see citing works
Engineering Therapeutic T Cells: From Synthetic Biology to Clinical Trials
Esensten, J. H., Bluestone, J. A., & Lim, W. A. (2017) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-052016-100304 · Cited by 62 · see citing works
Is cancer gene therapy an empty suit?
Brenner, M. K., Gottschalk, S., Leen, A. M., & Vera, J. F. (2013) · The Lancet Oncology · doi:10.1016/s1470-2045(13)70173-6 · Cited by 52 · see citing works
Self-citationBreaking Bottlenecks for the TCR Therapy of Cancer
Gaissmaier, L., Elshiaty, M., & Christopoulos, P. (2020) · Cells · doi:10.3390/cells9092095 · Cited by 52 · see citing works
Fabricius, W. A., & Ramanathan, M. (2016) · Advances in Hematology · doi:10.1155/2016/5726132 · Cited by 46 · see citing works
IFITM proteins assist cellular uptake of diverse linked chemotypes
Lou, K., Wassarman, D. R., Yang, T., Paung, Y., Zhang, Z., O’Loughlin, T. A., Moore, M. K., Egan, R. K., Greninger, P., Benes, C. H., et al. (2022) · Science · doi:10.1126/science.abl5829 · Cited by 42 · see citing works
Genetically Modified T-Cell Therapy for Osteosarcoma: Into the Roaring 2020s
DeRenzo, C., & Gottschalk, S. (2020) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-030-43032-0_10 · Cited by 12 · see citing works
The Safety of Embryonic Stem Cell Therapy Relies on Teratoma Removal
Tang, C., Weissman, I. L., & Drukker, M. (2012) · Oncotarget · doi:10.18632/oncotarget.434 · Cited by 12 · see citing works
- Authors
- Di Stasi, A., Tey, S.-K., Dotti, G., Fujita, Y., Kennedy-Nasser, A., Martinez, C., Straathof, K., Liu, E., Durett, A. G., Grilley, B., Liu, H., Cruz, C. R., Savoldo, B., Gee, A. P., Schindler, J., Krance, R. A., Heslop, H. E., Spencer, D. M., Rooney, C. M., & Brenner, M. K.
- Affiliations
- Houston Methodist (US)
- The University of Texas Southwestern Medical Center (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2011-11-03
- Volume
- 365
- Issue
- 18
- Pages
- 1673-1683
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3236370
- OpenAlex
- W2122465970
- Cited by
- 1,512
- References
- 31
- Citations by year
- 2026: 112 · 2025: 83 · 2024: 81 · 2023: 83 · 2022: 97 · 2021: 108 · 2020: 115 · 2019: 104 · 2018: 91 · 2017: 128 · 2016: 107 · 2015: 133 · 2014: 86 · 2013: 100 · 2012: 76
- FWCI
- 42.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (U54HL081007, U54HL08100)
- National Cancer Institute (P01CA094237, P30CA125123, K12CA090433, P50CA126752)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- caspase-9, graft-versus-host disease, adoptive T cell therapy, haploidentical hematopoietic stem cell transplantation, relapsed acute leukemia, pediatric patients, cell suicide
- MeSH terms
- Adolescent, Child, Child, Preschool, Female, Graft vs Host Disease, Humans, Leukemia, Male, Organic Chemicals, Recurrence, T-Lymphocytes, Immunotherapy, Adoptive, Apoptosis, Gene Transfer Techniques, Tacrolimus Binding Proteins, Stem Cell Transplantation, Genes, Transgenic, Suicide, Caspase 9
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
