Immune Toxicities Elicted by CTLA-4 Blockade in Cancer Patients Are Associated with Early Diversification of the T-cell Repertoire
Open accessPublished version of a preprint
Abstract
While immune checkpoint blockade elicits efficacious responses in many patients with cancer, it also produces a diverse and unpredictable number of immune-related adverse events (IRAE). Mechanisms driving IRAEs are generally unknown. Because CTLA-4 blockade leads to proliferation of circulating T cells, we examined in this study whether ipilimumab treatment leads to clonal expansion of tissue-reactive T cells. Rather than narrowing the T-cell repertoire to a limited number of clones, ipilimumab induced greater diversification in the T-cell repertoire in IRAE patients compared with patients without IRAEs. Specifically, ipilimumab triggered increases in the numbers of clonotypes, including newly detected clones and a decline in overall T-cell clonality. Initial broadening in the repertoire occurred within 2 weeks of treatment, preceding IRAE onset. IRAE patients exhibited greater diversity of CD4+ and CD8+ T cells, but showed no differences in regulatory T-cell numbers relative to patients without IRAEs. Prostate-specific antigen responses to ipilimumab were also associated with increased T-cell diversity. Our results show how rapid diversification in the immune repertoire immediately after checkpoint blockade can be both detrimental and beneficial for patients with cancer. Cancer Res; 77(6); 1322–30. ©2016 AACR.
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?
Autoimmune colitis, vitiligo, and autoantibody production are now included in CTCAE grading of immune-related adverse events due to immunotherapy.
“Autoimmune colitis, vitiligo, and autoantibody production are now included in CTCAE grading of irAEs due to immunotherapy [1, 4, 6, 20, 22, 34].”
From Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm (2021) · cites this paper as [22]
The Introduction identifies colitis as an immune-related adverse event of checkpoint therapy, and the Results discuss grading adverse events. Neither section establishes that colitis, vitiligo, and autoantibody production are included in CTCAE grading; searches for CTCAE, vitiligo, and autoantibodies found no such passage in our copy. Page numbers were unavailable. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn some cancer patients, immune checkpoint blockade produces immune-related adverse events during short-term follow-up, but reliable immune biomarkers for these effects remain under study.
“Immune checkpoint blockade induces irAEs during short-term follow-up of some patients with cancer, though robust immune biomarkers correlating with adverse effects of therapy are still being investigated [1, 4, 7, 20–25].”
From Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm (2021) · cites this paper as [22]
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
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989 · see citing works
Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review
Wanchoo, R., Karam, S., Uppal, N. N., Barta, V. S., Deray, G., Devoe, C., Launay‐Vacher, V., Jhaveri, K. D., & on behalf of Cancer and Kidney International Network Workgroup on Immune Checkpoint Inhibitors (2017) · American Journal of Nephrology · doi:10.1159/000455014 · Cited by 15,314 · see citing works
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma
Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J. C., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1003466 · Cited by 15,155 · see citing works
Safety, activity, and immune correlates of anti–PD-1 antibody in cancer
Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F., Powderly, J. D., Carvajal, R. D., Sosman, J. A., Atkins, M. B., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200690 · Cited by 12,628 · see citing works
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma
Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J. J., Cowey, C. L., Lao, C. D., Schadendorf, D., Dummer, R., Smylie, M., Rutkowski, P., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1504030 · Cited by 8,157 · see citing works
Diversity and Evenness: A Unifying Notation and Its Consequences
Hill, M. O. (1973) · Ecology · doi:10.2307/1934352 · Cited by 6,355 · see citing works
Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma
Robert, C., Thomas, L., Bondarenko, I., O'Day, S., Weber, J., Garbe, C., Lebbe, C., Baurain, J.-F., Testori, A., Grob, J.-J., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1104621 · Cited by 4,496 · see citing works
Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma
Snyder, A., Makarov, V., Merghoub, T., Yuan, J., Zaretsky, J. M., Desrichard, A., Walsh, L. A., Postow, M. A., Wong, P., Ho, T. S., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1406498 · Cited by 4,286 · see citing works
Tivol, E. A., Borriello, F., Schweitzer, A. N., Lynch, W. P., Bluestone, J. A., & Sharpe, A. H. (1995) · Immunity · doi:10.1016/1074-7613(95)90125-6 · Cited by 2,914 · see citing works
Lymphoproliferative Disorders with Early Lethality in Mice Deficient in <i>Ctla-4</i>
Waterhouse, P., Penninger, J. M., Timms, E., Wakeham, A., Shahinian, A., Lee, K. P., Thompson, C. B., Griesser, H., & Mak, T. W. (1995) · Science · doi:10.1126/science.270.5238.985 · Cited by 2,766 · see citing works
Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer
Twyman-Saint Victor, C., Rech, A. J., Maity, A., Rengan, R., Pauken, K. E., Stelekati, E., Benci, J. L., Xu, B., Dada, H., Odorizzi, P. M., et al. (2015) · Nature · doi:10.1038/nature14292 · Cited by 2,434 · see citing works
Kwon, E. D., Drake, C. G., Scher, H. I., Fizazi, K., Bossi, A., van den Eertwegh, A. J. M., Krainer, M., Houede, N., Santos, R., Mahammedi, H., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(14)70189-5 · Cited by 1,511 · see citing works
Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab
Weber, J. S., Kähler, K. C., & Hauschild, A. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.41.6750 · Cited by 1,415 · see citing works
Attia, P., Phan, G. Q., Maker, A. V., Robinson, M. R., Quezado, M. M., Yang, J. C., Sherry, R. M., Topalian, S. L., Kammula, U. S., Royal, R. E., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.06.205 · Cited by 1,012 · see citing works
van Rooij, N., van Buuren, M. M., Philips, D., Velds, A., Toebes, M., Heemskerk, B., van Dijk, L. J. A., Behjati, S., Hilkmann, H., el Atmioui, D., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.47.7521 · Cited by 798 · see citing works
Toxicities of Immunotherapy for the Practitioner
Weber, J. S., Yang, J. C., Atkins, M. B., & Disis, M. L. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.60.0379 · Cited by 652 · see citing works
Improved Survival with T Cell Clonotype Stability After Anti–CTLA-4 Treatment in Cancer Patients
Cha, E., Klinger, M., Hou, Y., Cummings, C., Ribas, A., Faham, M., & Fong, L. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3008211 · Cited by 383 · see citing works
Self-citationYuan, J. D., Gnjatic, S., Li, H., Powel, S., Gallardo, H. F., Ritter, E., Ku, G. Y., Jungbluth, A. A., Segal, N. H., Rasalan, T. S., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810114105 · Cited by 346 · see citing works
Yuan, J. D., Adamow, M. J., Ginsberg, B. A., Rasalan, T. S., Ritter, E., Gallardo, H. F., Xu, Y., Pogoriler, E., Terzulli, S. L., Kuk, D., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1110814108 · Cited by 329 · see citing works
Delyon, J., Mateus, C., Lefeuvre, D., Lanoy, E., Zitvogel, L., Chaput, N., Roy, S., Eggermont, A. M. M., Routier, E., & Robert, C. (2013) · Annals of Oncology · doi:10.1093/annonc/mdt027 · Cited by 318 · see citing works
Fong, L. H., Kwek, S. S., O’Brien, S., Kavanagh, B., McNeel, D. G., WEINBERG, V. K., Lin, A., Rosenberg, J. E., Ryan, C. J., Rini, B. I., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3529 · Cited by 245 · see citing works
Self-citationIncreased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy
Ng Tang, D., Shen, Y., Sun, J., Wen, S., Wolchok, J. D., Yuan, J., Allison, J. P., & Sharma, P. (2013) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-13-0020 · Cited by 203 · see citing works
Hannani, D., Vétizou, M., Enot, D. P., Rusakiewicz, S., Chaput, N., Klatzmann, D., Desbois, M., Jacquelot, N., Vimond, N., Chouaı̈b, S., et al. (2015) · Cell Research · doi:10.1038/cr.2015.3 · Cited by 161 · see citing works
Thymocyte development is normal in CTLA-4-deficient mice
Chambers, C. A., Cado, D., Truong, T. V., & Allison, J. P. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.17.9296 · Cited by 147 · see citing works
Hannani, D., Vétizou, M., Enot, D. P., Rusakiewicz, S., Chaput, N., Klatzmann, D., Desbois, M., Jacquelot, N., Vimond, N., Chouaı̈b, S., et al. (2015) · Cell Research · doi:10.1038/cr.2015.28 · Cited by 133 · see citing works
Meyer, E. H., Hsu, A. R., Liliental, J., Löhr, A., Florek, M., Zehnder, J. L., Strober, S., Lavori, P. W., Miklos, D. B., Johnson, D. S., et al. (2013) · Blood · doi:10.1182/blood-2013-03-489757 · Cited by 71 · see citing works
Kwek, S. S., Lewis, J., Zhang, L., WEINBERG, V. K., Greaney, S. K., Harzstark, A. L., Lin, A., Ryan, C. J., Small, E. J., & Fong, L. H. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0227 · Cited by 61 · see citing works
Self-citationSheikh, N. A., Cham, J., Zhang, L., DeVries, T. A., Letarte, S., Pufnock, J., Hamm, D. E., Trager, J. B., & Fong, L. H. (2016) · Cancer Research · doi:10.1158/0008-5472.can-15-3173 · Cited by 61 · see citing works
Self-citationThe adaptive immune response in celiac disease
Qiao, S., Iversen, R., Ráki, M., & Sollid, L. M. (2012) · Seminars in Immunopathology · doi:10.1007/s00281-012-0314-z · Cited by 58 · see citing works
Optimal management of immune-related toxicities associated with checkpoint inhibitors in lung cancer
Howell, M., Lee, R. J., Bowyer, S. E., Fusi, A., & Lorigan, P. C. (2015) · Lung Cancer · doi:10.1016/j.lungcan.2015.02.007 · Cited by 50 · see citing works
Immunologic functions as prognostic indicators in melanoma
Bouwhuis, M. G., ten Hagen, T. L. M., & Eggermont, A. M. M. (2011) · Molecular Oncology · doi:10.1016/j.molonc.2011.01.004 · Cited by 21 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The immune contexture in cancer prognosis and treatment
Fridman, W. H., Zitvogel, L., Sautès–Fridman, C., & Kroemer, G. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.101 · Cited by 2,263 · see citing works
Hallmarks of response, resistance, and toxicity to immune checkpoint blockade
Morad, G., Helmink, B. A., Sharma, P., & Wargo, J. A. (2021) · Cell · doi:10.1016/j.cell.2021.09.020 · Cited by 1,648 · see citing works
CTLA-4: a moving target in immunotherapy
Rowshanravan, B., Halliday, N., & Sansom, D. M. (2018) · Blood · doi:10.1182/blood-2017-06-741033 · Cited by 1,233 · 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
Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade
Andrews, M. C., Duong, C. P. M., Gopalakrishnan, V., Iebba, V., Chen, W.-S., Derosa, L., Khan, M. A. W., Cogdill, A. P., White, M. G., Wong, M. C., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01406-6 · Cited by 437 · see citing works
Moving towards personalized treatments of immune-related adverse events
Esfahani, K., Elkrief, A., Calabrese, C., Lapointe, R., Hudson, M., Routy, B., Miller, W. H., & Calabrese, L. (2020) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0352-8 · Cited by 351 · see citing works
Treatment Outcomes of Immune-Related Cutaneous Adverse Events
Phillips, G. S., Wu, J., Hellmann, M. D., Postow, M. A., Rizvi, N. A., Freites-Martinez, A., Chan, D., Dusza, S., Motzer, R. J., Rosenberg, J. E., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.18.02141 · Cited by 241 · see citing works
Autoantibody Development under Treatment with Immune-Checkpoint Inhibitors
de Moel, E. C., Rozeman, E. A., Kapiteijn, E. H., Verdegaal, E. M. E., Grummels, A., Bakker, J. A., Huizinga, T. W. J., Haanen, J. B., Toes, R. E. M., & van der Woude, D. (2019) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0245 · Cited by 191 · see citing works
Fizazi, K., Drake, C. G., Beer, T. M., Kwon, E. D., Scher, H. I., Gerritsen, W. R., Bossi, A., den Eertwegh, A. J. M. V., Krainer, M., Houede, N., et al. (2020) · European Urology · doi:10.1016/j.eururo.2020.07.032 · Cited by 185 · see citing works
Dovedi, S. J., Elder, M. J., Yang, C., Sitnikova, S. I., Irving, L., Hansen, A., Hair, J., Jones, D. C., Hasani, S., Wang, B., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1445 · Cited by 186 · see citing works
Mechanisms of immune checkpoint inhibitor-mediated liver injury
Shojaie, L., Ali, M., Iorga, A., & Dara, L. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.10.003 · Cited by 98 · see citing works
Arakawa, A., Vollmer, S., Tietze, J., Galinski, A., Heppt, M. V., Bürdek, M., Berking, C., & Prinz, J. C. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01336 · Cited by 74 · see citing works
T‐cell receptor and B‐cell receptor repertoire profiling in adaptive immunity
Minervina, A., Pogorelyy, M., & Mamedov, I. (2019) · Transplant International · doi:10.1111/tri.13475 · Cited by 65 · see citing works
Immunotherapy to treat malignancy in patients with pre-existing autoimmunity
Boland, P., Pavlick, A. C., Weber, J., & Sandigursky, S. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2019-000356 · Cited by 50 · see citing works
Panoskaltsis, N., McCarthy, N. E., Stagg, A. J., Mummery, C. J., Husni, M., Arebi, N., Greenstein, D., Price, C. L., Al-Hassi, H. O., Koutinas, M., et al. (2021) · Cancer Immunology, Immunotherapy · doi:10.1007/s00262-020-02725-2 · Cited by 16 · see citing works
- Authors
- Oh, D. Y., Cham, J., Zhang, L., Fong, G., Kwek, S. S., Klinger, M., Faham, M., & Fong, L.
- Affiliations
- University of California, San Francisco (US)
- 2Adaptive Biotechnologies, South San Francisco, California.
- Corresponding author
- Fong, Lawrence
- Venue
- Cancer Research
- Published
- 2017-03-14
- Volume
- 77
- Issue
- 6
- Pages
- 1322-1330
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC5398199
- OpenAlex
- W2566809924
- Cited by
- 236
- References
- 31
- Citations by year
- 2026: 7 · 2025: 19 · 2024: 30 · 2023: 30 · 2022: 36 · 2021: 39 · 2020: 29 · 2019: 23 · 2018: 16 · 2017: 6
- FWCI
- 8.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (1R01 CA163012, 1R01 CA136753, 4T32 CA177555)
- Peter Michael Foundation (S.S. Kwek)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- CTLA-4 blockade, ipilimumab, immune-related adverse events, clonotype expansion, immune checkpoint inhibitors, CD4+ T cells, CD8+ T cells, regulatory T cells, prostate-specific antigen, cancer immunotherapy
- MeSH terms
- Ipilimumab, Antibodies, Monoclonal, Humans, Male, Prognosis, T-Lymphocyte Subsets, Granulocyte-Macrophage Colony-Stimulating Factor, T-Lymphocytes, Regulatory, CTLA-4 Antigen, Prostatic Neoplasms, Castration-Resistant
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
