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Clinical Trials: IL-12 Deaths: Explanation and a Puzzle
Abstract
Researchers investigating toxic reactions that killed two patients in a trial of interleukin-12 earlier this year have reached a surprising conclusion: The drug is highly toxic if it is given in multiple high doses, but those effects can be avoided if the multiple doses are preceded by a single dose followed by a rest period. The initial dose apparently imprints a memory on the immune system, but the mechanism is unclear.
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“The administration of recombinant cytokines (e.g., interleukin-1, interleukin-6, interleukin-12, interleukin-18, tumor necrosis factor [TNF], and interferon-γ) in animal models and for cancer treatment in humans induces severe toxic effects or lethality consistent with the central role of cytokines as mediators of hyperinflammation in cytokine storm.”
From Cytokine storm (2020) · cites this paper as [28]
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“Safety concerns surrounding acute and chronic toxicities, as well as the reliable prediction of which patients will experience adverse events, remain problematic for its development [13].”
BackgroundDiaz-Montero, C. M., El-Naggar, S. A., Khami, A. A., Naggar, R. A. R. E., Montero, A. J., Cole, D. J., & Salem, M. L. (2007) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-007-0394-0 · Cited by 63
“hindered by considerable toxicities [3, 5].”
Dunussi‐Joannopoulos, K., Runyon, K., Erickson, J., Schaub, R. G., Hawley, R. G., & Leonard, J. P. (1999) · Blood · doi:10.1182/blood.v94.12.4263.424k30_4263_4273 · Cited by 67
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Long-Lasting Anti-Metastatic Efficiency of Interleukin 12-Encoding Plasmid DNA
Schultz, J. G., Pavlovic, J., Strack, B., et al. (1999) · Human Gene Therapy · doi:10.1089/10430349950018850 · Cited by 62
“IL-12 has been administered previously as recombinant protein to patients (Cohen, 1995; Marshall, 1995).”
Yoo, E. M., Chintalacharuvu, K. R., Penichet, M. L., & Morrison, S. L. (2002) · Journal of Immunological Methods · doi:10.1016/s0022-1759(01)00559-2 · Cited by 61
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“However, exogenous recombinant cytokines have a shorter half-life in vivo , and systemic administration at high doses, especially of IL-12, may cause substantial adverse effects (Cohen, 1995; Mohapatra, 1995).”
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A Phase I/Ii Study of Recombinant Human Interleukin–12 in Patients With Chronic Hepatitis C
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Interleukin-12 as an in situ cancer vaccine component: a review
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Metadata
- Authors
- Cohen, J.
- Corresponding author
- Cohen, J.
- Venue
- Science
- Published
- 1995-11-10
- Volume
- 270
- Issue
- 5238
- Pages
- 908a-908
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W1609710757
- Cited by
- 332
- References
- 0
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 15 · 2023: 11 · 2022: 13 · 2021: 11 · 2020: 16 · 2019: 15 · 2018: 8 · 2017: 9 · 2016: 15 · 2015: 8 · 2014: 5 · 2013: 13 · 2012: 15
- FWCI
- 2.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Keywords
- IL-12, drug toxicity, dose scheduling, immunological memory, cytokine therapy
- MeSH terms
- Animals, Carcinoma, Renal Cell, Clinical Trials as Topic, Drug Administration Schedule, Humans, Kidney Neoplasms, Macaca fascicularis, Recombinant Proteins, United States, United States Food and Drug Administration, Multicenter Studies as Topic, Th1 Cells, Th2 Cells, Interleukin-12, Mice
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