Cited by 333Immunotoxicology and immune responsesImmunotherapy and Immune ResponsesPharmacovigilance and Adverse Drug Reactions

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Clinical Trials: IL-12 Deaths: Explanation and a Puzzle

Cohen, J.·1995·Science

DOI 10.1126/science.270.5238.908a

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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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Crossref · 10.1126/science.270.5238.908a

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“Pre-clinical and clinical trials performed to evaluate the potential of recombinant IL-12 as an adjuvant in treating several cancers and viral hepatitis resulted in enhanced immune response [45–49], but also resulted in unfavorable side effects and systemic toxicity [50, 51].”
Background
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BackgroundInfluential
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Background
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“However, in some instances severe complications in both the experimental models and in clinical trials have been observed [56,57].”
Background
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Hudson, L. C., Garg, R., Fernalld, R., Bost, K. L., & Piller, K. J. (2017) · Toxicon · doi:10.1016/j.toxicon.2017.05.005 · Cited by 6
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Background
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Sacco, S., Heremans, H., Echtenacher, B., et al. (1997) · Blood · doi:10.1182/blood.v90.11.4473.4473_4473_4479 · Cited by 6
Preclinical study of an ex vivo gene therapy protocol for hepatocarcinoma
Lortal, B., Gross, F., Péron, J., Pénary, M., Berg, D., Hennebelle, I., Favre, G., & Couderc, B. C. (2008) · Cancer Gene Therapy · doi:10.1038/cgt.2008.88 · Cited by 5
Maintenance and Gene Electrotransfer Efficiency of Antibiotic Resistance Gene-Free Plasmids Encoding Mouse, Canine and Human Interleukin-12 Orthologues
Kamenšek, U., Renčelj, A., Jesenko, T., Remic, T., Serša, G., & Čemažar, M. (2021) · Heliyon · doi:10.1016/j.heliyon.2022.e08879 · Cited by 5
“However, IL-12 has a narrow therapeutic index, meaning it has to be released locally, without a systemic spillover [6, 7, 8, 9].”
Background
The role of mesenchymal stem cells in oncology and regenerative medicine
Maliha, K., Syeda Ezze Rukhshan, A., & Amanda L, O. (2017) · Future Oncology · doi:10.2217/fon-2016-0264 · Cited by 5
Multiple-Sklerose-Update zur Pathophysiologie und neuen immuntherapeutischen Ansätzen
Kleinschnitz, C., Meuth, S. G., Kieseier, B. C., & Wiendl, H. (2007) · Der Nervenarzt · doi:10.1007/s00115-007-2261-9 · Cited by 6
Tumor Recurrence After Partial Hepatectomy for Liver Metastases in Rats: Prevention by In Vivo Injection of Irradiated Cancer Cells Expressing GMCSF and IL-12
Aussilhou, B., Panis, Y. H., Alvès, A., et al. (2008) · Journal of Surgical Research · doi:10.1016/j.jss.2007.12.789 · Cited by 5
“However, despite a substantial antitumor activity, severe toxicity was reported in several clinical trials after systemic administration of IL-2 [8, 9] or IL-12 [10].”
Background
Natural killer cell depletion confounds the antitumor mechanism of endogenous IL‐12 overexpression
Miller, G., Bleier, J. I. S., Antonescu, C. R., et al. (2004) · International Journal of Cancer · doi:10.1002/ijc.20131 · Cited by 5
Delivery of IL-12 by neoantigen-reactive T cells promotes antitumor immunity in murine osteosarcoma mode
Tian, C., Sun, X., Zhu, H., Zhou, M., Chen, Q., Min, D., Huang, Y. T., & Han, K. (2024) · Immunotherapy Advances · doi:10.1093/immadv/ltae010 · Cited by 4
“However, systemic administration of IL-12 leads to severe toxicities, including deaths, which extremely limited its clinical application [14, 31].”
Nanosphere pharmacodynamics improves safety of immunostimulatory cytokine therapy
Lacinski, R. A., Dziadowicz, S. A., Stewart, A., Chaharbakhshi, E. O., Akhter, H., Pisquiy, J. J., Victory, J. H., Hardham, J. B., Chew, C., Prorock, A. J., et al. (2024) · iScience · doi:10.1016/j.isci.2024.108836 · Cited by 4
“Here, the bolus (unencapsulated) MTD delivery strategy recapitulated the immune ﬁndings from previous human clinical trials 23,24,126 : peripheral immune stimulation with repeated bolus IL-12 dosinginducesinitialpro-inﬂammatoryresponsesthat eventually result inthedevelopmentof…”
Clinical Trials with IL-12 in Cancer Immunotherapy
Lasek, W., & Zagożdżon, R. (2016) · SpringerBriefs in immunology · doi:10.1007/978-3-319-46906-5_3 · Cited by 4
Combining local cytokine delivery and systemic immunization with recombinant artLCMV boosts antitumor efficacy in several preclinical tumor models
Pojar, K., Reckendorfer, D., Strauß, J., Szaffich, S., Ahmadi-Erber, S. M., Schippers, T., Berraondo, P., Orlinger, K. K., Raguz, J., & Lauterbach, H. (2025) · OncoImmunology · doi:10.1080/2162402x.2025.2514040 · Cited by 3
“9 Owing to the strong clinical and preclinical evidence of its antitumor activity, current research is focused on limiting toxicity while maintaining the biological activity of IL-12.”
Tumor Cell Clone Expressing the Membrane-bound Form of IL-12p35 Subunit Stimulates Antitumor Immune Responses Dominated by CD8+T Cells
Lim, H., Do, S. A., Park, S. M., et al. (2013) · Immune Network · doi:10.4110/in.2013.13.2.63 · Cited by 3
Nanopharmacology
Aguilar, Z. P. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-385089-8.00007-8 · Cited by 3
IL-12 encoding oNDV synergizes with CAR-T cells in orthotopic models of non-small cell lung cancer
Shaw, A. R., Morita, D., Porter, C. E., et al. (2024) · Molecular Therapy Oncology · doi:10.1016/j.omton.2024.200899 · Cited by 3
Cytokine-driven cancer immune evasion mechanisms
Arenas, E. J. (2025) · International review of cytology · doi:10.1016/bs.ircmb.2025.01.004 · Cited by 5
Prevention of human adenocarcinoma with CpG-ODN in a mouse model
Wright, S. E., Rewers‐Felkins, K., Chowdhury, N. I., et al. (2012) · Oncology Letters · doi:10.3892/ol.2012.849 · Cited by 3
“In addition, IL-12 has been reported to cause mortality (24).”
Background
Immunostimulatory Activity of Specific CpG Oligonucleotides from Bifidobacterium longum Genome on RAW 264.7 Macrophage Cells
Seo, J. M. (2009) · Journal of the Korean Society for Applied Biological Chemistry · doi:10.3839/jksabc.2009.089 · Cited by 3
“However, an early study of inhaled IL-12 in human asthmatic patients was terminated because of adverse effects and systemic use in mild asthmatic cases was disappointing [Cohen, 1995; Bryan et al., 2002].”
Background
Pharmacokinetics and Pharmacodynamics of Subcutaneous Injection and Intravenous Infusion of Recombinant Human Interleukin-12 and Recombinant Human Interleukin-12 Combined with Hepatitis B Surface Antigen in Cynomolgus Monkeys
Li, R., Deng, F., Fu, Y., et al. (2010) · Pharmacology · doi:10.1159/000302725 · Cited by 3
“demonstrated that the t 1/2 of 0.25–0.5 μg/kg rhIL-12 by s.c. injection was 30 h in patients with chronic HBV. Roche Inc. stopped a clinical trial of rhIL-12 because of the severe toxic reactions in patients [”
BackgroundInfluential
Combined Interleukin 12 and Granulocyte-macrophage Colony-stimulating Factor Gene Therapy Synergistically Suppresses Tumor Growth in the Murine Fibrosarcoma
Soofiyani, S. R., Lotfipour, F., Kazemi, T., et al. (2017) · International Journal of Cancer Management · doi:10.5812/ijcm.8462 · Cited by 3
Enhanced antitumor efficacy of STING agonist MSA-2 by lipid nanoparticles delivering circular IL-23 mRNA and platinum-modified MSA-2 combination
Tian, H., Li, Y., Li, W., Zhang, M., Wang, G., Zhou, P., Song, G., & Li, W. (2025) · Materials Today Bio · doi:10.1016/j.mtbio.2025.101446 · Cited by 3
“The i.v. injection will be potentially leading to dose-related cytokine storms, liver damage, or injury to other organ tissues, which are serious adverse reactions, for example, IL-12 have been stopped for the clinical use [28 – 30].”
Antibody-Based Targeting of Tumor Vasculature and Stroma
Frey, K., & Neri, D. (2011) · Springer eBooks · doi:10.1007/978-94-007-0659-0_22 · Cited by 2
Lethal NK-mediated inflammation induced by IL-12 in the absence of polymorphic and nonpolymorphic MHC class I molecules
Eickhoff, C. S., Schnapp, A. R., Sagartz, J. E., et al. (2013) · Cytokine · doi:10.1016/j.cyto.2013.06.320 · Cited by 2
“Introduction ing in hospitalization of 12 of the 17 subjects and 2 deaths [8,9].”
Background
Redox Polyion Complex Micelle-Based Injectable Hydrogel as Local Reactive Oxygen Species Scavenging Therapeutics
Vong, L. B., & Nagasaki, Y. (2019) · ACS symposium series · doi:10.1021/bk-2019-1309.ch012 · Cited by 2
Interleukin-12
Kaufman, H. L., & Dharmadhikari, N. (2016) · Springer eBooks · doi:10.1007/978-1-4614-6613-0_144-1 · Cited by 1

Authors: Cohen, J.
Corresponding author: Cohen, J.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 1995-11-10
Volume: 270
Issue: 5238
Pages: 908a-908
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.270.5238.908a
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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Clinical Trials: IL-12 Deaths: Explanation and a Puzzle

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