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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Target-Dependent Expression of IL12 by synNotch Receptor-Engineered NK92 Cells Increases the Antitumor Activities of CAR-T Cells
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Background
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Background
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Background
Interleukin 12 shows a better curative effect on lung cancer than paclitaxel and cisplatin doublet chemotherapy
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Background
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Background
Development of an Interleukin-12 Fusion Protein That Is Activated by Cleavage with Matrix Metalloproteinase 9
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Background
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Background
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BackgroundInfluential
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Background
Improving therapeutic efficacy of IL-12 intratumoral gene electrotransfer through novel plasmid design and modified parameters
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“Compared with the toxicity associated with systemic treatment [20], localized”
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A dose-escalation and pharmacokinetic study of subcutaneously administered recombinant human interleukin 12 and its biological effects in Japanese patients with advanced malignancies.
Ohno, R., Yamaguchi, Y., Toge, T., et al. (2000) · PubMed · Cited by 30
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3D-Printed Biodegradable Microswimmer for Drug Delivery and Targeted Cell LabelingPreprint
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Enhanced Immunogenicity of B Cell Lymphoma Genetically Engineered to Express Both B7-1 and Interleukin-12
Pizzoferrato, E., Chu, N. R., Hawley, T. S., Lieu, F. H. L., Barber, B. H., Hawley, R. G., Watts, T. H., & Berinstein, N. L. (1997) · Human Gene Therapy · doi:10.1089/hum.1997.8.18-2217 · Cited by 28
“…tumor immunogenicity (Nanda and Sercarz, 1995) while minimizing any possible side-effects as sociated with high circulating cytokine levels (Cohen, 1995) Our data demonsttate that tumor cells modified with IL-12 were superior to tamor cells modified with B7-1 alone in con ferring…”
Overcoming lung cancer immunotherapy resistance by combining nontoxic variants of IL-12 and IL-2
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“As systemic cytokine therapy has been previously hampered by dose-limiting toxicity (9-11), developing approaches that mitigate dose-limiting toxicity while maintaining anti-tumor efficacy will be critical.”
Background
Interleukin-12 in multimodal tumor therapies for induction of anti-tumor immunity
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“In a phase II trial, the maximum dose of 0.5 μg/kg/day resulted in serious side effects in 12 of 17 patients and death in 2 patients (40 patients) [30, 31].”
BackgroundInfluential
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Background
A therapeutic cancer vaccine delivers antigens and adjuvants to lymphoid tissues using genetically modified T cells
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Background
Mesenchymal stromal cells as carriers of IL-12 reduce primary and metastatic tumors of murine melanoma
Kułach, N., Pilny, E., Cichoń, T., Czapla, J., Jarosz–Biej, M., Rusin, M., Drzyzga, A., Matuszczak, S., Szala, S., & Smolarczyk, R. (2021) · Scientific Reports · doi:10.1038/s41598-021-97435-9 · Cited by 27
Cancer immunotherapy from biology to nanomedicine
Abdelbaky, S. B., Ibrahim, M. T., Samy, H., Mohamed, M., Mohamed, H., Mustafa, M., Abdelaziz, M. M., Forrest, M. L., & Khalil, I. A. H. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.06.025 · Cited by 28
Interferon‐γ‐inducing Factor Gene Transfection into Lewis Lung Carcinoma Cells Reduces Tumorigenicity in vivo
Fukumoto, H., Nishio, M., Nishio, K., et al. (1997) · Japanese Journal of Cancer Research · doi:10.1111/j.1349-7006.1997.tb00409.x · Cited by 26
Hypoxia-regulated secretion of IL-12 enhances antitumor activity and safety of CD19 CAR-T cells in the treatment of DLBCL
Zhou, W., Miao, J., Cheng, Z., et al. (2023) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2023.08.009 · Cited by 25
“Unfortunately, the occurrence of severe side effects associated with lethal inflammatory syndrome poses a challenge for the clinical application of IL-12-based therapy.(23,24) To date, IL-12armed CAR-T cells have shown enhanced antitumor efficacy against a diverse range of murine tumor models of melanoma,(25) ovarian…”
Background
Engineering for Success: Approaches to Improve Chimeric Antigen Receptor T Cell Therapy for Solid Tumors
Mata, M., & Gottschalk, S. M. (2019) · Drugs · doi:10.1007/s40265-019-01071-7 · Cited by 25
Is Th1 the solution for Th2 in asthma?
Tournoy, K. G., KIPS, J. C., & Pauwels, R. (2002) · Clinical & Experimental Allergy · doi:10.1046/j.0022-0477.2001.01279.x · Cited by 24
Tetracycline-regulatable adenovirus vectors: pharmacologic properties and clinical potential
Nakagawa, S., Massie, B., & Hawley, R. G. (2001) · European Journal of Pharmaceutical Sciences · doi:10.1016/s0928-0987(00)00207-4 · Cited by 25
Influenza Virus-like Particle-Based Hybrid Vaccine Containing RBD Induces Immunity against Influenza and SARS-CoV-2 Viruses
Bommireddy, R., Stone, S., Bhatnagar, N., Kumari, P., Muñoz, L. E., Oh, J., Kim, K., Berry, J. T. L., Jacobsen, K. M., Jaafar, L., et al. (2022) · Vaccines · doi:10.3390/vaccines10060944 · Cited by 24
“Preclinical and clinical trials demonstrated the potential of recombinant soluble IL-12 as an adjuvant in treating several cancers and viral hepatitis, resulting in enhanced immune response [14,29–33]; however, it also resulted in unfavorable side effects and systemic toxicity [34,35].”
Background
Intratumoral aluminum hydroxide–anchored IL-12 drives potent antitumor activity by remodeling the tumor microenvironment
Battula, S. K., Papastoitsis, G., Kaufman, H. L., Wittrup, K. D., & Schmidt, M. M. (2023) · JCI Insight · doi:10.1172/jci.insight.168224 · Cited by 24
“However, clinical translation of IL-12 has been hindered by severe dose-limiting toxicities when delivered intravenously (i.v.) or subcutaneously (s.c.), including lymphopenia, hepatotoxicity, and gastrointestinal inflammation leading to deaths of 2 patients in early clinical trials (8–10).”
Background
Clostridium sporogenes delivers interleukin-12 to hypoxic tumours, producing antitumour activity without significant toxicity
Zhang, Y.-L., Lü, R., Chang, Z.-S., Zhang, W.-Q., Wang, Q., Ding, S., & Zhao, W. (2014) · Letters in Applied Microbiology · doi:10.1111/lam.12322 · Cited by 25
“However, systemic application of IL-12 in the clinic is hindered by its severe toxicity (Cohen 1995; Leonard et al. 1997; Car et al. 1999).”
Background
Bioengineering heterodimeric cytokines: turning promiscuous proteins into therapeutic agents
Belladonna, M. L., & Grohmann, U. (2013) · Biotechnology and Genetic Engineering Reviews · doi:10.1080/02648725.2013.801228 · Cited by 25
Polyethyleneimine-based gene therapy by inhalation
Densmore, C. L. (2003) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.3.7.1083 · Cited by 27
Retracted
Promising immunotherapies with Th1-related cytokines against infectious diseases
Kawakami, K. (2003) · Journal of Infection and Chemotherapy · doi:10.1007/s10156-003-0263-5 · Cited by 24
Lentiviral vectors in cancer immunotherapy
Lin, S., Wang, B., & Wang, L. (2008) · 国际外科学杂志 · doi:10.3760/cma.j.issn.1673-4203.2008.03.011 · Cited by 23
Immunoengineering approaches for cytokine therapy
Mansurov, A., Lauterbach, A. L., Budina, E., Alpar, A. T., Hubbell, J. A., & Ishihara, J. (2021) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00515.2020 · Cited by 23
Tumor cells expressing membrane-bound form of IL-4 induce antitumor immunity
Kim, Y.-R., Sonn, C. H., Paik, S.-G., et al. (2000) · Gene Therapy · doi:10.1038/sj.gt.3301175 · Cited by 23
mWTX-330, an IL-12 INDUKINE Molecule, Activates and Reshapes Tumor-Infiltrating CD8+ T and NK Cells to Generate Antitumor Immunity
Nirschl, C. J., Brodkin, H. R., Domonkos, C., Dwyer, C. J., Hicklin, D. J., Ismail, N. S., Seidel‐Dugan, C., Steiner, P., Steuert, Z., Sullivan, J. M., et al. (2023) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-22-0705 · Cited by 22
“Nevertheless, despite this interest, the poor pharmacokinetic properties of this cytokine and the unacceptable levels of toxicity associated with its systemic administration have prevented its use in clinical settings (9, 14, 26, 40) weredosedtwiceaweekfor2weekswithmWTX-330orvehicle.”
Treatment of murine hepatocellular carcinoma using genetically modified cells to express interleukin‐12
Péron, J., Couderc, B. C., Rochaix, P., et al. (2004) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2003.03295.x · Cited by 22
Growth control of genetically modified cells using an antibody/c-Kit chimera
Kaneko, E., Kawahara, M., Ueda, H., et al. (2012) · Journal of Bioscience and Bioengineering · doi:10.1016/j.jbiosc.2011.12.005 · Cited by 21
Fueling chimeric antigen receptor T cells with cytokines.
Jin, J., Cheng, J., Huang, M., Luo, H., & Zhou, J. (2020) · PubMed Central · Cited by 21
Evaluation of p21 promoter for interleukin 12 radiation induced transcriptional targeting in a mouse tumor model
Kamenšek, U., Serša, G., & Čemažar, M. (2013) · Molecular Cancer · doi:10.1186/1476-4598-12-136 · Cited by 21
“Recombinant IL-12 was proven to have potent antitumor and antimetastatic effects against murine tumors [19], yet its clinical application was hindered by dose-limiting toxicity associated by its systemic administration [20,21].”
Background
A single intratumoral injection of a fiber-mutant adenoviral vector encoding interleukin 12 induces remarkable anti-tumor and anti-metastatic activity in mice with Meth-A fibrosarcoma
Gao, J., Sugita, T., Kanagawa, N., et al. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.01.061 · Cited by 21
Gene Therapy of Anaplastic Thyroid Carcinoma with a Single-Chain Interleukin-12 Fusion Protein
Shi, Y., Parhar, R. S., Zou, M., et al. (2003) · Human Gene Therapy · doi:10.1089/104303403322611755 · Cited by 21
“…of IL-12 (approximately 4.5–7.7 m g/kg) is well tolerated and almost no side effects are manifested (Cavallo et al ., 1999), the use of recombinant protein in humans is complicated by schedule-and dose-dependent toxicity (Cohen, 1995; Atkins et al ., 1997; Car et al ., 1999; Gollob et al ., 2000).”
Influential

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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