Novel strategies exploiting interleukin-12 in cancer immunotherapy
Section snippets
The IL-12 family in cancer
Interleukin (IL)-12 belongs to a family of heterodimeric cytokines, including IL-12, IL-23, IL-27 and IL-35. The first two are mostly proinflammatory cytokines and the latter two are mostly considered to be inhibitory (Vignali & Kuchroo, 2012). Chain sharing is a characteristic of this cytokine family (Fig. 1). IL-23 and IL-12 share the β chain p40, while IL-27 and IL-35 share the β chain Epstein-Barr virus-induced 3 (Ebi3). The p35α chain is also shared between IL-12 and IL-35. The receptors
Historical perspective on IL-12 as an antitumor agent
To better understand the biological function of the IL-12, several transgenic mouse models were created and studied. Mice in which the p40 gene had been mutated were viable and fertile and did not show any alterations during embryonic development (Magram et al., 1996). Immune cell lineages were intact, thus confirming that IL-12 is not relevant in the development of immune cells. The most obvious difference in these IL-12 deficient mice was the low level of IFNγ production in response to
The need for localized IL-12 release: a case for gene therapy
Despite the disappointing initial clinical results, IL-12 was still considered an interesting target to potentiate anti-cancer immunity. For this reason, investigators preclinically proposed several ways to take advantage of the biological functions of IL-12, while avoiding its on-target systemic toxicity. To date, many approaches have been evaluated to achieve in situ overexpression of IL-12, minimizing leakage and the ensuing toxicity. Some of these new approaches are reaching clinical
Future perspectives
IL-12 is one of the most powerful immunotherapy agents ever discovered. Its translation to the clinic has proved to be very difficult because of IFNγ-associated toxicity. A preclinical and clinical quest is ongoing (Table 1) to mitigate this problem favoring local actions in the tumor microenvironment and tumor-draining lymph nodes. Local delivery, mainly using IL-12-encoding nucleic acids, is showing promising results in the clinic but has problems in terms of injections to multiple tumor
Conflict of interest statement
I.M. reports advisory roles with Roche-Genentech, Bristol-Myers Squibb, CYTOMX, Incyte, MedImmune, Tusk, F-Star, Genmab, Molecular Partners, Third Rock Ventures, Amunix Pharmaceuticals, Alligator, Bioncotech, MSD, Merck Serono, Boehringer Ingelheim, Astra Zeneca, Numab, Catalym, and Bayer, and research funding from Roche, BMS, Alligator, and Bioncotech. The rest of the authors have no conflict of interest to declare.
Acknowledgments
We are grateful to Dr. Paul Miller for English editing. This work was supported by Spanish Ministry of Economy and Competitiveness (MINECO SAF 2017-83267-C2-1R and PID2020-112892RB-100 [AEI/FEDER,UE]), Cancer Research Institute under the CRI-CLIP, Asociación Española Contra el Cancer (AECC) Foundation under Grant GCB15152947MELE, Joint Translational Call for Proposals 2015 (JTC 2015) TRANSCAN-2 (code: TRS-2016-00000371), projects PI19/01128, funded by Instituto de Salud Carlos III and co-funded
References (159)
- et al.
Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17
The Journal of Biological Chemistry
(2003) - et al.
Intratumoral delivery of tavokinogene telseplasmid yields systemic immune responses in metastatic melanoma patients
Annals of Oncology : Official Journal of the European Society for Medical Oncology
(2020) - et al.
Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding for interleukin 12
Hepatology (Baltimore, Md.)
(2001) - et al.
Rejection of disseminated metastases of colon carcinoma by synergism of IL-12 gene therapy and 4-1BB costimulation
Molecular Therapy : The Journal of the American Society of Gene Therapy
(2000) - et al.
Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells
Cell
(2021) - et al.
An ionizable lipid toolbox for RNA delivery
Nature Communications 2021 12:1
(2021) - et al.
Single injection of IL-12 coacervate as an effective therapy against B16-F10 melanoma in mice
Journal of Controlled Release: Official Journal of the Controlled Release Society
(2020) - et al.
Delivering the messenger: Advances in technologies for therapeutic mRNA delivery
Molecular Therapy : The Journal of the American Society of Gene Therapy
(2019) - et al.
Effects of single-dose interleukin-12 exposure on interleukin-12–associated toxicity and interferon-γ production
Blood
(1997) - et al.
IL-12 plasmid delivery by in vivo electroporation for the successful treatment of established subcutaneous B16.F10 melanoma
Molecular Therapy : The Journal of the American Society of Gene Therapy
(2002)
IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses
Immunity
TGF-beta is necessary for induction of IL-23R and Th17 differentiation by IL-6 and IL-23
Biochemical and Biophysical Research Communications
Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12
Immunity
Intratumourally injected alum-tethered cytokines elicit potent and safer local and systemic anticancer immunity
Nature Biomedical Engineering
Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma
Nature Communications
Phase II trial of IL-12 plasmid transfection and PD-1 blockade in immunologically quiescent melanoma
Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Phase-I clinical trial of IL-12 plasmid/lipopolymer complexes for the treatment of recurrent ovarian cancer
Gene Therapy 2010 17:3
Transfer of the murine interleukin-12 gene in vivo by a Semliki Forest virus vector induces B16 tumor regression through inhibition of tumor blood vessel formation monitored by Doppler ultrasonography
Gene Therapy
Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies
Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells
Nature Immunology
Pilot study of subcutaneous recombinant human interleukin 12 in metastatic melanoma
Regulated intratumoral expression of IL-12 using a RheoSwitch therapeutic system ® (RTS ®) gene switch as gene therapy for the treatment of glioma
Cancer Gene Therapy
Phase I trial of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for the treatment of metastatic pancreatic cancer
Molecular Therapy Oncolytics
391 A first-in-human study of intratumoral SAR441000, an mRNA mixture encoding IL-12sc, interferon alpha2b, GM-CSF and IL-15sushi as monotherapy and in combination with cemiplimab in advanced solid tumors
Journal for Immunotherapy of Cancer
Construction of a double recombinant adenovirus vector expressing a heterodimeric cytokine: In vitro and in vivo production of biologically active interleukin-12
Human Gene Therapy
Direct intratumoral injection of an adenovirus expressing interleukin-12 induces regression and long-lasting immunity that is associated with highly localized expression of interleukin-12
Human Gene Therapy
Antitumor and antimetastatic activity of interleukin 12 against murine tumors
The Journal of Experimental Medicine
Cytokine gene therapy of mesothelioma. Immune and antitumor effects of transfected interleukin-12
American Journal of Respiratory Cell and Molecular Biology
Adenovirus-mediated interleukin-12 gene therapy for metastatic colon carcinoma
Proceedings of the National Academy of Sciences of the United States of America
Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: Results of a phase 1 trial
Science Translational Medicine
Expression cloning of a human IL-12 receptor component: A new member of the cytokine receptor superfamily with strong homology to gp130
The Journal of Immunology
The composition and signaling of the IL-35 receptor are unconventional
Nature Immunology
The inhibitory cytokine IL-35 contributes to regulatory T-cell function
Nature
Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with mycobacterium tuberculosis
The Journal of Experimental Medicine
Gene therapy for cancer treatment: Past, present and future
Clinical Medicine & Research
Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain
Nature
Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells
Journal of Experimental Medicine
Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Epstein-Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin
Proceedings of the National Academy of Sciences of the United States of America
IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells
Journal of Immunology (Baltimore, Md. : 1950)
Interleukin-22: Immunobiology and pathology
Annual Review of Immunology
Intratumor adoptive transfer of IL-12 mRNA transiently engineered antitumor CD8 + T cells
Cancer Cell
Engineering bionic T cells: Signal 1, signal 2, signal 3, reprogramming and the removal of inhibitory mechanisms
Cellular & Molecular Immunology
The immunocytokine NHS-IL12 as a potential cancer therapeutic
Oncotarget
Efficacy of oncolytic adenovirus expressing suicide genes and interleukin-12 in preclinical model of prostate cancer
Gene Therapy 2013 20:12
Augmentation of local antitumor immunity in the liver by tumor vaccine modified to secrete murine interleukin 12
Gene Therapy 1999 6:6
An engineered antibody-interleukin-12 fusion protein with enhanced tumor vascular targeting properties
International Journal of Cancer
Novel antibodies that selectively block mouse IL-12 enable the re-evaluation of the role of IL-12 in immune protection and pathology
European Journal of Immunology
Induction of antitumor immunity by direct intratumoral injection of a recombinant adenovirus vector expressing interleukin-12
Cancer Gene Therapy 1999 6:1
Administration of recombinant IL-12 to normal mice enhances cytolytic lymphocyte activity and induces production of IFN-gamma in vivo
International Immunology
Cited by (32)
Immunoenhancement effect of cinobufagin on macrophages and the cyclophosphamide-induced immunosuppression mouse model
2024, International ImmunopharmacologyModeling of the human interleukin 12:receptor complex allows to engineer attenuated cytokine variants
2023, Molecular ImmunologyIntratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-β antagonists
2023, Molecular Therapy Nucleic AcidsIntratumoral injection of IL-12-encoding mRNA targeted to CSFR1 and PD-L1 exerts potent anti-tumor effects without substantial systemic exposure
2023, Molecular Therapy Nucleic AcidsCytokine sustained delivery for cancer therapy; special focus on stem cell- and biomaterial- based delivery methods
2023, Pathology Research and Practice
- 1
PB and IM will share credit for senior authorship.