Novel strategies exploiting interleukin-12 in cancer immunotherapy

https://doi.org/10.1016/j.pharmthera.2022.108189Get rights and content

Abstract

Interleukin-12 is considered a potent agent to enhance antitumor immune responses. It belongs to a family of heterodimeric cytokines with key roles in the up-regulation and down-regulation of cellular immunity. Since its discovery, recombinant IL-12 was found to exert potent antitumor effects in rodent tumor models and was rapidly tested in the clinic with an unfavorable benefit/toxicity profile. Localized delivery of IL-12 dramatically improves the therapeutic index and this approach is being applied in the clinic based on in-vivo electroporation of naked plasmid DNA encoding IL-12, mRNA formulations, viral vectors and tumor-targeted fusion proteins. Other biotechnology strategies such as IL-12-engineered local adoptive cell therapy and pro-cytokines can also be used to improve results and broaden the therapeutic window. Combination strategies of such localized IL-12-based approaches with checkpoint inhibitors are yielding promising results both preclinically and in the early-phase clinical trials.

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)

  • J. Magram et al.

    IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses

    Immunity

    (1996)
  • N. Morishima et al.

    TGF-beta is necessary for induction of IL-23R and Th17 differentiation by IL-6 and IL-23

    Biochemical and Biophysical Research Communications

    (2009)
  • B. Oppmann et al.

    Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12

    Immunity

    (2000)
  • Y. Agarwal et al.

    Intratumourally injected alum-tethered cytokines elicit potent and safer local and systemic anticancer immunity

    Nature Biomedical Engineering

    (2022)
  • G. Agliardi et al.

    Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma

    Nature Communications

    (2021)
  • A.P. Algazi et al.

    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

    (2020)
  • K. Anwer et al.

    Phase-I clinical trial of IL-12 plasmid/lipopolymer complexes for the treatment of recurrent ovarian cancer

    Gene Therapy 2010 17:3

    (2009)
  • C. Asselin-Paturel et al.

    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

    (1999)
  • M.B. Atkins et al.

    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

    (1997)
  • A. Awasthi et al.

    A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells

    Nature Immunology

    (2007)
  • E. Bajetta et al.

    Pilot study of subcutaneous recombinant human interleukin 12 in metastatic melanoma

    (1998)
  • J.A. Barrett et al.

    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

    (2018)
  • K.N. Barton et al.

    Phase I trial of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for the treatment of metastatic pancreatic cancer

    Molecular Therapy Oncolytics

    (2020)
  • O. Bechter et al.

    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

    (2020)
  • J. Bramson et al.

    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

    (1996)
  • J.L. Bramson et al.

    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

    (1996)
  • M.J. Brunda et al.

    Antitumor and antimetastatic activity of interleukin 12 against murine tumors

    The Journal of Experimental Medicine

    (1993)
  • I. Caminschi et al.

    Cytokine gene therapy of mesothelioma. Immune and antitumor effects of transfected interleukin-12

    American Journal of Respiratory Cell and Molecular Biology

    (1999)
  • M. Caruso et al.

    Adenovirus-mediated interleukin-12 gene therapy for metastatic colon carcinoma

    Proceedings of the National Academy of Sciences of the United States of America

    (1996)
  • E.A. Chiocca et al.

    Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: Results of a phase 1 trial

    Science Translational Medicine

    (2019)
  • A.O. Chua et al.

    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

    (1994)
  • L.W. Collison et al.

    The composition and signaling of the IL-35 receptor are unconventional

    Nature Immunology

    (2012)
  • L.W. Collison et al.

    The inhibitory cytokine IL-35 contributes to regulatory T-cell function

    Nature

    (2007)
  • A.M. Cooper et al.

    Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with mycobacterium tuberculosis

    The Journal of Experimental Medicine

    (1997)
  • D. Cross et al.

    Gene therapy for cancer treatment: Past, present and future

    Clinical Medicine & Research

    (2006)
  • D.J. Cua et al.

    Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain

    Nature

    (2003)
  • A. D’Andrea et al.

    Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells

    Journal of Experimental Medicine

    (1992)
  • A.I. Daud et al.

    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

    (2008)
  • O. Devergne et al.

    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

    (1997)
  • C. Diveu et al.

    IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells

    Journal of Immunology (Baltimore, Md. : 1950)

    (2009)
  • J.A. Dudakov et al.

    Interleukin-22: Immunobiology and pathology

    Annual Review of Immunology

    (2015)
  • I. Etxeberria et al.

    Intratumor adoptive transfer of IL-12 mRNA transiently engineered antitumor CD8 + T cells

    Cancer Cell

    (2019)
  • I. Etxeberria et al.

    Engineering bionic T cells: Signal 1, signal 2, signal 3, reprogramming and the removal of inhibitory mechanisms

    Cellular & Molecular Immunology

    (2020)
  • J. Fallon et al.

    The immunocytokine NHS-IL12 as a potential cancer therapeutic

    Oncotarget

    (2014)
  • S.O. Freytag et al.

    Efficacy of oncolytic adenovirus expressing suicide genes and interleukin-12 in preclinical model of prostate cancer

    Gene Therapy 2013 20:12

    (2013)
  • N. Fuji et al.

    Augmentation of local antitumor immunity in the liver by tumor vaccine modified to secrete murine interleukin 12

    Gene Therapy 1999 6:6

    (1999)
  • V. Gafner et al.

    An engineered antibody-interleukin-12 fusion protein with enhanced tumor vascular targeting properties

    International Journal of Cancer

    (2006)
  • M. Gaignage et al.

    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

    (2021)
  • A. Gambotto et al.

    Induction of antitumor immunity by direct intratumoral injection of a recombinant adenovirus vector expressing interleukin-12

    Cancer Gene Therapy 1999 6:1

    (1999)
  • M.K. Gately et al.

    Administration of recombinant IL-12 to normal mice enhances cytolytic lymphocyte activity and induces production of IFN-gamma in vivo

    International Immunology

    (1994)
  • Cited by (32)

    View all citing articles on Scopus
    1

    PB and IM will share credit for senior authorship.

    View full text