-
Nature Immunology Jul 2012The interleukin 12 (IL-12) family is unique in having the only heterodimeric cytokines, including IL-12, IL-23, IL-27 and IL-35. This feature endows these cytokines with... (Review)
Review
The interleukin 12 (IL-12) family is unique in having the only heterodimeric cytokines, including IL-12, IL-23, IL-27 and IL-35. This feature endows these cytokines with a unique set of connections and functional interactions not shared by other cytokine families. Despite sharing many structural features and molecular partners, cytokines of the IL-12 family mediate surprisingly diverse functional effects. Here we discuss the unique and unusual structural and functional characteristics of this cytokine family. We outline how cells might interpret seemingly similar cytokine signals to give rise to the diverse functional outcomes that characterize this cytokine family. We also discuss the therapeutic implications of this complexity.
Topics: Humans; Inflammation; Inflammation Mediators; Interleukin-12; Interleukin-17; Interleukin-23; Interleukins; Protein Multimerization; Signal Transduction; T-Lymphocytes
PubMed: 22814351
DOI: 10.1038/ni.2366 -
Immunity Apr 2019The discovery of interleukin (IL)-6 and its receptor subunits provided a foundation to understand the biology of a group of related cytokines: IL-12, IL-23, and IL-27.... (Review)
Review
The discovery of interleukin (IL)-6 and its receptor subunits provided a foundation to understand the biology of a group of related cytokines: IL-12, IL-23, and IL-27. These family members utilize shared receptors and cytokine subunits and influence the outcome of cancer, infection, and inflammatory diseases. Consequently, many facets of their biology are being therapeutically targeted. Here, we review the landmark discoveries in this field, the combinatorial biology inherent to this family, and how patient datasets have underscored the critical role of these pathways in human disease. We present significant knowledge gaps, including how similar signals from these cytokines can mediate distinct outcomes, and discuss how a better understanding of the biology of the IL-12 family provides new therapeutic opportunities.
Topics: Animals; Autoimmune Diseases; Cytokines; Humans; Immunity, Cellular; Inflammation; Interleukin-12; Interleukin-27; Lymphocyte Subsets; Lymphopoiesis; Mice; Mice, Knockout; Multigene Family; Neoplasms, Experimental; Protein Subunits; Structure-Activity Relationship
PubMed: 30995503
DOI: 10.1016/j.immuni.2019.03.011 -
Frontiers in Immunology 2022Natural killer (NK) cells are lymphocytes with a key role in the defense against viral infections and tumor cells. Although NK cells are classified as innate lymphoid... (Review)
Review
Natural killer (NK) cells are lymphocytes with a key role in the defense against viral infections and tumor cells. Although NK cells are classified as innate lymphoid cells (ILCs), under certain circumstances they exhibit adaptive and memory-like features. The latter may be achieved, among others, by a brief stimulation with interleukin (IL)-12, IL-15 and IL-18. These cytokine-induced memory-like (CIML) NK cells resemble the trained immunity observed in myeloid cells. CIML NK cells undergo transcriptional, epigenetic and metabolic reprogramming that, along with changes in the expression of cell surface receptors and components of cytotoxic granules, are responsible for their enhanced effector functions after a resting period. In addition, these memory-like NK cells persist for a long time, which make them a good candidate for cancer immunotherapy. Currently, several clinical trials are testing CIML NK cells infusions to treat tumors, mostly hematological malignancies. In relapse/refractory acute myeloid leukemia (AML), the adoptive transfer of CIML NK cells is safe and complete clinical remissions have been observed. In our review, we sought to summarize the current knowledge about the generation and molecular basis of NK cell memory-like responses and the up-to-date results from clinical trials with CIML NK cells.
Topics: Cytokines; Immunity, Innate; Immunologic Memory; Interleukin-12; Killer Cells, Natural
PubMed: 35603208
DOI: 10.3389/fimmu.2022.884648 -
Frontiers in Immunology 2020Interleukin-12 (IL-12) is a potent, pro-inflammatory type 1 cytokine that has long been studied as a potential immunotherapy for cancer. Unfortunately, IL-12's... (Review)
Review
Interleukin-12 (IL-12) is a potent, pro-inflammatory type 1 cytokine that has long been studied as a potential immunotherapy for cancer. Unfortunately, IL-12's remarkable antitumor efficacy in preclinical models has yet to be replicated in humans. Early clinical trials in the mid-1990's showed that systemic delivery of IL-12 incurred dose-limiting toxicities. Nevertheless, IL-12's pleiotropic activity, i.e., its ability to engage multiple effector mechanisms and reverse tumor-induced immunosuppression, continues to entice cancer researchers. The development of strategies which maximize IL-12 delivery to the tumor microenvironment while minimizing systemic exposure are of increasing interest. Diverse IL-12 delivery systems, from immunocytokine fusions to polymeric nanoparticles, have demonstrated robust antitumor immunity with reduced adverse events in preclinical studies. Several localized IL-12 delivery approaches have recently reached the clinical stage with several more at the precipice of translation. Taken together, localized delivery systems are supporting an IL-12 renaissance which may finally allow this potent cytokine to fulfill its considerable clinical potential. This review begins with a brief historical account of cytokine monotherapies and describes how IL-12 went from promising new cure to ostracized black sheep following multiple on-study deaths. The bulk of this comprehensive review focuses on developments in diverse localized delivery strategies for IL-12-based cancer immunotherapies. Advantages and limitations of different delivery technologies are highlighted. Finally, perspectives on how IL-12-based immunotherapies may be utilized for widespread clinical application in the very near future are offered.
Topics: Animals; Antineoplastic Agents; Drug Carriers; Drug Compounding; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Immunotherapy; Interleukin-12; Neoplasms; Treatment Outcome; Tumor Microenvironment
PubMed: 33178203
DOI: 10.3389/fimmu.2020.575597 -
Cell Feb 2021Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that are produced by antigen-presenting cells to regulate the activation and differentiation of lymphocytes,...
Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that are produced by antigen-presenting cells to regulate the activation and differentiation of lymphocytes, and they share IL-12Rβ1 as a receptor signaling subunit. We present a crystal structure of the quaternary IL-23 (IL-23p19/p40)/IL-23R/IL-12Rβ1 complex, together with cryoelectron microscopy (cryo-EM) maps of the complete IL-12 (IL-12p35/p40)/IL-12Rβ2/IL-12Rβ1 and IL-23 receptor (IL-23R) complexes, which reveal "non-canonical" topologies where IL-12Rβ1 directly engages the common p40 subunit. We targeted the shared IL-12Rβ1/p40 interface to design a panel of IL-12 partial agonists that preserved interferon gamma (IFNγ) induction by CD8 T cells but impaired cytokine production from natural killer (NK) cells in vitro. These cell-biased properties were recapitulated in vivo, where IL-12 partial agonists elicited anti-tumor immunity to MC-38 murine adenocarcinoma absent the NK-cell-mediated toxicity seen with wild-type IL-12. Thus, the structural mechanism of receptor sharing used by IL-12 family cytokines provides a protein interface blueprint for tuning this cytokine axis for therapeutics.
Topics: Amino Acid Sequence; Animals; Binding Sites; Cryoelectron Microscopy; Crystallography, X-Ray; Epitopes; Female; HEK293 Cells; Humans; Immunity; Interleukin-12; Interleukin-12 Subunit p40; Killer Cells, Natural; Mice, Inbred C57BL; Models, Molecular; Neoplasms; Protein Structure, Quaternary; Receptors, Interleukin; Receptors, Interleukin-12; Signal Transduction; Structure-Activity Relationship; T-Lymphocytes; Mice
PubMed: 33606986
DOI: 10.1016/j.cell.2021.01.018 -
Med (New York, N.Y.) May 2023Interleukin-12 (IL-12) has emerged as one of the most potent cytokines for tumor immunotherapy due to its ability to induce interferon γ (IFNγ) and polarize Th1...
BACKGROUND
Interleukin-12 (IL-12) has emerged as one of the most potent cytokines for tumor immunotherapy due to its ability to induce interferon γ (IFNγ) and polarize Th1 responses. Clinical use of IL-12 has been limited by a short half-life and narrow therapeutic index.
METHODS
We generated a monovalent, half-life-extended IL-12-Fc fusion protein, mDF6006, engineered to retain the high potency of native IL-12 while significantly expanding its therapeutic window. In vitro and in vivo activity of mDF6006 was tested against murine tumors. To translate our findings, we developed a fully human version of IL-12-Fc, designated DF6002, which we characterized in vitro on human cells and in vivo in cynomolgus monkeys in preparation for clinical trials.
FINDINGS
The extended half-life of mDF6006 modified the pharmacodynamic profile of IL-12 to one that was better tolerated systemically while vastly amplifying its efficacy. Mechanistically, mDF6006 led to greater and more sustained IFNγ production than recombinant IL-12 without inducing high, toxic peak serum concentrations of IFNγ. We showed that mDF6006's expanded therapeutic window allowed for potent anti-tumor activity as single agent against large immune checkpoint blockade-resistant tumors. Furthermore, the favorable benefit-risk profile of mDF6006 enabled effective combination with PD-1 blockade. Fully human DF6002, similarly, demonstrated an extended half-life and a protracted IFNγ profile in non-human primates.
CONCLUSION
An optimized IL-12-Fc fusion protein increased the therapeutic window of IL-12, enhancing anti-tumor activity without concomitantly increasing toxicity.
FUNDING
This research was funded by Dragonfly Therapeutics.
Topics: Animals; Mice; Immunologic Factors; Interferon-gamma; Interleukin-12; Neoplasms; Odonata; Recombinant Fusion Proteins; Recombinant Proteins; Therapeutic Index
PubMed: 37059099
DOI: 10.1016/j.medj.2023.03.007 -
Cancer Immunology, Immunotherapy : CII Sep 2022Interleukin-12 (IL-12) is a type I cytokine involved in both innate and adaptive immunity that stimulates T and natural killer cell activity and induces interferon gamma... (Review)
Review
Interleukin-12 (IL-12) is a type I cytokine involved in both innate and adaptive immunity that stimulates T and natural killer cell activity and induces interferon gamma production. IL-12 has been identified as a potential immunotherapeutic component for combinatorial cancer treatments. While IL-12 has successfully been used to treat a variety of cancers in mice, it was associated with toxicity when administered systemically in cancer patients. In this review, we discuss the research findings and progress of IL-12 used in combination with other cancer treatment modalities. We describe different methods of IL-12 delivery, both systemic and local, and ultimately highlight the potential of an in situ vaccination approach for minimizing toxicities and providing antitumor efficacy. This review offers a basis for pursuing an in situ vaccine approach that may eventually allow IL-12 to be more readily integrated as an immunotherapy into the clinical treatment of cancers.
Topics: Animals; Cancer Vaccines; Humans; Immunotherapy; Interferon-gamma; Interleukin-12; Mice; Neoplasms
PubMed: 35024897
DOI: 10.1007/s00262-022-03144-1 -
Journal of Leukocyte Biology Sep 2022IL-12 is a proinflammatory cytokine capable of inducing a wide range of effects on both innate and adaptive immune responses. Its stimulatory effects on T cells and NK... (Review)
Review
IL-12 is a proinflammatory cytokine capable of inducing a wide range of effects on both innate and adaptive immune responses. Its stimulatory effects on T cells and NK cells have led to its classification as a potential inducer of antitumor immunity. Clinical trials have been attempting to harness its immune-stimulating capacity since the 1990s and have had much success despite notable toxicity issues early on. Several methods of IL-12 delivery have been employed including i.v., s.c., and local administrations as well as plasmid and gene therapies. However, despite differing methods, dosages, and cancer types utilized in these clinical trials, there are still many patients who do not respond to IL-12 therapy. This creates an opportunity for further investigation into the immunologic differences between responding and nonresponding patients in order to better understand the variable efficacy of IL-12 therapy. This review focuses on a limited collection of IL-12 clinical trials, which further analyzed these individual subsets and detected biologic variables correlating with differential patient responses. A comprehensive review of these potential biomarkers identified 7 analytes that correlated with beneficial patient responses in 3 or more clinical trials. These were increased levels of IFN-γ, IP-10, TNF-α, MIP-1α, MIG, and CD4 and CD8 T cells, with a decrease in VEGF, bFGF, FoxP3 T regulatory cells, and M2 macrophages. These potential biomarkers highlight the possibility of identifying immunologic determinants of patient response to IL-12 therapy to conserve valuable resources and benefit patients.
Topics: Biomarkers; Cytokines; Humans; Interleukin-12; Killer Cells, Natural; T-Lymphocyte Subsets
PubMed: 35790025
DOI: 10.1002/JLB.5RU1221-675R -
Cell Cycle (Georgetown, Tex.) 2014
Topics: Animals; Disease Models, Animal; Glioblastoma; Immunotherapy; Interleukin-12; Oncolytic Virotherapy; Simplexvirus
PubMed: 24241205
DOI: 10.4161/cc.27039 -
Cold Spring Harbor Perspectives in... Jul 2018The balance of proinflammatory cytokines interleukin (IL)-12 and IL-23 plays a key role in shaping the development of antitumor or protumor immunity. In this review, we... (Review)
Review
The balance of proinflammatory cytokines interleukin (IL)-12 and IL-23 plays a key role in shaping the development of antitumor or protumor immunity. In this review, we discuss the role IL-12 and IL-23 plays in tumor biology from preclinical and clinical data. In particular, we discuss the mechanism by which IL-23 promotes tumor growth and metastases and how the IL-12/IL-23 axis of inflammation can be targeted for cancer therapy.
Topics: Animals; Gene Expression Regulation, Neoplastic; Humans; Interleukin-12; Interleukin-23; Neoplasms
PubMed: 28716888
DOI: 10.1101/cshperspect.a028530