Impact of IL-12 in Cancer

Lu, Xinjie

doi:10.2174/1568009617666170427102729

Cited by 85 publications

(62 citation statements)

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“…As IL-12 is a master anti-tumor cytokine and has distinct multifaceted anti-cancer properties [1][2][3]6,8,10], IL-12 expression by OVs is not limited to OHSVs. Several other OVs encoding IL-12 have been developed ( Table 2), including adenoviruses [18,42,[46][47][48][49][133][134][135][136][137][138], measles virus [20,50], maraba virus [51], Newcastle disease virus [52], Semliki forest virus [53][54][55][56][139][140][141], vesicular stomatitis virus [57,142], and Sindbis virus [58].…”

Section: Anti-cancer Potential Of Other Ovs Encoding Il-12mentioning

confidence: 99%

“…Interleukin 12 (IL-12) is a powerful master regulator of both innate and adaptive anti-tumor immune responses. As a heterodimeric cytokine, it produces multifaceted anti-tumor effects [1,2], including stimulation of growth and cytotoxic activity of natural killer (NK) cells and T cells (both CD4 + and CD8 + ) [1,[3][4][5], induction of differentiation of CD4 + T cells towards Th1 phenotype [6,7], increased production of IFN-γ from NK and T cells [1,8,9], and inhibition of tumor angiogenesis [1,10]. Despite encouraging success in preclinical studies [4], the early stages of IL-12 clinical trials did not meet expectations.…”

Section: Introductionmentioning

confidence: 99%

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Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy

Nguyen

Guz-Montgomery

Saha

2020

Cells

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Oncolytic viruses (OVs) are genetically modified or naturally occurring viruses, which preferentially replicate in and kill cancer cells while sparing healthy cells, and induce anti-tumor immunity. OV-induced tumor immunity can be enhanced through viral expression of anti-tumor cytokines such as interleukin 12 (IL-12). IL-12 is a potent anti-cancer agent that promotes T-helper 1 (Th1) differentiation, facilitates T-cell-mediated killing of cancer cells, and inhibits tumor angiogenesis. Despite success in preclinical models, systemic IL-12 therapy is associated with significant toxicity in humans. Therefore, to utilize the therapeutic potential of IL-12 in OV-based cancer therapy, 25 different IL-12 expressing OVs (OV-IL12s) have been genetically engineered for local IL-12 production and tested preclinically in various cancer models. Among OV-IL12s, oncolytic herpes simplex virus encoding IL-12 (OHSV-IL12) is the furthest along in the clinic. IL-12 expression locally in the tumors avoids systemic toxicity while inducing an efficient anti-tumor immunity and synergizes with anti-angiogenic drugs or immunomodulators without compromising safety. Despite the rapidly rising interest, there are no current reviews on OV-IL12s that exploit their potential efficacy and safety to translate into human subjects. In this article, we will discuss safety, tumor-specificity, and anti-tumor immune/anti-angiogenic effects of OHSV-IL12 as mono-and combination-therapies. In addition to OHSV-IL12 viruses, we will also review other IL-12-expressing OVs and their application in cancer therapy.

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Section: Anti-cancer Potential Of Other Ovs Encoding Il-12mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy

Nguyen

Guz-Montgomery

Saha

2020

Cells

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“…[22][23][24] To circumvent (at least in part) this issue, increasing attention is being devoted to cytokines that naturally exhibit a relatively restricted cell specificity, such as IL-12, IL-15 or IL-21. 49,50,52,297 Moreover, efforts are being dedicated at the development of highly targeted cytokine variants aimed at focusing the biological effects of cytokine signaling onto a rather specific cell population. 138,298 Alongside, the panel of immunotherapeutic agents available for inclusion in combinatorial regimens has tremendously expanded over the past few years, [299][300][301] opening multiple new avenues of clinical investigation.…”

Section: Discussionmentioning

confidence: 99%

“…[37][38][39][40][41][42] Second, multiple immunotherapeutics with comparatively more specific mechanisms of action and robust clinical activity have been developed, including (but not limited to) immune checkpoint blockers (ICBs). [43][44][45][46][47][48] Nonetheless, research on the use of recombinant cytokines as immunostimulants against cancer continues as attention has shifted (1) to molecules with restricted selectivity for one or a few cell types, such as IL12, IL-15 and IL-21 [49][50][51][52] ; and (2) on regimens involving the concomitant or sequential administration of one or more recombinant cytokines with other agents that trigger or boost anticancer immunity, 53 including (but not limited to): ICBs, [54][55][56] immunostimulatory monoclonal antibodies (mAbs), [57][58][59][60] DNA-, dendritic cell (DC)-or peptide-based vaccines, [61][62][63][64][65][66][67] chemotherapy with immunogenic cell death inducers, [68][69][70][71][72][73] radiation therapy delivered according to specific fractionation protocols, [74][75][76] small molecules targeting the tumor microenvironment, [77]…”

Section: Introductionmentioning

confidence: 99%

Trial Watch: Immunostimulation with recombinant cytokines for cancer therapy

et al. 2018

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Cytokines regulate virtually aspects of innate and adaptive immunity, including the initiation, execution and extinction of tumor-targeting immune responses. Over the past three decades, the possibility of using recombinant cytokines as a means to elicit or boost clinically relevant anticancer immune responses has attracted considerable attention. However, only three cytokines have been approved so far by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, namely, recombinant interleukin (IL)-2 and two variants of recombinant interferon alpha 2 (IFN-α2a and IFN-α2b). Moreover, the use of these cytokines in the clinics is steadily decreasing, mostly as a consequence of: (1) the elevated pleiotropism of IL-2, IFN-α2a and IFN-α2b, resulting in multiple unwarranted effects; and (2) the development of highly effective immunostimulatory therapeutics, such as immune checkpoint blockers. Despite this and other obstacles, research in the field continues as alternative cytokines with restricted effects on specific cell populations are being evaluated. Here, we summarize research preclinical and clinical developments on the use of recombinant cytokines for immunostimulation in cancer patients.

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“…In an LPS-activated dendritic cell model, quercetin modulated DC activation and reduced secretion of TNF, IL-1β, IL-6, IL-10 and IL-12p70, [196]. Properties of quercetin, and other identified compounds, that reduce IL-6 and IL-10 show promise as a potential anti-cancer therapeutic, though reductions in TNF and IL-12 may not be favourable for anti-tumour activity as these cytokines can promote the anti-tumour response [197,198]. However, systemic activation of TNF (and IL-12) outside the TME can lead to adverse inflammatory responses and off-target effects of TNF therapy [199,200].…”

Section: Quercetinmentioning

confidence: 99%

Natural Compounds with Potential to Modulate Cancer Therapies and Self-Reactive Immune Cells

Moody

Wilson

Jaworowski

et al. 2020

Cancers

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Cancer-related deaths are approaching 10 million each year. Survival statistics for some cancers, such as ovarian cancer, have remained unchanged for decades, with women diagnosed at stage III or IV having over 80% chance of a lethal cancer recurrence after standard first-line treatment (reductive surgery and chemotherapy). New treatments and adjunct therapies are needed. In ovarian cancer, as in other cancers, the immune response, particularly cytotoxic (CD8+) T cells are correlated with a decreased risk of recurrence. As well as completely new antigen targets resulting from DNA mutations (neo-antigens), these T cells recognize cancer-associated overexpressed, re-expressed or modified self-proteins. However, there is concern that activation of self-reactive responses may also promote off-target pathology. This review considers the complex interplay between cancer-reactive and self-reactive immune cells and discusses the potential uses for various leading immunomodulatory compounds, derived from plant-based sources, as a cancer therapy option or to modulate potential autoimmune pathology. Along with reviewing well-studied compounds such as curcumin (from turmeric), epigallocatechin gallate (EGCG, from green tea) and resveratrol (from grapes and certain berries), it is proposed that compounds from novel sources, for example, native Australian plants, will provide a useful source for the fine modulation of cancer immunity in patients.

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Impact of IL-12 in Cancer

Cited by 85 publications

References 0 publications

Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy

Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy

Trial Watch: Immunostimulation with recombinant cytokines for cancer therapy

Natural Compounds with Potential to Modulate Cancer Therapies and Self-Reactive Immune Cells

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