Intratumoral delivery of IL-12 and IL-27 mRNA using lipid nanoparticles for cancer immunotherapy

Liu, Jinqing; Zhang, Chengxiang; Zhang, Xinfu; Yan, Jiajie; Zeng, Chunxi; Talebian, Fatemeh; Lynch, Kimberly; Zhao, Weiliang; Hou, Xucheng; Du, Shi; Kang, Diana D.; Deng, Binbin; McComb, David W.; Bai, Xue‐Feng; Dong, Yizhou

doi:10.1016/j.jconrel.2022.03.021

Cited by 107 publications

(76 citation statements)

References 50 publications

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“…The cholesterolcontaining formulation displayed better transfection than the cholesterol-free nanocomplex in vivo after direct injection into syngeneic tumours of B16-F10 in C57Bl/6 J mice. Intratumoural delivery offers many therapeutic routes and has been described for testing mRNA cancer therapeutics [44]. IL-15 has long been proposed as an immunotherapy for cancers by activating natural killer (NK) cells, B cells and T cells, and increasing the production of cytokine-like tumour necrosis factor-alpha (TNF-α) and interferongamma (IFN-γ) [22,46].…”

Section: Discussionmentioning

confidence: 99%

Lipid-peptide nanocomplexes for mRNA delivery in vitro and in vivo

Grant-Serroukh

Hunter

Maeshima

et al. 2022

Journal of Controlled Release

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Section: Discussionmentioning

confidence: 99%

Lipid-peptide nanocomplexes for mRNA delivery in vitro and in vivo

Grant-Serroukh

Hunter

Maeshima

et al. 2022

Journal of Controlled Release

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“…Thus, for potent antitumor effects, deep and broad interstitial distribution of immunocytokines is important to stimulate the population and cytotoxicity of antitumor effector immune cells in situ throughout the tumor tissues. We found that the extent of intratumoral diffusion of HCT-mono-mIL12 is strongly correlated with the numbers of CD4 + and CD8 + T cells and the cytotoxicity of CD8 + T cells as well as their even distribution in the TME, suggesting that sufficient presence of IL12 in the TME can induce the tumor infiltration of T cells ( 41 ) and/or stimulate the in situ proliferation and activation of preexisting T cells to kill tumor cells in the TME. This correlation further clarifies the observed variation in the antitumor activity of HCT-mono-mIL12 according to the anti-HER2 binding kinetic parameters.…”

Section: Discussionmentioning

confidence: 94%

“…Treatment of HCT/130-mono-IL12, with the most efficient intratumoral diffusive penetrating activity, increased the number of CD4 + and CD8 + T cells in the tumors by ~3-fold compared with those found after treatment with higher-affinity variants. Thus, HCT/130-mono-IL12 demonstrated the ability to efficiently promote tumor infiltration and activation of antitumor CD4 + and CD8 + T cells, thereby increasing the antitumor immunity in the TME ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

Improved intratumoral penetration of IL12 immunocytokine enhances the antitumor efficacy

et al. 2022

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Tumor-targeting antibody (Ab)-fused cytokines, referred to as immunocytokines, are designed to increase antitumor efficacy and reduce toxicity through the tumor-directed delivery of cytokines. However, the poor localization and intratumoral penetration of immunocytokines, especially in solid tumors, pose a challenge to effectively stimulate antitumor immune cells to kill tumor cells within the tumor microenvironment. Here, we investigated the influence of the tumor antigen-binding kinetics of a murine interleukin 12 (mIL12)-based immunocytokine on tumor localization and diffusive intratumoral penetration, and hence the consequent antitumor activity, by activating effector T cells in immunocompetent mice bearing syngeneic colon tumors. Based on tumor-associated antigen HER2-specific Ab Herceptin (HCT)-fused mIL12 carrying one molecule of mIL12 (HCT-mono-mIL12 immunocytokine), we generated a panel of HCT-mono-mIL12 variants with different affinities (KD) mainly varying in their dissociation rates (koff) for HER2. Systemic administration of HCT-mono-mIL12 required an anti-HER2 affinity above a threshold (KD = 130 nM) for selective localization and antitumor activity to HER2-expressing tumors versus HER2-negative tumors. However, the high affinity (KD = 0.54 or 46 nM) due to the slow koff from HER2 antigen limited the depth of intratumoral penetration of HCT-mono-mIL12 and the consequent tumor infiltration of T cells, resulting in inferior antitumor activity compared with that of HCT-mono-mIL12 with moderate affinity of (KD = 130 nM) and a faster koff. The extent of intratumoral penetration of HCT-mono-mIL12 variants was strongly correlated with their tumor infiltration and intratumoral activation of CD4+ and CD8+ T cells to kill tumor cells. Collectively, our results demonstrate that when developing antitumor immunocytokines, tumor antigen-binding kinetics and affinity of the Ab moiety should be optimized to achieve maximal antitumor efficacy.

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“…The combination demonstrated synergistic effects, thus allowing using low doses of IL-12, leading to lower side effects. The combined therapies were reported to produce the infiltration of IFN-γ and TNF-α producing NK and CD8 + T cells into tumors, whereas the monotherapies could not …”

Section: Prospects For Advanced Delivery Of Approved Drugs In the Tre...mentioning

confidence: 99%

Options of Therapeutics and Novel Delivery Systems of Drugs for the Treatment of Melanoma

et al. 2022

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Melanoma is one of the most severe cancerous diseases. The cells employ multiple signaling pathways, such as ERK, HGF/c-MET, WNT, and COX-2 to cause the cell proliferation, survival, and metastasis. Treatment of melanoma, including surgery, chemotherapy, immunotherapy, radiation, and targeted therapy, is based on 4 major or 11 substages of the disease. Fourteen drugs, including dacarbazine, interferon α-2b, interleukin-12, ipilimumab, peginterferon α-2b, vemurafenib, trametinib, talimogene laherparepvec, cobimetinib, pembrolizumab, dabrafenib, binimetinib, encorafenib, and nivolumab, have been approved by the FDA for the treatment of melanoma. All of them are in conventional dosage forms of injection solutions, suspensions, oral tablets, or capsules. Major drawbacks of the treatment are side effects of the drugs and patients' incompliance to them. These are consequences of high doses and long-term treatments for the diseases. Currently more than 350 NCI-registered clinical trials are being carried out to treat advanced and/or metastatic melanoma using novel treatment methods, such as immune cell therapy, cancer vaccines, and new therapeutic targets. In addition, novel delivery systems using biomaterials of the approved drugs have been developed attempting to increase the drug delivery, targeting, stability, bioavailability, thus potentially reducing the toxicity and increasing the treatment effectiveness. Nanoparticles and liposomes have been emerging as advanced delivery systems which can improve drug stability and systemic circulation time. In this review, the most recent findings in the options for treatment and development of novel drug delivery systems for the treatment of melanoma are comprehensively discussed.

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Intratumoral delivery of IL-12 and IL-27 mRNA using lipid nanoparticles for cancer immunotherapy

Cited by 107 publications

References 50 publications

Lipid-peptide nanocomplexes for mRNA delivery in vitro and in vivo

Lipid-peptide nanocomplexes for mRNA delivery in vitro and in vivo

Improved intratumoral penetration of IL12 immunocytokine enhances the antitumor efficacy

Options of Therapeutics and Novel Delivery Systems of Drugs for the Treatment of Melanoma

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