Local delivery of mRNA-encoded cytokines promotes antitumor immunity and tumor eradication across multiple preclinical tumor models

Hotz, Christian; Wagenaar, Timothy R.; Gieseke, Friederike; Bangari, Dinesh S.; Callahan, Michelle; Cao, Hui; Diekmann, Jan; Diken, Mustafa; Grunwitz, Christian; Hebert, Andy; Hsu, Karl; Bernardo, Marie; Karikó, Katalin; Kreiter, Sebastian; Kuhn, Andreas N.; Levit, Mikhail; Malkova, Natalia; Masciari, Serena; Pollard, Jack; Qü, Hui; Ryan, Sue; Selmi, Abderraouf; Schlereth, Julia; Singh, Kuldeep; Sun, Fangxian; Tillmann, Bodo; Tolstykh, Tatiana; Weber, William; Wicke, Lena; Witzel, Sonja; Yu, Qunyan; Zhang, Yuan; Zheng, Gang; Lager, Joanne; Nabel, Gary J.; Şahin, Uğur; Wiederschain, Dmitri

doi:10.1126/scitranslmed.abc7804

Cited by 94 publications

(76 citation statements)

References 46 publications

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“…For example, the short half-life requires frequent administration, leading to dose-limiting toxicity. Existing preclinical studies demonstrated that the toxic side effects of systemic administration can be avoided by intratumoral administration ( 96 , 97 ). In addition, the main active site of immunostimulants is in the TIME, so clinical studies have mainly adopted intratumoral injection.…”

Section: Clinical Development Of Mrna Cancer Vaccinementioning

confidence: 99%

mRNA Vaccines: The Dawn of a New Era of Cancer Immunotherapy

Deng

Tian²,

Song³

et al. 2022

Front. Immunol.

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mRNA therapy is a novel anticancer strategy based on in vitro transcription (IVT), which has potential for the treatment of malignant tumors. The outbreak of the COVID-19 pandemic in the early 21st century has promoted the application of mRNA technologies in SARS-CoV-2 vaccines, and there has been a great deal of interest in the research and development of mRNA cancer vaccines. There has been progress in a number of key technologies, including mRNA production strategies, delivery systems, antitumor immune strategies, etc. These technologies have accelerated the progress and clinical applications of mRNA therapy, overcoming problems encountered in the past, such as instability, inefficient delivery, and weak immunogenicity of mRNA vaccines. This review provides a detailed overview of the production, delivery systems, immunological mechanisms, and antitumor immune response strategies for mRNA cancer vaccines. We list some mRNA cancer vaccines that are candidates for cancer treatment and discuss clinical trials in the field of tumor immunotherapy. In addition, we discuss the immunological mechanism of action by which mRNA vaccines destroy tumors as well as challenges and prospects for the future.

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Section: Clinical Development Of Mrna Cancer Vaccinementioning

confidence: 99%

mRNA Vaccines: The Dawn of a New Era of Cancer Immunotherapy

Deng

Tian²,

Song³

et al. 2022

Front. Immunol.

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“…Saline-formulated mRNA for four cytokines gene (IL-2, IL-15, IFN-α, and GM-CSF) when administered at the tumor site led to systemic antigen-specific T cell expansion, granzyme B + T cell infiltration, and immunological memory development. Moreover, profound tumor regression was identified when this mRNA-based cytokine therapy was combined with immunomodulatory agents [ 56 ].…”

Section: Targeting Time Using Rna-based Platformsmentioning

confidence: 99%

RNA-mediated immunotherapy regulating tumor immune microenvironment: next wave of cancer therapeutics

et al. 2022

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Accumulating research suggests that the tumor immune microenvironment (TIME) plays an essential role in regulation of tumor growth and metastasis. The cellular and molecular nature of the TIME influences cancer progression and metastasis by altering the ratio of immune- suppressive versus cytotoxic responses in the vicinity of the tumor. Targeting or activating the TIME components show a promising therapeutic avenue to combat cancer. The success of immunotherapy is both astounding and unsatisfactory in the clinic. Advancements in RNA-based technology have improved understanding of the complexity and diversity of the TIME and its effects on therapy. TIME-related RNA or RNA regulators could be promising targets for anticancer immunotherapy. In this review, we discuss the available RNA-based cancer immunotherapies targeting the TIME. More importantly, we summarize the potential of various RNA-based therapeutics clinically available for cancer treatment. RNA-dependent targeting of the TIME, as monotherapy or combined with other evolving therapeutics, might be beneficial for cancer patients’ treatment in the near future.

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“…For example, co-delivery of stimulatory cytokines, such as GM-CSF, IL-12, and IL-15, with mRNA encoding tumor antigen in dendritic cell vaccines promotes remodeling of the TME, enhances cytotoxic T cell responses, and controls tumor growth in preclinical models (128)(129)(130)(131). Further, in situ vaccination with a cocktail of naked mRNAs encoding IL-12, GM-CSF, IL-15, and IFN-α4 promotes tumor infiltration of polyfunctional Th1-like CD4 + cells, cytotoxic CD8 + T cells, and pro-immune monocytic cell types while decreasing Tregs, leading to survival benefits in murine models of cancer including metastatic melanoma (132). Similarly, in melanoma patients, coexpression of immunostimulatory molecules, such as CD40L, CD70, and constitutively active TLR4 (TriMix, eTheRNA Immunotherapies), along with the tumor antigen mRNA potentiates APC maturation and cognate T cell activation (133,134).…”

Section: Biologic and Immunologic Qualities Underpinning Mrna Vaccine...mentioning

confidence: 99%

Messenger RNA vaccines for cancer immunotherapy: progress promotes promise

Huff¹,

Jaffee²,

Zaidi³

2022

Journal of Clinical Investigation

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Local delivery of mRNA-encoded cytokines promotes antitumor immunity and tumor eradication across multiple preclinical tumor models

Abstract: Local immunotherapy with an mRNA mixture encoding four cytokines mobilizes a systemic antitumor response and promotes tumor eradication.

Cited by 94 publications

References 46 publications

mRNA Vaccines: The Dawn of a New Era of Cancer Immunotherapy

mRNA Vaccines: The Dawn of a New Era of Cancer Immunotherapy

RNA-mediated immunotherapy regulating tumor immune microenvironment: next wave of cancer therapeutics

Messenger RNA vaccines for cancer immunotherapy: progress promotes promise

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