首页|Cancer immunotherapy with enveloped self-amplifying mRNA CARG-2020 that modulates IL-12,IL-17 and PD-L1 pathways to prevent tumor recurrence
Cancer immunotherapy with enveloped self-amplifying mRNA CARG-2020 that modulates IL-12,IL-17 and PD-L1 pathways to prevent tumor recurrence
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Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans.Here,we describe the application of virus-like vesicles(VLV)for delivery of three immunomodulators alone and in combination,as a promising approach for cancer immunotherapy.VLV vectors were designed to deliver single chain interleukin(IL)-12,short-hairpin RNA(shRNA)targeting programmed death ligand 1(PD-L1),and a dominant-negative form of IL-17 receptor A(dn-IL17RA)as a single payload or as a combination payload.Intralesional delivery of the VLV vector expressing IL-12 alone,as well as the trivalent vector(designated CARG-2020)erad-icated large established tumors.However,only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice,indicating a benefit of the combined immunomodulation.The abscopal effects of CARG-2020 on the non-injected contralateral tumors,as well as protection from the tumor cell re-challenge,suggest immune-mediated mechanism of protection and establishment of immunological memory.Mechanistically,CARG-2020 potently activates Th1 im-mune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting inflammation.The ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.
Ju Chen、Bhaskara Reddy Madina、Elham Ahmadi、Timur Olegovich Yarovinsky、Marie Marthe Krady、Eileen Victoria Meehan、Isabella China Wang、Xiaoyang Ye、Elise Pitmon、Xian-Yong Ma、Bijan Almassian、Valerian Nakaar、Kepeng Wang
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Department of Immunology,School of Medicine,University of Connecticut Health Center,Farmington,CT 06030,USA
The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine,Foshan Hospital of Traditional Chinese Medicine,Foshan 528000,China
CaroGen Corporation,Farmington,CT 06030,USA
The Loomis Chaffee School,Windsor,CT 06095,USA
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an American Association of Immunologists Careers in Immunology FellowshipNIDDKNIDDKNIDDKNIAIDNIAIDNational Institute of Health/National Cancer InstituteNational Institute of Health/National Cancer Institute
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