Neoadjuvant ICI and Mitochondrial Vaccine for Resectable HNSCC

Summary

Head and neck squamous cell carcinoma (HNSCC) presents a significant clinical challenge, as over 60% of patients are diagnosed at a locally advanced stage with a high risk of recurrence. Although the landmark KEYNOTE-689 trial established neoadjuvant immune checkpoint inhibitor (ICI) therapy as a new standard of care, the pathological complete response (pCR) rate remains unsatisfactory at only 3.0%, highlighting an urgent need for optimized combination strategies. This prospective, single-arm, single-center clinical study aims to evaluate the safety, tolerability, and preliminary efficacy of a novel neoadjuvant and adjuvant regimen combining an engineered mitochondrial vaccine (IMP3-Mito) with ICIs for patients with resectable, IMP3-positive locally advanced HNSCC. The rationale is based on a "Prime-and-Release" synergistic mechanism: the engineered mitochondrial vaccine serves as a potent "natural adjuvant" to activate dendritic cells and prime tumor-specific T-cell responses against the IMP3 antigen, while the ICI subsequently releases the immune brakes within the tumor microenvironment. By integrating these two modalities, the study seeks to achieve deeper pathological responses and improve long-term survival, while simultaneously providing clinical evidence for the transformative potential of the mitochondrial engineering platform in overcoming the limitations of conventional tumor vaccines.

Timeline

Start

2026-04-28

Primary completion

2027-05-01

Completion

2028-05-01

Publications

• Background Gulley JL, Borre M, Vogelzang NJ, Ng S, Agarwal N, Parker CC, Pook DW, Rathenborg P, Flaig TW, Carles J, Saad F, Shore ND, Chen L, Heery CR, Gerritsen WR, Priou F, Langkilde NC, Novikov A, Kantoff PW. Phase III Trial of PROSTVAC in Asymptomatic or Minimally Symptomatic Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. 2019 May 1;37(13):1051-1061. doi: 10.1200/JCO.18.02031. Epub 2019 Feb 28.
• Background Fan L, Wu D, Goremykin V, Xiao J, Xu Y, Garg S, Zhang C, Martin WF, Zhu R. Phylogenetic analyses with systematic taxon sampling show that mitochondria branch within Alphaproteobacteria. Nat Ecol Evol. 2020 Sep;4(9):1213-1219. doi: 10.1038/s41559-020-1239-x. Epub 2020 Jul 13.
• Background Pierini S, Fang C, Rafail S, Facciponte JG, Huang J, De Sanctis F, Morgan MA, Uribe-Herranz M, Tanyi JL, Facciabene A. A Tumor Mitochondria Vaccine Protects against Experimental Renal Cell Carcinoma. J Immunol. 2015 Oct 15;195(8):4020-7. doi: 10.4049/jimmunol.1500281. Epub 2015 Sep 16.
• Background Tse SW, McKinney K, Walker W, Nguyen M, Iacovelli J, Small C, Hopson K, Zaks T, Huang E. mRNA-encoded, constitutively active STINGV155M is a potent genetic adjuvant of antigen-specific CD8+ T cell response. Mol Ther. 2021 Jul 7;29(7):2227-2238. doi: 10.1016/j.ymthe.2021.03.002. Epub 2021 Mar 5.
• Background Fang C, Mo F, Liu L, Du J, Luo M, Men K, Na F, Wang W, Yang H, Wei X. Oxidized mitochondrial DNA sensing by STING signaling promotes the antitumor effect of an irradiated immunogenic cancer cell vaccine. Cell Mol Immunol. 2021 Sep;18(9):2211-2223. doi: 10.1038/s41423-020-0456-1. Epub 2020 May 12.
• Background Luo J, Mo F, Zhang Z, Hong W, Lan T, Cheng Y, Fang C, Bi Z, Qin F, Yang J, Zhang Z, Li X, Que H, Wang J, Chen S, Wu Y, Yang L, Li J, Wang W, Chen C, Wei X. Engineered mitochondria exert potent antitumor immunity as a cancer vaccine platform. Cell Mol Immunol. 2024 Nov;21(11):1251-1265. doi: 10.1038/s41423-024-01203-4. Epub 2024 Aug 20.

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