SENTI-101, a Preparation of Mesenchymal Stromal Cells Engineered to Express IL12 and IL21, Induces Localized and Durable Antitumor Immunity in Preclinical Models of Peritoneal Solid Tumors

间充质干细胞 白细胞介素12 骨髓 癌症研究 免疫系统 间质细胞 医学 免疫疗法 免疫学 化学 细胞毒性T细胞 体外 病理 生物化学
作者
Alba Gonzàlez-Juncà,Frances D. Liu,Archana S. Nagaraja,Alyssa Mullenix,Chen-Ting Lee,Russell M. Gordley,Daniel O. Frimannsson,Ori Maller,Brian S. Garrison,Dharini Iyer,Anissa Benabbas,Tiffany Truong,Allison Quach,Mengxi Tian,Rowena Martinez,Rishi Savur,Alyssa Perry-McNamara,Denny Nguyen,Niran Almudhfar,Carmina Blanco,Christina Huynh,Asish Nand,Yu-An E. Lay,Ashita Magal,Sravani Mangalampalli,Philip Lee,Timothy K. Lu,Gary Lee
出处
期刊:Molecular Cancer Therapeutics [American Association for Cancer Research]
卷期号:20 (9): 1508-1520 被引量:10
标识
DOI:10.1158/1535-7163.mct-21-0030
摘要

Advanced peritoneal carcinomatosis including high-grade ovarian cancer has poor prognoses and a poor response rate to current checkpoint inhibitor immunotherapies; thus, there is an unmet need for effective therapeutics that would provide benefit to these patients. Here we present the preclinical development of SENTI-101, a cell preparation of bone marrow-derived mesenchymal stromal (also known as stem) cells (MSC), which are engineered to express two potent immune-modulatory cytokines, IL12 and IL21. Intraperitoneal administration of SENTI-101 results in selective tumor-homing and localized and sustained cytokine production in murine models of peritoneal cancer. SENTI-101 has extended half-life, reduced systemic distribution, and improved antitumor activity when compared with recombinant cytokines, suggesting that it is more effective and has lower risk of systemic immunotoxicities. Treatment of tumor-bearing immune-competent mice with a murine surrogate of SENTI-101 (mSENTI-101) results in a potent and localized immune response consistent with increased number and activation of antigen presenting cells, T cells and B cells, which leads to antitumor response and memory-induced long-term immunity. Consistent with this mechanism of action, co-administration of mSENTI-101 with checkpoint inhibitors leads to synergistic improvement in antitumor response. Collectively, these data warrant potential clinical development of SENTI-101 for patients with peritoneal carcinomatosis and high-grade ovarian cancer.Graphical abstract: SENTI-101 schematic and mechanism of actionSENTI-101 is a novel cell-based immunotherapeutic consisting of bone marrow-derived mesenchymal stromal cells (BM-MSC) engineered to express IL12 and IL21 intended for the treatment of peritoneal carcinomatosis including high-grade serous ovarian cancer. Upon intraperitoneal administration, SENTI-101 homes to peritoneal solid tumors and secretes IL12 and IL21 in a localized and sustained fashion. The expression of these two potent cytokines drives tumor infiltration and engagement of multiple components of the immune system: antigen-presenting cells, T cells, and B cells, resulting in durable antitumor immunity in preclinical models of cancer.
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