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 action SENTI-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. This article is featured in Highlights of This Issue, [p. 1497][1] [1]: /lookup/volpage/20/1497?iss=9

中文翻译：

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SENTI-101，一种经工程改造以表达 IL12 和 IL21 的间充质基质细胞制剂，可在腹膜实体瘤的临床前模型中诱导局部和持久的抗肿瘤免疫

包括高级别卵巢癌在内的晚期腹膜癌病预后不良，对当前检查点抑制剂免疫疗法的反应率低；因此，对可为这些患者带来益处的有效治疗方法的需求尚未得到满足。在这里，我们介绍了 SENTI-101 的临床前开发，这是一种骨髓来源的间充质基质（也称为干）细胞 (MSC) 的细胞制剂，经过工程改造以表达两种有效的免疫调节细胞因子 IL12 和 IL21。SENTI-101 的腹膜内给药导致选择性肿瘤归巢以及在腹膜癌小鼠模型中局部和持续的细胞因子产生。与重组细胞因子相比，SENTI-101 的半衰期延长，全身分布减少，抗肿瘤活性提高，表明它更有效并且具有更低的全身免疫毒性风险。用 SENTI-101 (mSENTI-101) 的鼠类替代物治疗荷瘤免疫能力强的小鼠会产生有效的局部免疫反应，这与抗原呈递细胞、T 细胞和 B 细胞的数量和活化增加一致，从而导致抗肿瘤反应和记忆诱导的长期免疫。与这种作用机制一致，mSENTI-101 与检查点抑制剂的共同给药导致抗肿瘤反应的协同改善。总的来说，这些数据保证了 SENTI-101 用于腹膜癌和高级别卵巢癌患者的潜在临床开发。图形概要：SENTI-101示意图和作用机制 SENTI-101是一种新型的基于细胞的免疫治疗药物，由骨髓来源的间充质基质细胞 (BM-MSC) 组成，旨在表达 IL12 和 IL21，用于治疗腹膜癌病，包括高级浆液性卵巢癌。在腹膜内给药后，SENTI-101 以局部和持续的方式集中于腹膜实体瘤并分泌 IL12 和 IL21。这两种有效细胞因子的表达驱动肿瘤浸润和免疫系统多个成分的参与：抗原呈递细胞、T 细胞和 B 细胞，从而在癌症的临床前模型中产生持久的抗肿瘤免疫。这篇文章被收录在本期的亮点中，[p. 1497][1][1]：/lookup/volpage/20/1497?iss=9 SENTI-101定位于腹膜实体瘤，并以局部和持续的方式分泌 IL12 和 IL21。这两种有效细胞因子的表达驱动肿瘤浸润和免疫系统多个成分的参与：抗原呈递细胞、T 细胞和 B 细胞，从而在癌症的临床前模型中产生持久的抗肿瘤免疫。这篇文章被收录在本期的亮点中，[p. 1497][1][1]：/lookup/volpage/20/1497?iss=9 SENTI-101定位于腹膜实体瘤，并以局部和持续的方式分泌 IL12 和 IL21。这两种有效细胞因子的表达驱动肿瘤浸润和免疫系统多个成分的参与：抗原呈递细胞、T 细胞和 B 细胞，从而在癌症的临床前模型中产生持久的抗肿瘤免疫。这篇文章被收录在本期的亮点中，[p. 1497][1][1]：/lookup/volpage/20/1497?iss=9 这篇文章被收录在本期的亮点中，[p. 1497][1][1]：/lookup/volpage/20/1497?iss=9 这篇文章被收录在本期的亮点中，[p. 1497][1][1]：/lookup/volpage/20/1497?iss=9