Bone marrow-derived mesenchymal stem cells (BM-MSCs) home to solid tumors in the peritoneum. In this report, BM-MSCs engineered to express any given cytokine delivered high cytokine concentrations to the TME, even as systemic levels remained low. Several BM-MSC lines, each engineered to express a cytokine, chemokine, or TME modifier (either alone or in various combinations) were generated and tested for antitumor activity in preclinical models. The combination of IL-12 and IL-21 (activators of T and NK cells) was most effective, prompting advocacy of BM-MSCs as feasible, standardizable, and toxicity-avoiding TME delivery systems.
Contributed by Margot O’Toole
ABSTRACT: Advanced peritoneal carcinomatosis including high-grade ovarian cancer has poor prognosis 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 (or Stem) cells (MSCs) that are engineered to express two potent immune-modulatory cytokines, IL-12 and IL-21. 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 anti-tumor activity when compared to 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 anti-tumor 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 anti-tumor response. Collectively, these data warrant potential clinical development of SENTI-101 for patients with peritoneal carcinomatosis and high-grade ovarian cancer.