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.
Author Info: (1) Research and Development, Senti Biosciences, Inc. alba.gonzalez@sentibio.com. (2) Research and Development, Senti Biosciences, Inc. (3) R&D, Second Genome (United States). (4)
Author Info: (1) Research and Development, Senti Biosciences, Inc. alba.gonzalez@sentibio.com. (2) Research and Development, Senti Biosciences, Inc. (3) R&D, Second Genome (United States). (4) Research and Development, Senti Biosciences, Inc. (5) Research and Development, Senti Biosciences, Inc. (6) Research and Development, Senti Biosciences, Inc. (7) Early Research and Development, Nutcracker Therapeutics. (8) N/A, N/A. (9) Research and Development, Senti Biosciences, Inc. (10) Technology and Operations, Senti Biosciences, Inc. (11) Research and Development, Senti Biosciences, Inc. (12) Research and Development, Senti Biosciences, Inc. (13) Research and Development, Senti Biosciences, Inc. (14) Research and Development, Senti Biosciences, Inc. (15) Research and Development, Senti Biosciences, Inc. (16) Research and Development, Senti Biosciences, Inc. (17) Research and Development, Senti Biosciences, Inc. (18) Research and Development, Senti Biosciences, Inc. (19) Research and Development, Senti Biosciences, Inc. (20) Technology and Operations, Senti Biosciences, Inc. (21) Technology and Operations, Senti Biosciences, Inc. (22) Technology and Operations, Senti Biosciences, Inc. (23) Technology and Operations, Senti Biosciences, Inc. (24) Technology and Operations, Senti Biosciences, Inc. (25) Technology and Operations, Senti Biosciences, Inc. (26) Technology and Operations, Senti Biosciences, Inc. (27) Research and Development, Senti Biosciences, Inc. (28) Research and Development, Senti Biosciences, Inc.
