<p>Supplementary Figure1 shows MSC homing to tumor and other organs in vivo using a bioluminescent reporter. Supplementary Figure 2. Characterization of tumor immune infiltrate of syngeneic preclinical intraperitoneal tumor models CT26-ip and B16F10-ip using IHC and flow cytometry. Supplementary Figure 3. Kaplan Meier Survival in B16F10-ip model comparing multiple combinations of effector cytokines expressed by MSCs. Supplementary Figure 4. Shows data supporting the construct optimization for SENTI-101 including promoter, orientation and signal sequence changes. Supplementary Figure 5. IL-21 functional validation using UO2S IL-21 receptor dimerization reporter assay. Supplementary Table 1. Shows the DNA sequence of SB00880, the lentiviral construct used to engineer SENTI-101. Supplementary Figure 6. Shows the SENTI-101 manufacturing process overview. Supplementary Figure 7. Shows supporting data for the study of pharmacokinetics and pharmacodynamics of SENTI-101. Supplementary Figure 8. Shows individual tumor burden for each mouse measured by bioluminescence imaging (BLI) after treatment with SENTI-101 or controls. Supplementary Figure 9. Percent change in mouse body weight after treatment. Supplementary Figure 10. Shows the controls and supporting data for the selective depletion of immune cell types. Supplementary Figure 11. Characterization of tumor infiltrating lymphocytes (TILs) in the B16F10-ip tumor model after treatment with mSENTI-101. Supplementary Figure 12. Anti-tumor immune response induced by SENTI-101 in CT-26ip model. Supplementary Figure 13. Shows individual tumor burden for each mouse measured by BLI after treatment with SENTI-101 and in combination with checkpoint inhibitor anti-PD-1.</p>
<div>Abstract<p>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.</p><p>Graphical abstract: SENTI-101 schematic and mechanism of action</p><p>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.</p></div>
<div>Abstract<p>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.</p><p>Graphical abstract: SENTI-101 schematic and mechanism of action</p><p>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.</p></div>
<p>Supplementary Figure1 shows MSC homing to tumor and other organs in vivo using a bioluminescent reporter. Supplementary Figure 2. Characterization of tumor immune infiltrate of syngeneic preclinical intraperitoneal tumor models CT26-ip and B16F10-ip using IHC and flow cytometry. Supplementary Figure 3. Kaplan Meier Survival in B16F10-ip model comparing multiple combinations of effector cytokines expressed by MSCs. Supplementary Figure 4. Shows data supporting the construct optimization for SENTI-101 including promoter, orientation and signal sequence changes. Supplementary Figure 5. IL-21 functional validation using UO2S IL-21 receptor dimerization reporter assay. Supplementary Table 1. Shows the DNA sequence of SB00880, the lentiviral construct used to engineer SENTI-101. Supplementary Figure 6. Shows the SENTI-101 manufacturing process overview. Supplementary Figure 7. Shows supporting data for the study of pharmacokinetics and pharmacodynamics of SENTI-101. Supplementary Figure 8. Shows individual tumor burden for each mouse measured by bioluminescence imaging (BLI) after treatment with SENTI-101 or controls. Supplementary Figure 9. Percent change in mouse body weight after treatment. Supplementary Figure 10. Shows the controls and supporting data for the selective depletion of immune cell types. Supplementary Figure 11. Characterization of tumor infiltrating lymphocytes (TILs) in the B16F10-ip tumor model after treatment with mSENTI-101. Supplementary Figure 12. Anti-tumor immune response induced by SENTI-101 in CT-26ip model. Supplementary Figure 13. Shows individual tumor burden for each mouse measured by BLI after treatment with SENTI-101 and in combination with checkpoint inhibitor anti-PD-1.</p>
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