Rupal P Soder1, Buddhadeb Dawn2, Mark L Weiss3, Neil Dunavin4, Scott Weir5, James Mitchell1, Meizhang Li6, Leyla Shune7, Anurag K Singh7, Siddhartha Ganguly7, Marc Morrison7, Haitham Abdelhakim7, Andrew K Godwin6, Sunil Abhyankar1,7, Joseph McGuirk8. 1. Midwest Stem Cell Therapy Center, University of Kansas Medical Center, Kansas City, KS, USA. 2. University of Nevada, Las Vegas School of Medicine, Las Vegas, NV, USA. 3. Midwest Institute of Comparative Stem Cell Biotechnology and Department of Anatomy and Physiology, Kansas State University, Manhattan, KS, USA. 4. University of California, San Francisco, CA, USA. 5. Institute for Advancing Medical Innovation Medical Center, University of Kansas, Kansas City, USA. 6. Pathology & Laboratory Medicine, Univeristy of Kansas Medical Center, Kansas City, USA. 7. Blood and Marrow Transplant Program, Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, 2330 Shawnee Mission Parkway, Suite 210, Westwood, KS, 66205, USA. 8. Blood and Marrow Transplant Program, Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, 2330 Shawnee Mission Parkway, Suite 210, Westwood, KS, 66205, USA. jmcguirk@kumc.edu.
Abstract
BACKGROUND: Because of their well-described immunosuppressive properties, allogeneic adult human mesenchymal stromal cells (MSC) derived from bone marrow have demonstrated safety and efficacy in steroid refractory acute graft versus host disease (SR aGVHD). Clinical trials have resulted in variable success and an optimal source of MSC has yet to be defined. Based on the importance of maternal-fetal interface immune tolerance, extraembryonic fetal tissues, such as the umbilical cord, may provide an superior tissue source of MSC to mediate immunomodulation in aGVHD. METHODS: A two-dose cohort trial allogeneic Wharton's Jelly-derived mesenchymal stromal cells (WJMSC, referred to as MSCTC-0010, here) were tested in 10 patients with de novo high risk (HR) or SR aGVHD post allogeneic hematopoietic stem cell transplantation (allo-HCT). Following Good Manufacturing Practices isolation, expansion and cryostorage, WJMSC were thawed and administered via intravenous infusions on days 0 and 7 at one of two doses (low dose cohort, 2 × 106/kg, n = 5; high dose cohort, 10 × 106/kg, n = 5). To evaluate safety, patients were monitored for infusion related toxicity, Treatment Related Adverse Events (TRAE) til day 42, or ectopic tissue formation at day 90. Clinical responses were monitored at time points up to 180 days post infusion. Serum biomarkers ST2 and REG3α were acquired 1 day prior to first MSCTC-0010 infusion and on day 14. RESULTS: Safety was indicated, e.g., no infusion-related toxicity, no development of TRAE, nor ectopic tissue formation in either low or high dose cohort was observed. Clinical response was suggested at day 28: the overall response rate (ORR) was 70%, 4 of 10 patients had a complete response (CR) and 3 had a partial response (PR). By study day 90, the addition of escalated immunosuppressive therapy was necessary in 2 of 9 surviving patients. Day 100 and 180 post infusion survival was 90% and 60%, respectively. Serum biomarker REG3α decreased, particularly in the high dose cohort, and with REG3α decrease correlated with clinical response. CONCLUSIONS: Treatment of patients with de novo HR or SR aGVHD with low or high dose MSCTC-0010 was safe: the infusion was well-tolerated, and no TRAEs or ectopic tissue formation was observed. A clinical improvement was seen in about 70% patients, with 4 of 10 showing a complete response that may have been attributable to MSCTC-0010 infusions. These observations indicate safety of two different doses of MSCTC-0010, and suggest that the 10 × 106 cells/ kg dose be tested in an expanded randomized, controlled Phase 2 trial. Graphical abstract.
BACKGROUND: Because of their well-described immunosuppressive properties, allogeneic adult human mesenchymal stromal cells (MSC) derived from bone marrow have demonstrated safety and efficacy in steroid refractory acute graft versus host disease (SR aGVHD). Clinical trials have resulted in variable success and an optimal source of MSC has yet to be defined. Based on the importance of maternal-fetal interface immune tolerance, extraembryonic fetal tissues, such as the umbilical cord, may provide an superior tissue source of MSC to mediate immunomodulation in aGVHD. METHODS: A two-dose cohort trial allogeneic Wharton's Jelly-derived mesenchymal stromal cells (WJMSC, referred to as MSCTC-0010, here) were tested in 10 patients with de novo high risk (HR) or SR aGVHD post allogeneic hematopoietic stem cell transplantation (allo-HCT). Following Good Manufacturing Practices isolation, expansion and cryostorage, WJMSC were thawed and administered via intravenous infusions on days 0 and 7 at one of two doses (low dose cohort, 2 × 106/kg, n = 5; high dose cohort, 10 × 106/kg, n = 5). To evaluate safety, patients were monitored for infusion related toxicity, Treatment Related Adverse Events (TRAE) til day 42, or ectopic tissue formation at day 90. Clinical responses were monitored at time points up to 180 days post infusion. Serum biomarkers ST2 and REG3α were acquired 1 day prior to first MSCTC-0010 infusion and on day 14. RESULTS: Safety was indicated, e.g., no infusion-related toxicity, no development of TRAE, nor ectopic tissue formation in either low or high dose cohort was observed. Clinical response was suggested at day 28: the overall response rate (ORR) was 70%, 4 of 10 patients had a complete response (CR) and 3 had a partial response (PR). By study day 90, the addition of escalated immunosuppressive therapy was necessary in 2 of 9 surviving patients. Day 100 and 180 post infusion survival was 90% and 60%, respectively. Serum biomarker REG3α decreased, particularly in the high dose cohort, and with REG3α decrease correlated with clinical response. CONCLUSIONS: Treatment of patients with de novo HR or SR aGVHD with low or high dose MSCTC-0010 was safe: the infusion was well-tolerated, and no TRAEs or ectopic tissue formation was observed. A clinical improvement was seen in about 70% patients, with 4 of 10 showing a complete response that may have been attributable to MSCTC-0010 infusions. These observations indicate safety of two different doses of MSCTC-0010, and suggest that the 10 × 106 cells/ kg dose be tested in an expanded randomized, controlled Phase 2 trial. Graphical abstract.
Authors: Madan Jagasia; Mukta Arora; Mary E D Flowers; Nelson J Chao; Philip L McCarthy; Corey S Cutler; Alvaro Urbano-Ispizua; Steven Z Pavletic; Michael D Haagenson; Mei-Jie Zhang; Joseph H Antin; Brian J Bolwell; Christopher Bredeson; Jean-Yves Cahn; Mitchell Cairo; Robert Peter Gale; Vikas Gupta; Stephanie J Lee; Mark Litzow; Daniel J Weisdorf; Mary M Horowitz; Theresa Hahn Journal: Blood Date: 2011-10-18 Impact factor: 22.113
Authors: Daniel Wolff; Armin Gerbitz; Francis Ayuk; Alexander Kiani; Gerhard C Hildebrandt; Georgia B Vogelsang; Sharon Elad; Anita Lawitschka; Gerard Socie; Steven Z Pavletic; Ernst Holler; Hildegard Greinix Journal: Biol Blood Marrow Transplant Date: 2010-06-25 Impact factor: 5.742