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A Phase I Study to Evaluate Two Doses of Wharton’s Jelly-Derived Mesenchymal Stromal Cells for the Treatment of De Novo High-Risk or Steroid-Refractory Acute Graft Versus Host Disease

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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.

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Acknowledgments

We acknowledge Mary Pilcher-Cook, a legislator in the Kansas state House and Senate, for her unwavering support for umbilical cord derived mesenchymal stromal cell research. The authors thank Carol Early for her extensive assistance and insightful suggestions, careful proofreading, editing, formatting, and organization of the manuscript. Mesenchymal stromal cell research Funding: Research reported in this publication was supported by the National Cancer Institute Cancer Center Support Grant P30 CA168524. This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (# UL1TR002366). The Midwest Stem Cell Therapy Center at University of Kansas and the Midwest Institute for Comparative Stem Cell Biotechnology are supported by the State of Kansas. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or NCATS.

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Authors and Affiliations

  1. Midwest Stem Cell Therapy Center, University of Kansas Medical Center, Kansas City, KS, USA

    Rupal P. Soder, James Mitchell & Sunil Abhyankar

  2. University of Nevada, Las Vegas School of Medicine, Las Vegas, NV, USA

    Buddhadeb Dawn

  3. Midwest Institute of Comparative Stem Cell Biotechnology and Department of Anatomy and Physiology, Kansas State University, Manhattan, KS, USA

    Mark L. Weiss

  4. University of California, San Francisco, CA, USA

    Neil Dunavin

  5. Institute for Advancing Medical Innovation Medical Center, University of Kansas, Kansas City, USA

    Scott Weir

  6. Pathology & Laboratory Medicine, Univeristy of Kansas Medical Center, Kansas City, USA

    Meizhang Li & Andrew K. Godwin

  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

    Leyla Shune, Anurag K. Singh, Siddhartha Ganguly, Marc Morrison, Haitham Abdelhakim, Sunil Abhyankar & Joseph McGuirk

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Conflict of Interest

  1. 1

    Rupal P. Soder- patent for GvHD applications of WJMSCs

  2. 2

    Buddhadeb Dawn- patent for GvHD applications of WJMSCs

  3. 3

    Mark L. Weiss- patent for GvHD applications of WJMSCs

  4. 4

    Neil Dunavin- No conflicts to disclose

  5. 5

    Scott Weir- No conflicts to disclose

  6. 6

    James Mitchell- patent for GvHD applications of WJMSCs; employed and now consult for the Midwest Stem Cell Therapy Center during the development of MSCTC-0010

  7. 7

    Meizhang Li- No conflicts to disclose

  8. 8

    Leyla Shune- No conflicts to disclose

  9. 9

    Anurag K. Singh- No conflicts to disclose

  10. 10

    Siddhartha Ganguly- No conflicts to disclose

  11. 11

    Marc Morrison- No conflicts to disclose

  12. 12

    Haitham Abdelhakim- No conflicts to disclose

  13. 13

    Andrew K. Godwin- Co-Founder of Sinochips Diagnostics

  14. 14

    Sunil Abhyankar- Director of Midwest Stem Cell Therapy Center; patent for GvHD applications of WJMSCs

  15. 15

    Joseph McGuirk- patent for GvHD applications of WJMSCs

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Soder, R.P., Dawn, B., Weiss, M.L. et al. A Phase I Study to Evaluate Two Doses of Wharton’s Jelly-Derived Mesenchymal Stromal Cells for the Treatment of De Novo High-Risk or Steroid-Refractory Acute Graft Versus Host Disease. Stem Cell Rev and Rep 16, 979–991 (2020). https://doi.org/10.1007/s12015-020-10015-8

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