Mesenchymal Stromal Cells for Graft-versus-Host Disease: A Trilogy

This issue of the journal showcases 3 clinical trials [1Kebriaei P. Hayes J. Daly A. et al.A phase 3 randomized study of remestemcel-l versus placebo added to second-line therapy in patients with steroid-refractory acute graft-versus-host disease.Biol Blood Marrow Transplant. 2020; 26: 835-844Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 2Kurtzberg J. Prockop S. Chaudhury S. et al.Study 275: updated expanded access program for remestemcel-l in steroid-refractory acute graft-versus-host disease in children.Biol Blood Marrow Transplant. 2020; 26: 855-864Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 3Kurtzberg J. Abdel-Azim H. Carpenter P. et al.A phase 3, single-arm, prospective study of remestemcel-l, ex vivo culture-expanded adult human mesenchymal stromal cells for the treatment of pediatric patients who failed to respond to steroid treatment for acute graft-versus-host disease.Biol Blood Marrow Transplant. 2020; 26: 845-854Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar], each focused on testing the utility of industrially sourced culture-adapted allogeneic mesenchymal stromal cells (MSCs; remestemcel-L) as a transfusion product to improve the outcome of steroid-refractory acute graft-versus-host disease (GHVD). Culture-adapted bone marrow (BM)-derived MSCs compose a polyclonal population of stromal cells with regenerative and immunomodulatory properties that buttress their clinical study as cellular pharmaceuticals [4Galipeau J. Sensébé L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities.Cell Stem Cell. 2018; 22: 824-833Abstract Full Text Full Text PDF PubMed Scopus (848) Google Scholar]. These culture-adapted MSCs will replicate vigorously in vitro as long as they are maintained in serum and display robust, predominantly paracrine anti-inflammatory, angiogenic, and bystander regenerative cell physiological properties [5Ferreira J.R. Teixeira G.Q. Santos S.G. Barbosa M.A. Almeida-Porada G. Gonçalves R.M. Mesenchymal stromal cell secretome: influencing therapeutic potential by cellular pre-conditioning.Front Immunol. 2018; 9: 2837Crossref PubMed Scopus (255) Google Scholar]. These effects arise from a matrix of cell physiological interactions involving a spectrum of small molecules, peptides, chemokines, cytokines, morphogens, and exosomes, reflecting in part their tissue endogenous role as marrow niche cells [6Wang Y Chen X. Cao W. Shi Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications.Nat Immunol. 2014; 15: 1009-1016Crossref PubMed Scopus (921) Google Scholar]. The translational human use of BM-MSCs as a cellular pharmaceutical was inaugurated in 1995 with the first published clinical trial of i.v. BM-MSCs in the setting of autologous peripheral hematopoietic stem cell transplantation (HSCT) with the aim of accelerating hematopoietic recovery [7Lazarus H.M. Haynesworth S.E. Gerson S.L. Rosenthal N.S. Caplan A.I. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use.Bone Marrow Transplant. 1995; 16: 557-564PubMed Google Scholar]. The discovery of MSCs' ability to profoundly affect the functionality of bystander innate and adaptive immune cells [8Bernardo M.E. Fibbe W.E. Mesenchymal stromal cells: sensors and switchers of inflammation.Cell Stem Cell. 2013; 13: 392-402Abstract Full Text Full Text PDF PubMed Scopus (948) Google Scholar] and this biological feature plausibly allowed reversal of steroid resistant acute GVHD, as first described in a case report and later validated in a well-designed phase II European trial [9Le Blanc K. Frassoni F. Ball L. et al.Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study.Lancet. 2008; 371: 1579-1586Abstract Full Text Full Text PDF PubMed Scopus (2183) Google Scholar]. In May 2009, Osiris Therapeutics (Columbia, MD) completed the first major industry-sponsored phase III trial of allogeneic, marrow-derived MSCs (remestemcel-L) for treating steroid-refractory acute GVHD (ClinicalTrials.gov identifier NCT00366145). The original clinical trial results had been presented as a society meeting abstract [10Martin P.J. Uberti J.P. Soiffer R.J. et al.Prochymal improves response rates in patients with steroid-refractory acute graft versus host disease (SR-GVHD) involving the liver and gut: results of a randomized, placebo-controlled, multicenter phase III trial in GVHD.Biol Blood Marrow Transplant. 2010; 16: S169-S170Abstract Full Text Full Text PDF Google Scholar], and now, 11 years later, the final published report is presented in this issue by Kebriaei et al [1Kebriaei P. Hayes J. Daly A. et al.A phase 3 randomized study of remestemcel-l versus placebo added to second-line therapy in patients with steroid-refractory acute graft-versus-host disease.Biol Blood Marrow Transplant. 2020; 26: 835-844Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. The MSCs were sourced from normal volunteers from whom up to 10,000 doses were manufactured per donor. The ensuing cryobanked product, remestemcel-L (Prochymal), was thawed, and multiple doses were transfused at the point of care in eligible adult and pediatric patients with steroid-refractory acute GVHD. The study did not meet the primary endpoint of durable complete response lasting at least 28 days on the intent-to-treat population versus placebo (35% versus 30%; P = .42). In the original unsuccessful industry-sponsored placebo-controlled study of Prochymal for treatment of steroid-resistant GVHD (ClinicalTrials.gov identifier NCT00366145), both children and adults with any grade B-D GVHD were treated if steroid-resistant for at least 3 days for up to 14 days. However, post hoc analysis showed that pediatric patients or those with liver involvement fared better, which informed an expanded access program for remestemcel-L (ClinicalTrials.gov identifier NCT00759018). Kurtzberg et al [2Kurtzberg J. Prockop S. Chaudhury S. et al.Study 275: updated expanded access program for remestemcel-l in steroid-refractory acute graft-versus-host disease in children.Biol Blood Marrow Transplant. 2020; 26: 855-864Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar] present the outcome of this 241 patient case series enrolled over 8 years between 2007 and 2015. Distinct from the original negative-outcome phase III study, only children were enrolled, and the definitions of response endpoints were modified (Table 1). The day 28 overall response rate was 65.1% (14.1% complete response [CR] and 51.3% partial response [PR]), and day 100 survival was predicted by an objective response at day 28.Table 1Design comparison of clinical trials of Remestemcel-L for steroid resistant acute GvHDCharacteristicStudyNCT00366145NCT00759018NCT02336230SponsorOsiris TherapeuticsMesoblastCell dosing2 × 106 cells/kg twice weekly for 4 wkPrimary outcomeComplete GVHD response of ≥28 d durationOverall GVHD response rate at day 28, to include both CR and PR:• CR: resolution of GVHD in all involved organs• PR: organ improvement by at least 1 stage without worsening of any other organTarget enrollment240241 (open access)60Ages eligible6 mo to 70 yr2 mo and 17 yrGVHD grade at enrollmentAny grade B-D (IBMTR grading) of acute GVHD• Grade C or D GVHD involving the skin, liver, and/or GI tract• Grade B GVHD involving the liver and/or GI tract, with or without concomitant skin disease• Exclusion: Grade B GVHD with skin-only involvementDefinition of steroid- refractoryNo improvement after 3 d and duration no longer than 2 wkNo improvement after 3 dProgression within 3 d or no improvement within 7 consecutive dStudy sites705023CompletedMay 2009March 2015February 2018Meaningful study design adaptations relative to NCT00366145 are in bold type.IBMTR indicates International Bone Marrow Transplant Registry; GI, gastrointestinal. Open table in a new tab Meaningful study design adaptations relative to NCT00366145 are in bold type. IBMTR indicates International Bone Marrow Transplant Registry; GI, gastrointestinal. In 2013, the Prochymal assets were divested from Osiris Therapeutics to Mesoblast (Melbourne, Australia), which sponsored an open-label, single-arm Phase III study examining the use of remestemcel-L for pediatric GVHD (ClinicalTrials.gov identifier NCT02336230). The adaptive clinical trial design from the original use of MSCs for GVHD (NCT00366145), the follow-on expanded-access case series (NCT00759018) to the recently completed phase III study of MSCs in pediatric GVHD (NCT02336230), provides important insight into the importance of empirical clinical observation informing selective patient enrollment to meet primary clinical endpoints. These data likely informed an adaptive clinical trial design for NCT02336230 in which an identical MSC product and dosing scheme was maintained across all studies but the definition of response, age of inclusion, severity of disease, and exclusion of skin-only GvHD, as well as a more aggressive start time for MSC transfusion, were implemented (Table 1). The latest Mesoblast-sponsored study of BM-MSCs in pediatric GVHD completed recruitment in December 2017. In February 2018, it was announced by press release that the study had successfully met the primary endpoint of an improved day 28 overall response rate in steroid-refractory pediatric subjects with severe disease. The day 28 overall response rate was 69%, a significantly improvement (P= .0003) over the protocol-defined historical control rate of 45%, and the effect was sustained at day 180. The results of this study by Kurtzberg et al [3Kurtzberg J. Abdel-Azim H. Carpenter P. et al.A phase 3, single-arm, prospective study of remestemcel-l, ex vivo culture-expanded adult human mesenchymal stromal cells for the treatment of pediatric patients who failed to respond to steroid treatment for acute graft-versus-host disease.Biol Blood Marrow Transplant. 2020; 26: 845-854Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar] are presented in this issue. A subset analysis of pediatric subjects enrolled in the original study completed in 2009 (NCT00366145) suggested that children with GVHD are responsive to remestemcel-L. On this basis, on May 17, 2012, Health Canada issued marketing approval for Prochymal to treat children with acute GVHD. Health Canada approved the drug via a Notice of Compliance with Conditions (NOC/c), which allows certain drugs onto the market without full efficacy data. However, following the transfer of Prochymal assets from Osiris to Mesoblast in 2013, the drug was never distributed on a reimbursement basis in Canada. In the intervening period, using technology licensed-in from Osiris, JCR Pharmaceuticals (Ashiya, Japan) developed TEMCELL for the treatment of acute GVHD. On September 15, 2015, JCR reported that the Japanese Ministry of Labor and Welfare had approved TEMCELL for acute GVHD. Therefore, with the exception of Japan and its approval of MSCs for acute GVHD, remestemcel-L remained available solely through clinical trial mechanisms for all indications in other major regulatory jurisdictions, including North America and Europe. However, the outcome of the most recent NCT02336230 phase 3 study is informing a formal Food and Drug Administration (FDA) Biologics License Application (BLA) application by Mesoblast. Indeed, on January 31 2020, Mesoblast announced submission of a completed BLA to the FDA for Ryoncil (remestemcel-L) to treat children with steroid-refractory acute GVHD. The clinical submission included analyses of 309 children with GVHD who received Ryoncil across the 3 separate studies reported herein. Mesoblast provided data in control pediatric subjects from the contemporaneous database of the Mount Sinai Acute GVHD International Consortium (MAGIC) to provide an unbiased and independent estimate of response rates and outcomes in matched pediatric control patients treated with institutional standard of care (http://investorsmedia.mesoblast.com/static-files/a46fe164-22f3-4272-a72f-58cff648d950). In Mesoblast's open-label Phase III trial of remestemcel-L in 55 children with GVHD, the primary endpoint of day 28 overall response was compared between children given remestemcel-L and a control group of 30 pediatric patients with GVHD from the MAGIC consortium matched for inclusion criteria and disease severity. In the MAGIC controls, day 28 overall response was 43%, and day 100 survival was 57%. The company has requested a priority review of the BLA by the FDA under the product candidate's existing fast track designation for steroid-resistant acute GVHD. If approved, Ryoncil is expected to be launched in the United States in 2020. Rigorous, peer-reviewed scientific inquiry and well-designed, regulator-compliant clinical trials can provide translational insights that may well demonstrate a useful role for MSCs in disorders with unmet medical needs, including GVHD and others [11Phinney D.G. Galipeau J. Krampera M. Martin I. Shi Y. Sensebe L. MSCs: science and trials.Nat Med. 2013; 19: 812Crossref PubMed Scopus (36) Google Scholar, 12Galipeau J. The mesenchymal stromal cells dilemma—does a negative phase III trial of random donor mesenchymal stromal cells in steroid-resistant graft-versus-host disease represent a death knell or a bump in the road?.Cytotherapy. 2013; 15: 2-8Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar, 13Fibbe W.E. Dazzi F. LeBlanc K. MSCs: science and trials.Nat Med. 2013; 19: 812-813Crossref PubMed Scopus (12) Google Scholar]. Indeed, in March 2018, the European Commission approved the first MSC pharmaceutical derived from allogeneic adipose-derived MSCs (Alofisel) to treat Crohn's disease-related enterocutaneous fistular disease [14Panés J. García-Olmo D. Van Assche G. et al.Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial.Lancet. 2016; 388: 1281-1290Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar]. After more than a decade of clinical study involving 3 distinct advanced trials, it appears that remestemcel-L, the allogeneic marrow-derived MSCs first developed by Osiris, may well have finally met the FDA's requirements for marketing approval in the United States for acute steroid-refractory GVHD in children as pursued by Mesoblast. Whether this industrial MSC product will find utility for adults with acute GVHD or other indications remains to be determined.

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