ASH 2011 aktualijos: MSC TPŠL gydyme. Mindaugas Stoškus VULSK HOTC MRMS

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1 ASH 2011 aktualijos: MSC TPŠL gydyme Mindaugas Stoškus VULSK HOTC MRMS

2 #3042. Yukiyasu Ozawa et al. Mesenchymal Stem Cells As a Treatment for Steroid-Resistant Acute Graft Versus Host Disease (agvhd); A Multicenter Phase I/II Study

3 #3042. Yukiyasu Ozawa et al. Rationale: Severe graft versus host disease (GVHD) remains a lifethreatening complication after allogeneic stem cell transplantation Especially, it is very difficult to treat steroid-resistant GVHD. Mesenchymal stem cells (MSCs) have a homing activity to inflammatory sites and modulate immune response MSCs might be effective for refractory agvhd. Recently, clinical studies have suggested that MSC infusion can also reduce the severity of GVHD.

4 #3042. Patients N=14. From January 2009 to November Age median age was 52 years old (range: 4-62) Gender Male (n=5) and Female (n=9) Disease status 9 pts with grade II agvhd 5 pts with grade III agvhd 0 pts with grade IV agvhd

5 #3042. MSC MSC source: derived from bone marrow of healthy volunteers and expanded in vitro MSC dosage: Twice a week for 4 weeks. All patients received 2 x 10 6 cells/kg of MSCs for each infusion. Patients with PR after 4 weeks were given continued weekly MSCs infusion for an additional 4 weeks.

6 #3042. Results 13/14 of pts (92.9%) responded to MSCs, achieving remmissions 4 weeks after treatment: CR (n=8) PR (n=5) 4. 11/14 of pts (78.6%) survived 24 weeks after treatment. 7/14 of pts (50%) showed severe adverse effects including thrombocytopenia, neutropenia and hepatic dysfunction. No patients had severe infections which was shown by existing salvage therapy for agvhd.

7 #3042. Conclusions Prognosis of steroid-resistant agvhd was poor, and the most effective salvage therapy remains to be clarified. This study shows that in vitro expanded MSCs might be a safe and effective salvage therapy for patients with steroid-resistant agvhd

8 #1907. Auletta JJ et al Human Mesenchymal Stem Cells Attenuate Graft-Versus-Host Disease and Maintain Graft- Versus-Leukemia in Murine Allogeneic Bone Marrow Transplantation

9 #1907. Rationale Defining in vivo effects and biodistribution of human bone marrow-derived hmscs following allobmt could impact the clinical utility of MSC therapy for the prevention and treatment of GvHD.

10 #1907. Objectives Definition of hmsc effects on GvHD and GvL activity using an established model of murine allobmt.

11 #1907. hmsc could modulate in vitro T-cell reactivity hmscs added to mixed leukocyte cultures (MLCs) significantly reduced T-cell proliferation in a concentration-dependent manner distinct from human fibroblasts. In contrast to MLC cultures alone, MLCs containing hmscs had significant reduction in TNFα, IFNγ, and IL-10 levels and higher levels of PGE2 and TGFβ1.

12 #1907. hmsc could modulate in vitro T-cell reactivity Modulation in the inflammatory milieu was associated with changes in T-cell phenotypes, including: more naïve and less activated T-cell surface marker expression (CD62L + CD69 - ) induction of CD4 + CD25 + FoxP3 + T-regulatory cells.

13 #1907. hmscs could modulate in vivo mt-cell alloreactivity Irradiated recipient B6D2F1 (H-2 bxd ) mice transplanted with: allogeneic C57BL/6 (H-2 b ) BM and purified splenic T- cells (B6 B6D2F1) Then, these mice were tail-vein injected with hmsc infusions (1x10 6 per injection) on Days 1 and 4 post-tx. Syngeneic transplant recipients (B6D2F1 B6D2F1) were used as controls.

14 #1907. hmscs could modulate in vivo mt-cell alloreactivity hmsc-treated vs. untreated allobmt mice mice had: Significantly prolonged survival Improved clinical GvHD scores Reduced splenic T-cell expansion and TNFα and IFNγ-producing T-cells Lower circulating TNFα and IFNγ levels

15 #1907. Redistribution of hmscs Bioluminescence imaging showed redistribution of labeled hmscs from the lungs to abdominal organs within 72 hours following infusion. GvHD target tissues (small and large bowel and liver) harvested from hmsc-treated allobmt mice had significantly lower GvHD pathology scores than untreated allobmt mice.

16 #1907. Effect of hmscs on GVL activity Effects of hmscs on GvL activity was assessed using the murine mastocytoma cell line, P815 (H-2 d ). T-cells co-cultured with hmscs maintained potent in vitro cytotoxic T-lymphocyte (CTL) activity comparable to untreated control CTLs. After challenge with P815 tumor cells hmscs-treated mice had: less severe GvHD Eradication of tumor burden Improved leukemia-free survival

17 #1907. hmsc effects might be mediated through PGE2 Indomethacin (IM) added to MLC-hMSC cocultures significantly reversed attenuation in: Murine T-cell alloreactivity Surface activation expression. IM administered to hmsc-treated allobmt mice reversed hmsc-associated survival advantage, suggesting: that PGE2 in part mediates hmsc immunomodulatory effects.

18 #1907 Conclusions Conclusions: Results show that hmsc infusions effectively attenuate GvHD and maintain GvL potency in allobmt mice and reveal potential biomarkers and mechanisms of action underlying hmsc effects.

19 #3046. te Boome et al Treatment of Steroid Resistant Grade II to IV Acute Gvhd by Infusion of Mesenchymal Stroma Cells Expanded with Human Plasma and Platelet Lysate - a Phase I/II Study

20 #3046. Rationale For numerous malignant and non-malignant hematological diseases allogeneic HSC Tx is the only curative therapy. However, a major complication is the acute graft versus host disease (agvhd), which is life-threatening and substantially reduces efficacy of HSCT. In particular, the outcome for patients with severe steroid-resistant agvhd is very poor. Therefore, it remains important to search for new therapeutic strategies for the treatment of agvhd.

21 #3046. Ojectives Feasibility of the generation mesenchymal stroma cells (MSCs) expanded with human plasma and platelet lysate (hppl) Feasibility and safety of the application of MSCs in patients with steroid-refractory extensive agvhd.

22 #3046. Study design An open-label, non-randomized prospective phase I/II study. MSCs were extracted from the bone marrow of healthy volunteers, expanded with human plasma and platelet lysate (hppl), and stored. Patients with steroid-refractory extensive agvhd were treated with ~2x10 6 /kg MSC. Response rate, transplantation-related deaths, and other adverse events were assessed for up to 12 months after the last infusion of the cells.

23 #3046. Results Between Jan and Dec. 2010, 18 patients were treated. 5 children and 13 adults, median age was 32.5 years (range ). Organ involvement of the agvhd was 67% skin, 83% gastro-intestinal and 28% liver. Overall grade was II for 4 (22%), III for 13 (72%), and IV for 1( 6%) patients.

24 #3046. Results 1 patient received one infusion. All other patients received two or more infusions. No patient had side-effects during or immediately after infusions of the MSC. Median follow-up was 5.5 months (range ).

25 #3046. Results Complete overall response was observed in 11 (61%) patients after a median of 65 days (range days). The overall survival was significant better (p <0.001) compared to non-responders.

26 #3046. Results Of the 11 patients who reached a CR, 8 relapsed median 59 days (1-244) after reaching CR: 3 children with subsequently limited cgvhd, allo immune lung and auto-immune cytopenia. 5 adults with all relapse GVHD of the gut, median 98 days ( days). However, GVHD of the gut was then sensitive for the treatment with steroids. Overall, 7 patients died, 4 due to progression of agvhd, 1 patient due to abdominal bleeding and 2 due to sepsis.

27 #3046. Conclusions Generation and infusion of MSCs in steroidresistant agvhd grade II- IV is a feasible, safe and very effective. Patients who initially responded to MSCs but develop later a relapse of agvhd during tapering or cessation of immunosuppressive drugs become again sensitive to the treatment with steroids.

28 #4086. Lai et al Selective Targeting of B Cells with Mesenchymal Stromal Cells Treatment Is An Efficacious Strategy for Cutaneous cgvhd

29 #4086. Rationale Cutaneous cgvhd is an increasingly common complication in long term survivors of hematopoietic stem cell transplantation, but currently available therapies have demonstrated limited efficacy. MSCs have been reported to be effective in various immune-mediated disease models, but their therapeutic potentials in cutaneous cgvhd have not been determined.

30 #4086. Methods 23 patients enrolled suffering from cutaneous cgvhd who had failed to respond to conventional immunosuppressive therapy or relapsed after reduction of prednisone. They received intravenous in vitro expanded bone marrow (BM)-derived MSCs. The median follow-up period was 90 days (range days).

31 #4086. Methods The dermal manifestations of cgvhd were monitored, and a score was given to the cutaneous response by the physician. B lymphocyte subsets and ratio of CD4/CD8 were detected by flow cytometry before the first and after the last MSC infusion. Plasma levels of TNF-α, sicam-1 and Th1 or Th2 factors, including IL-2 and IL-4, were measured by enzyme-linked immunosorbent assay (ELISA).

32 #4086. Results Nineteen patients (82.61%) had skin symptom abatement after MSCs treatment with the skin scores improved according to the NIH criteria. Most patients had healing of skin ulceration, regression on skin findings and increased flexibility of involved joint. Steroid sparing or discontinuation of immunosuppressive medications was possible in all of the patients.

33 #4086. Results Clinical improvement was accompanied by increasing levels of CD19 + CD5 + B cells and elevated ratio of CD4/CD8. In addition, after the last MSCs treatment, the patients had significantly higher levels of IL-2 compared to before the first MSC infusion, while they had lower levels of TNF-α, sicam-1 and IL-4.

34 #4086. Conclusions MSCs infusion represents an effective treatment option for cutaneous cgvhd. MSCs alter allo-reactivity by: affecting CD19 + CD5 + B cells possibly normalize the ratio of CD4/CD8 and Th1/Th2 decreased the level of proinflammatory cytokine TNF-α and proadhesive cytokine sicam-1. Study demonstrates CD19 + CD5 + B cells could be a possible target for therapeutic intervention in cutaneous cgvhd.