Experience of patients transplanted with naïve T cell depleted stem cell graft in CMUH Tzu-Ting Chen, Wen-Jyi Lo, Chiao-Lin Lin, Ching-Chan Lin, Li-Yuan Bai, Supeng Yeh, Chang-Fang Chiu Hematology and oncology, China Medical University Hospital
Transplant outcome for active leukemia is poor The outcomes were similar between different graft sources and protocols Matched Related donor (N=91) Unrelated donor (N=87) Haploidentical (N=4) 2 yr OS P value.16 (.8-.27).41 (.28-.53).3 (.16-.46).12 Better transplant protocols are needed " To maximize the number of T cells (GVL effects and infection protection) " To minimize the use of immunosuppressive agents ( GVHD) " Rapid engraftment (to avoid damage to grafts and help tolerate myeloablative regimens)
CD45RA-depleted lymphocytes can prevent GVHD without losing GVL effects T naïve! GVHD T memory! GVL p11δ inhibition à T n inhibition à Prevent GVHD, preserve GVL Human trials for high risk hematologic malignancy Haploidentical transplantation Matched related donors Cell Report 215; 1:712 71. J Clin Invest 215; 125(7):2677-89 Bone Marrow Transplant. 215 July ; 5(7): 968 977. JADIS 212; 59:59
CMUH experiences with CD45RA+ T cell-depleted stem cell transplantation
Patient characteristics Case 1 Case 2 Case 3 Age/Gender 64/F 48/M 58/F Disease ALL ALL ALL Prior Treatment HyperCVAD, MUD-PBSCT, CAR-T, Blinatumomab GRAALL 23, Blinatumomab GRAALL 23, hyper CVAD, Blinatumomab, Disease status before transplantation Transient remission Refractory Refractory Abbreviations: ALL:acute lymphoblastic leukemia; CAR-T: chimeric antigen receptor-t cell therapy; F:female; MUD- PBSCT:matched unrelated donor-peripheral blood stem cell transplantation; M:male
Protocol:CD45RA+ T cell depleted stem cell grafts Peripheral blood Target: A CD34+ cell dose of >5. 1 6 cells/kg Peripheral blood Target: CD45RA+ T cells 7.5 1 4 cells/kg Condition regimen Day 1:CD45RA+ depletion PBSC Day :CD34+ PBSC infusion Sirolimus
Treatment regimens Case 1 Case 2 Case 3 Source of stem cell Haploidentical Haploidentical MSD Conditioning regimen FM-TBI 4 BuCy2 FB3 GVHD prophylaxis Sirolimus Sirolimus Methotrexate/ cyclosporine Abbreviation: Haploidentical: haploidentical peripheral stem cell transplantation; MSD: matched sibling donor; F:fludarabin; M:melphalan; TBI:total body irradiation; Bu:Busulfan; Cy:cyclophosphamide;
Stem cell and CD45RA+ depletion grafts Case 1 Case 2 Case 3 Total CD34+ cell doses (x 1 6 /Kg) 1.6 8.91 12.71 CD34+ cell purity (%) 95.54 99.38 96.6 CD45RA depletion rate (%) 1 1 99.99 CD45RA+ cells in final product (cells/kg) <1 CD3+ cells (cells/ kgx16) 17.89 13.22 42.56
Clinical outcomes WBC engraftment (Day post transplant) Platelet engraftment (Day post transplant) Immune reconstitution syndrome Mucositis Case 1 Case 2 Case 3 1 Graft failure 12 Graft failure 1 11 Yes No No Grade 1 No No Infection No Yes No Case 1 Case 2 Case 3 agvhd No No No cgvhd No NA NA OS (days) Cause of death Death (243) PD Death (36) Pneumonia (pseudomo nas) Death (77) PD Abbreviation:aGvHD: acute graft versus host disease; cgvhd:chronic graft versus host disease; OS:overall survival; NA: no assessment; PD: progressive disease
Immune reconstitution syndrome 42 Temperature( C) 41 4 39 38 37 36 35 Methylprednisolone 1mg/kg for 5 days 4 5 6 7 8 9 1 1
Rapid immune recovery after transplantation CD4+CD3+ (%) 1 8 6 4 2 3 6 9 12 Day post transplant Case 1 CUMH(sirolimus HIT) CMUH (ATG+cyclosporine) Haplo (Dominietto A et al.) 15 18 CD8+CD3+ (%) 4 3 2 15 1 5 3 6 9 12 Day post transplant Case 1 CUMH(sirolimus HIT) CMUH (ATG+cyclosporine) Haplo (Dominietto A et al.) 15 18 B cells(%) 1 8 6 4 2 3 Case 1 HaploBM(from Ciurea et al) CUMH(sirolimus HIT) CMUH (ATG+cyclosporine) 6 9 12 Day post transplant 15 18 CD56+ CD3-cells/ μl 6 Case1 CUMH(sirolimus HIT) CMUH (ATG+cyclosporine) 4 HaploBM(from Ciurea et al) 2 Day9 post transplant
Early detection of CD45RA+CD3+ cells in refractory cases CD45RA+CD3+ (%) 75 6 45 3 15 Case 1 Case 2 (refractory & graft failure) Case 3 (refractory) Relapse " Data from Fred Hutchinson Cancer Research Center and St Jude Children s Research HospitalHospital :Naïve T cells are rare before Day 18 " Terminally effector lymphocytes?? Predepletion 3 6 9 12 15 18 Day post transplant 21 24 " Associated with disease relapse???
Conclusion: CD45 RA depleted stem cell transplantation Feasible Rapid engraftment, Short term and low dose immune suppressor Rapid immune recovery Cost Unsatisfactory outcome for active leukemia patient NK cell infusion?