Ignite Creation Date:
2024-05-06 @ 6:29 PM
Last Modification Date:
2024-10-26 @ 2:49 PM
Study NCT ID:
NCT05686538
Status:
RECRUITING
Last Update Posted:
2024-04-10
First Post:
2022-12-20
Brief Title:
Innate Donor Effector Allogeneic Lymphocyte Infusion After Stem Cell Transplantation the IDEAL Trial
Sponsor:
Rigshospitalet Denmark
Organization:
Rigshospitalet Denmark
Study Overview
Official Title:
Innate Donor Effector Allogeneic Lymphocyte Infusion After Stem Cell Transplantation The IDEAL Trial
Status:
RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
IDEAL
Brief Summary:
The curative principle behind allogeneic hematopoietic stem cell transplantation HSCT is eradication of the malignant cells of the patient recipient by donor graft cells a process termed graft-versus-leukemia GVL effect GVL is traditionally mediated by donor αβ T cells in an immunological process driven by genetical differences between individuals ie an allogeneic response For this reason αβ T cells also cause an unwanted and dangerous complication of HSCT called graft-versus-host disease GVHD in which healthy recipient cells are targeted by donor cells with great risk of morbidity and mortality to the patient In addition to αβ T cells other cells from the donor stem cell graft termed innate effector lymphocytes can contribute to the GVL effect These are termed natural killer NK cells and T-cell receptor TCR γδ cells the latter being a subset of T cells NK and TCR γδ cells can recognize and eliminate leukemic cells in a direct tumor response independent of conventional allogeneicity Therefore opposite αβ T cells innate effector lymphocytes cells can mediate GVL but are not likely to cause GVHD The main indications for HSCT in adults are acute myeloid leukemia AML and myelodysplastic syndrome MDS Approximately 50 of AMLMDS transplant patients experience significant acute GVHD and 30 experience relapse of the malignant disease Prospective clinical studies from the research group of the investigators have shown that patients with high doses of innate lymphocytes in stem cell grafts and during early immune reconstitution after HSCT have a reduced risk of both GVHD and relapse The aim of this clinical trial is therefore to administer innate donor lymphocyte infusion iDLI enriched in NK and TCR γδ cells and depleted of αβ T cells in patients early after HSCT By improving the HSCT procedure with iDLI cell therapy the scope is less GVHD and less relapse of the malignant disease and thereby improved survival and life quality in AMLMDS patients
Detailed Description:
PROJECT DESCRIPTION PURPOSE To address whether transplant outcomes in patients treated with HSCT for AMLMDS can be improved by addition of innate donor lymphocyte infusion iDLI early after transplantation The primary outcomes are acute GVHD relapse and relapse-free survival after HSCT
BACKGROUND Allogeneic hematopoietic stem cell transplantation HSCT is a potential curative treatment for malignant hematologic diseases The main indication for HSCT in adults is acute leukemia followed by myelodysplastic syndrome In HSCT the bone marrow and immune system of the patient is replaced with that from a donor during an extensive clinical procedure carried out in a highly specialized transplant center The curable principle of HSCT is an immune-based cell-to-cell killing of residual leukemic cells mediated by donor cells termed the graft-versus-leukemia GVL effect
The basic principles of HSCT are given below
Conditioning regimen Prior to donor graft infusion a conditioning regimen is given in order to reduce the tumor burden and weaken the recipient immune system to allow engraftment of donor cells The conditioning regimen can contain different degrees of myeloablation depending on the desired grade of immune suppression suitable for the disease patient age and comorbidity
Stem cell donors and grafts The stem cell graft is most often obtained from an HLA-matched sibling 25 of patients or an HLA-matched unrelated register donor
The graft is obtained from the donor either by aspiration of bone marrow or by leukapheresis cell separation and removal of leucocytes from the remaining blood after administration of granulocyte-colony stimulating factor G-CSF which mobilizes stem cells to the blood The latter is known as a peripheral blood stem cell PBSC graft and is by far the most common graft type used in current era
Graft contents and patient immune reconstitution The stem cell graft contains stem cells that establish donor derived hematopoiesis including a functional immune system in the patient but also mature immune cells responsible for early elimination of residual tumor cells through the graft-versus-leukemia GVL effect Immune reconstitution is dependent on the dose and contents of the transplanted donor cells and both the graft contents and patient immune reconstitution is crucial for the overall outcome of the transplantation
GVL and GVHD The GVL effect is carried out by lymphocytotoxic donor cells that kill residual malignant cells of the patient GVL is traditionally mediated by donor αβ T cells in an immunological process driven by HLA-differences between individuals ie an allogeneic response
In acute graft versus-host-disease GVHD also involving HLA allo-recognition donor αβ T cells attack the normal tissue in skin liver and gastro-intestinal system of the recipient leading to a potential deadly immune disease Acute GVHD occurs during the first 3 months after HSCT and the clinical course is highly variable from a mild curable presentation to a full-blown immune attack which is fatal in 80-90 of the patients fig 2 Acute GVHD is seen in 40-60 of the patients
Relapse after HSCT Relapse of the hematologic cancer after HSCT is a major cause of mortality In patients with AMLMDS approximately 30 experience disease recurrence after HSCT The prognosis in patients relapsed after HSCT is dismal
Donor lymphocyte infusion In order to prevent relapse or treat manifest relapse after HSCT a dose of additional cells from the original stem cell donors donor lymphocyte infusion DLI can be infused into the patient with the purpose of initiating a renewedboosted GVL effect and eradicate remaining malignant cells However the effect on the leukemic cells of conventional DLI containing primarily TCR αβ cells from the donor is uncertain and limited by the risk of lethal GVHD why new methods of DLI are constantly under development
Natural killer cells and T-cell receptor γδ cells During recent years natural killer NK cells and T-cell receptor TCR γδ cells also termed innate effector cells have proven capable of eliminating cancer cells and thereby contributing to the GVL-effect in HSCT NK cells are innate lymphocytes comprising approximately 10 of all lymphocytes and purposed to eradicate stressed malignant and virus-infected cells They are able to lyse and eliminate tumor cells of leukemia through activating receptors of the natural killer NK and natural cytotoxicity receptor NCR families independent of HLA disparities
T cells of the TCR αβ type CD4 and CD8 T cells comprise the majority of all circulating T cells and lymphocytes in general TCR γδ cells are a subgroup of T cells different from αβ T cells which constitute approximately 5 of all T cells The repertoire of TCR γδ cell functions combine features of the adoptive immune system with innate-like responses They are involved in control of inflammation fighting of pathogens and maintaining tolerance towards self-antigens TCR γδ are also capable of recognizing tumor cells through their TCR and activating receptors shared with NK cells eg NKG2D and their anti-tumor effects are being increasingly documented against leukemic cells NK and TCR γδ cell recognition is independent of HLA-disparities making their contribution to GVHD less likely and their immunoregulatory features may actually protect against GVHD These innate effector cells therefore have the potential to mediate GVL without GVHD in the HSCT setting
Results from the research group of the investigators
Under this hypothesis our group conducted a prospective clinical study throughout 2015-2018 investigating concentrations of NK and TCR γδ cells in stem cell grafts and during immune reconstitution early after transplantation and associated these with patient outcomes in terms of GVHD relapse and relapse-free survival Results showed that patients transplanted with high doses of NK cells in the graft and high concentrations of NK cells in peripheral blood early after transplantation day 28 and 56 had significantly improved relapse-free survival compared to patients with low transplant doses and early post-transplant concentrations of NK cells Regarding TCR γδ cells patients with high concentration of TCR γδ cells in peripheral blood early day 28 and 56 after transplantation has significantly less GVHD and less relapse resulting in improved overall survival and relapse-free survival compared to patients with low post-transplant TCR γδ cell concentrations
Based on these results and existing literature the aim of this study is infusion of an innate DLI iDLI containing purified NK and TCR γδ cell from the original stem cell donor early after HSCT The expected effect of additional cell therapy with these innate effector cells during early immune reconstitution are reduced relapse as well as GVHD rates and thereby improved outcomes after HSCT in AMLMDS patients
Procedure This is a collaborative project between the Bone Marrow Transplant Unit at the Department of Hematology and the Department of Clinical Immunology at Rigshospitalet Copenhagen University Hospital
Approximately 60 patients per year receive PBSC-HSCT for the diagnoses of AML or MDS at our center One out of four patients has an HLA-identical sibling while the remaining patients receive stem cell grafts from matched unrelated donors from international donor registries For this study genetic randomization will be applied so that patients with HLA-identical siblings will be included for intervention while patients with unrelated donors receiving a standard-HSCT will be included in the control group The background for the design is donor availability only sibling donors can be recruited to donate iDLI With an estimated recruiting rate of approximately 85 13-15 patientdonor pairs in the intervention group are expected to be enrolled per year over a total of three years giving at total of 39-45 pairs In a previous prospective study the investigators obtained a recruiting rate of 97 Historically a higher incidence of GVHD was observed in transplants using an unrelated donor but due to more precise HLA-typing and better protocols for immune suppression GVHD and relapse incidence are nowadays comparable between related and unrelated transplants This is also the case at the transplant center at Rigshospitalet as previously published6
For intervention
Donors will undergo health screening at the Cell Therapy Facility Department of Clinical Immunology within 30 days before donation standard procedure Day 7 before HSCT Start of the conditioning regimen preparing the patient for HSCT standard procedure Day 5 before HSCT Start of G-CSF stimulation of the donor in order to mobilize stem cells for leukapheresis standard procedure
Donor leukapheresis and graft infusion to the patients termed day 0 of HSCT standard procedure Day 14 after HSCT donor leukapheresis without preceding G-CSF stimulation product manipulation and transfusion of iDLI to the patient intervention
Control group Standard HSCT-procedure as described above in patients receiving grafts from unrelated donors
Procedure of modified DLI iDLI
White blood cells are obtained from the donor by leukapheresis using the Spectra Optia Apheresis System Terumo BCT at the Blood Bank Unit Department of Clinical Immunology Rigshospitalet Purification of innate effector cells is carried out by TCRαβCD19-depletion of the fresh leukapheresis product with the CliniMACS Prodigy System Miltenyi Biotec This procedure removes TCRαβ T cells together with B-cells CD19positive cells rendering a cell product enriched in NK cells and TCR γδ cells and is routinely used at Rigshospitalet for procedures involved in pediatric transplantations
The intended dose of harvested cells is 108 lymphocyteskg resulting in expected cell doses of 107 NK cellskg and 1-5 x106 TCR γδ cellskg after the depletion The iDLI product is freshly infused into the patient at the Department of Hematology shortly after the depletion procedure
Immune phenotyping
Immune phenotyping of the iDLI product as well as the original stem cell graft will be performed using a highly standardized customer designed freeze dried flowcytometry panel DuraClone product from Beckman Coulter developed and routinely used for immune function monitoring at the Department of Clinical Immunology Two tubes will be included for detailed lymphocyte phenotyping in this study
Tube 1 includes markers of overall T cells CD3 CD4 CD8 NK cell subtypes CD16 CD56 B cells CD19 and monocytes CD14 Tube 2 includes markers of overall TCR αβ cells overall TCR γδ cells the two main TCR γδ subtypes TCR Vδ1 TCR Vδ2 and TCR γδ cell activation markers HLA-DR CD8 CD8beta
The same panel will be used for characterization of immune reconstitution in peripheral blood samples in patients at the day of iDLI infusion and 14 and 21 days hereafter ie day 14 28 and 56 after transplantation Viable cells will be cryopreserved for later functional studies
Data management plan Clinical data on patient and transplant outcomes will be acquired from the clinical transplant database IBMTR 2019 situated and administrated at the Transplant Unit Department of Hematology Flowcytometry data from characterization of iDLI products stem cell grafts and patient immune reconstitution will be acquired from the Department of Clinical Immunology and processed by appropriate analysis software Kaluza Flow Cytometry Analysis Software Beckman Coulter Clinical and laboratory data will be assembled structured and processed in SPSS SPSS Statistics IBM witch together with R The R Project for Statistical Computing wwwr-projectorg will be used for statistical analyses All data will be stored at Rigshospitalet Copenhagen University Hospital in accordance with data protection rules of The Danish Data Protection Agency
Statistical Analyses The cumulative incidence of acute GVHD and relapse in patients treated with iDLI compared to patients receiving a standard HSCT will be compared used Grays competing risk analysis Relapse-free survival between the two groups will be compared using the Kaplan Meier survival analysis and Cox proportional hazard models Cell doses and immune phenotyping of iDLI and original stem cells grafts and cell concentrations and phenotyping during patient immune reconstitution will be entered using descriptive statistics SPSS SPSS Statistics IBM and R The R Project for Statistical Computing wwwr-projectorg will be applied for statistical computing
Power Based on results from previous study from the investigators research group describing GVHD relapse and relapse-free survival in patients with high versus low doses of NKTCR γδ cells in transplant grafts and during early immune reconstitution The investigators anticipate a reduction in relapse incidence from 30 to 5 and a reduction in acute GVHD incidence from 50 to 20 With genetic randomization patients with HLA-identical siblings will be included for intervention while patients with unrelated donors receiving a standard-HSCT will be included as controls Tested at a significance level of 005 with a power of 80 beta 02 a sample size of 35-38 patients in each group is appropriate for the study
BACKGROUND Allogeneic hematopoietic stem cell transplantation HSCT is a potential curative treatment for malignant hematologic diseases The main indication for HSCT in adults is acute leukemia followed by myelodysplastic syndrome In HSCT the bone marrow and immune system of the patient is replaced with that from a donor during an extensive clinical procedure carried out in a highly specialized transplant center The curable principle of HSCT is an immune-based cell-to-cell killing of residual leukemic cells mediated by donor cells termed the graft-versus-leukemia GVL effect
The basic principles of HSCT are given below
Conditioning regimen Prior to donor graft infusion a conditioning regimen is given in order to reduce the tumor burden and weaken the recipient immune system to allow engraftment of donor cells The conditioning regimen can contain different degrees of myeloablation depending on the desired grade of immune suppression suitable for the disease patient age and comorbidity
Stem cell donors and grafts The stem cell graft is most often obtained from an HLA-matched sibling 25 of patients or an HLA-matched unrelated register donor
The graft is obtained from the donor either by aspiration of bone marrow or by leukapheresis cell separation and removal of leucocytes from the remaining blood after administration of granulocyte-colony stimulating factor G-CSF which mobilizes stem cells to the blood The latter is known as a peripheral blood stem cell PBSC graft and is by far the most common graft type used in current era
Graft contents and patient immune reconstitution The stem cell graft contains stem cells that establish donor derived hematopoiesis including a functional immune system in the patient but also mature immune cells responsible for early elimination of residual tumor cells through the graft-versus-leukemia GVL effect Immune reconstitution is dependent on the dose and contents of the transplanted donor cells and both the graft contents and patient immune reconstitution is crucial for the overall outcome of the transplantation
GVL and GVHD The GVL effect is carried out by lymphocytotoxic donor cells that kill residual malignant cells of the patient GVL is traditionally mediated by donor αβ T cells in an immunological process driven by HLA-differences between individuals ie an allogeneic response
In acute graft versus-host-disease GVHD also involving HLA allo-recognition donor αβ T cells attack the normal tissue in skin liver and gastro-intestinal system of the recipient leading to a potential deadly immune disease Acute GVHD occurs during the first 3 months after HSCT and the clinical course is highly variable from a mild curable presentation to a full-blown immune attack which is fatal in 80-90 of the patients fig 2 Acute GVHD is seen in 40-60 of the patients
Relapse after HSCT Relapse of the hematologic cancer after HSCT is a major cause of mortality In patients with AMLMDS approximately 30 experience disease recurrence after HSCT The prognosis in patients relapsed after HSCT is dismal
Donor lymphocyte infusion In order to prevent relapse or treat manifest relapse after HSCT a dose of additional cells from the original stem cell donors donor lymphocyte infusion DLI can be infused into the patient with the purpose of initiating a renewedboosted GVL effect and eradicate remaining malignant cells However the effect on the leukemic cells of conventional DLI containing primarily TCR αβ cells from the donor is uncertain and limited by the risk of lethal GVHD why new methods of DLI are constantly under development
Natural killer cells and T-cell receptor γδ cells During recent years natural killer NK cells and T-cell receptor TCR γδ cells also termed innate effector cells have proven capable of eliminating cancer cells and thereby contributing to the GVL-effect in HSCT NK cells are innate lymphocytes comprising approximately 10 of all lymphocytes and purposed to eradicate stressed malignant and virus-infected cells They are able to lyse and eliminate tumor cells of leukemia through activating receptors of the natural killer NK and natural cytotoxicity receptor NCR families independent of HLA disparities
T cells of the TCR αβ type CD4 and CD8 T cells comprise the majority of all circulating T cells and lymphocytes in general TCR γδ cells are a subgroup of T cells different from αβ T cells which constitute approximately 5 of all T cells The repertoire of TCR γδ cell functions combine features of the adoptive immune system with innate-like responses They are involved in control of inflammation fighting of pathogens and maintaining tolerance towards self-antigens TCR γδ are also capable of recognizing tumor cells through their TCR and activating receptors shared with NK cells eg NKG2D and their anti-tumor effects are being increasingly documented against leukemic cells NK and TCR γδ cell recognition is independent of HLA-disparities making their contribution to GVHD less likely and their immunoregulatory features may actually protect against GVHD These innate effector cells therefore have the potential to mediate GVL without GVHD in the HSCT setting
Results from the research group of the investigators
Under this hypothesis our group conducted a prospective clinical study throughout 2015-2018 investigating concentrations of NK and TCR γδ cells in stem cell grafts and during immune reconstitution early after transplantation and associated these with patient outcomes in terms of GVHD relapse and relapse-free survival Results showed that patients transplanted with high doses of NK cells in the graft and high concentrations of NK cells in peripheral blood early after transplantation day 28 and 56 had significantly improved relapse-free survival compared to patients with low transplant doses and early post-transplant concentrations of NK cells Regarding TCR γδ cells patients with high concentration of TCR γδ cells in peripheral blood early day 28 and 56 after transplantation has significantly less GVHD and less relapse resulting in improved overall survival and relapse-free survival compared to patients with low post-transplant TCR γδ cell concentrations
Based on these results and existing literature the aim of this study is infusion of an innate DLI iDLI containing purified NK and TCR γδ cell from the original stem cell donor early after HSCT The expected effect of additional cell therapy with these innate effector cells during early immune reconstitution are reduced relapse as well as GVHD rates and thereby improved outcomes after HSCT in AMLMDS patients
Procedure This is a collaborative project between the Bone Marrow Transplant Unit at the Department of Hematology and the Department of Clinical Immunology at Rigshospitalet Copenhagen University Hospital
Approximately 60 patients per year receive PBSC-HSCT for the diagnoses of AML or MDS at our center One out of four patients has an HLA-identical sibling while the remaining patients receive stem cell grafts from matched unrelated donors from international donor registries For this study genetic randomization will be applied so that patients with HLA-identical siblings will be included for intervention while patients with unrelated donors receiving a standard-HSCT will be included in the control group The background for the design is donor availability only sibling donors can be recruited to donate iDLI With an estimated recruiting rate of approximately 85 13-15 patientdonor pairs in the intervention group are expected to be enrolled per year over a total of three years giving at total of 39-45 pairs In a previous prospective study the investigators obtained a recruiting rate of 97 Historically a higher incidence of GVHD was observed in transplants using an unrelated donor but due to more precise HLA-typing and better protocols for immune suppression GVHD and relapse incidence are nowadays comparable between related and unrelated transplants This is also the case at the transplant center at Rigshospitalet as previously published6
For intervention
Donors will undergo health screening at the Cell Therapy Facility Department of Clinical Immunology within 30 days before donation standard procedure Day 7 before HSCT Start of the conditioning regimen preparing the patient for HSCT standard procedure Day 5 before HSCT Start of G-CSF stimulation of the donor in order to mobilize stem cells for leukapheresis standard procedure
Donor leukapheresis and graft infusion to the patients termed day 0 of HSCT standard procedure Day 14 after HSCT donor leukapheresis without preceding G-CSF stimulation product manipulation and transfusion of iDLI to the patient intervention
Control group Standard HSCT-procedure as described above in patients receiving grafts from unrelated donors
Procedure of modified DLI iDLI
White blood cells are obtained from the donor by leukapheresis using the Spectra Optia Apheresis System Terumo BCT at the Blood Bank Unit Department of Clinical Immunology Rigshospitalet Purification of innate effector cells is carried out by TCRαβCD19-depletion of the fresh leukapheresis product with the CliniMACS Prodigy System Miltenyi Biotec This procedure removes TCRαβ T cells together with B-cells CD19positive cells rendering a cell product enriched in NK cells and TCR γδ cells and is routinely used at Rigshospitalet for procedures involved in pediatric transplantations
The intended dose of harvested cells is 108 lymphocyteskg resulting in expected cell doses of 107 NK cellskg and 1-5 x106 TCR γδ cellskg after the depletion The iDLI product is freshly infused into the patient at the Department of Hematology shortly after the depletion procedure
Immune phenotyping
Immune phenotyping of the iDLI product as well as the original stem cell graft will be performed using a highly standardized customer designed freeze dried flowcytometry panel DuraClone product from Beckman Coulter developed and routinely used for immune function monitoring at the Department of Clinical Immunology Two tubes will be included for detailed lymphocyte phenotyping in this study
Tube 1 includes markers of overall T cells CD3 CD4 CD8 NK cell subtypes CD16 CD56 B cells CD19 and monocytes CD14 Tube 2 includes markers of overall TCR αβ cells overall TCR γδ cells the two main TCR γδ subtypes TCR Vδ1 TCR Vδ2 and TCR γδ cell activation markers HLA-DR CD8 CD8beta
The same panel will be used for characterization of immune reconstitution in peripheral blood samples in patients at the day of iDLI infusion and 14 and 21 days hereafter ie day 14 28 and 56 after transplantation Viable cells will be cryopreserved for later functional studies
Data management plan Clinical data on patient and transplant outcomes will be acquired from the clinical transplant database IBMTR 2019 situated and administrated at the Transplant Unit Department of Hematology Flowcytometry data from characterization of iDLI products stem cell grafts and patient immune reconstitution will be acquired from the Department of Clinical Immunology and processed by appropriate analysis software Kaluza Flow Cytometry Analysis Software Beckman Coulter Clinical and laboratory data will be assembled structured and processed in SPSS SPSS Statistics IBM witch together with R The R Project for Statistical Computing wwwr-projectorg will be used for statistical analyses All data will be stored at Rigshospitalet Copenhagen University Hospital in accordance with data protection rules of The Danish Data Protection Agency
Statistical Analyses The cumulative incidence of acute GVHD and relapse in patients treated with iDLI compared to patients receiving a standard HSCT will be compared used Grays competing risk analysis Relapse-free survival between the two groups will be compared using the Kaplan Meier survival analysis and Cox proportional hazard models Cell doses and immune phenotyping of iDLI and original stem cells grafts and cell concentrations and phenotyping during patient immune reconstitution will be entered using descriptive statistics SPSS SPSS Statistics IBM and R The R Project for Statistical Computing wwwr-projectorg will be applied for statistical computing
Power Based on results from previous study from the investigators research group describing GVHD relapse and relapse-free survival in patients with high versus low doses of NKTCR γδ cells in transplant grafts and during early immune reconstitution The investigators anticipate a reduction in relapse incidence from 30 to 5 and a reduction in acute GVHD incidence from 50 to 20 With genetic randomization patients with HLA-identical siblings will be included for intervention while patients with unrelated donors receiving a standard-HSCT will be included as controls Tested at a significance level of 005 with a power of 80 beta 02 a sample size of 35-38 patients in each group is appropriate for the study
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None