Study Evaluating the Safety and the Efficacy of Human T Lymphoid Progenitor (HTLP) Injection to Accelerate Immune Reconstitution After Umbilical Cord Blood (UCB) Transplantation in Adult Patients With Hematologic Malignancies (HTLP-ONCO)

Study Overview
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Brief Summary
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This is an open-labelled and non-controlled Phase I/II clinical trial, evaluating the safety and the efficacy of Human T Lymphoid Progenitor (HTLP) injection to accelerate immune reconstitution after umbilical cord blood (UCB) transplantation in adult patients with hematologic malignancies. The dose limiting toxicity of HTLP injection will be evaluated using a model-based design.

Detailed Description
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Allogeneic bone marrow transplantation (AlloSCT) is the treatment of choice for high- risk acute myeloid leukemias in complete first remission after induction therapy and other high-risk hematological malignancies. Umbilical cord blood grafts are frequently used for patients lacking an HLA- matched family donor (Matched-sibling donor, MSD) as well as in the absence of an appropriate unrelated donor (10/10 MUD). As any HSCT, UCB transplantations are associated with the risk of acute and chronic GVHD, post- transplant immunodeficiency with increased risk of infections as well as relapse. Especially the risk of infection and therefore non- relapse mortality (NRM) or transplant- related mortality (TRM) is significantly higher in UCB transplantations as compared to MSD or 10/10 MUD transplantations. All of these risks have been linked to a significant delay in immune reconstitution including various immune cell populations like CD4 and CD8 T cells, Treg, NK, iNKT, pDC and others. The investigators therefore make the hypothesis that if T-cell-mediated immunity was rapidly generated after a partially HLA-compatible UCB transplantation will reduce the risk of infection and to prevent relapse without increasing the risk of GVHD.

Official Title
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A Phase I/II Study Evaluating the Safety and the Efficacy of Human T Lymphoid Progenitor (HTLP) Injection to Accelerate Immune Reconstitution After Umbilical Cord Blood (UCB) Transplantation in Adult Patients With Hematologic Malignancies

Conditions
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Hematologic Malignancy

Intervention / Treatment
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* Drug: Human T Lymphoid Progenitor (HTLP) injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (≥ 18 years old and <66 years old) at the time of inclusion and eligible for an allogeneic stem cells transplantation and fit to receive the specified conditioning regimen Patients with hematologic malignancies Absence of a matched - related sibling donor (MSD) or a matched unrelated donor (MUD) 10/10 SORROR score compatible with the pre specified conditioning and to discuss with the Principal Investigator Presence of two UCB units with the following criteria*: HLA- matched 4/8, 5/8, 6/8, 7/8 or 8/8 for HLA- A, -B, -C and DRB1 loci AND Presence of at least one UCB unit with the following criteria*: ≥ 3 x 10e7 TNC/kg or ≥ 1.5 10e5 CD34+/kg pre- freezing * For the UCB taken into HTLP culture, the CD34+ content does not need to meet the above cellularity criteria, as expansion during HTLP culture has been proven to ensure the appropriate number of CD7+ needed for each dose. The non- cultured UCB will be chosen to have a higher CD34+ cell content in order to enable long- term hematopoietic engraftment No treatment with another investigational drug within one month before inclusion Patient affiliated to social security Written, informed consent of the patient Absence of Donor Specific Antibodies (DSA) with a MFI > 5000 Exclusion Criteria: Any of the standard contraindications to allogeneic transplant Left ventricular ejection fraction <50% Abnormal biochemistry results (ALT/AST>10xULN, total bilirubin>2.5xULN, creatinin clearance <60ml/min) Inability to understand and provide informed consent Concomitant infectious disease: HTLV-I, HIV-I or HIV-II Pregnancy or breastfeeding for women of childbearing potential Patients with progressive hematologic malignancies

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 66 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Human T Lymphoid Progenitor (HTLP) injection<br>HTLP cellular product obtained after 7 days of culture of immune-selected CB | Drug: Human T Lymphoid Progenitor (HTLP) injection<br>* The HTLP cell suspension will be injected intravenously at the time of UCB HSCT on D0<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of grade III-IV graft-versus-host disease (GvHD) | according to Glucksberg grading system, to define toxicity | 100 Days following HSCT | 
| CD4 + T cells analysis | Efficacy defined by the presence of >50/μl CD4+ CD3+ TCRαβ+ T cells at 2 consecutive measures < within 4 months post HSCT. | 100 days following HSCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time course of T cell immune reconstitution | time needed to exceed a count of 100 naive CD4+ and >100 total CD8+ cells per μL | Month 1, 2, 3, 4, 5, 6 and 12 post-transplantation | 
| Time to hematologic engraftment | Time to ANC > 0.5G/L with platelets > 20G/L | Up to 24 months post-transplantation | 
| Numbers of neutrophils, platelets and red blood cell transfusions |  | Month 1,2, 3, 6 and 12 post -transplantation | 
| time course of reconstitution of the different T-cell subpopulations | by immunophenotyping (flow cytometry analysis) | Month 1,2, 3, 6 and 12 post -transplantation | 
| Presence of Recent thymic emigrants (RTEs) | by immunophenotyping (flow cytometry analysis) | Month 1,2, 3, 6 and 12 post -transplantation | 
| Tregs numbers | by immunophenotyping (flow cytometry analysis) | Month 1,2, 3, 6 and 12 post -transplantation | 
| B-cell reconstitution | number and phenotype for naïve IgD+CD27-, marginal zone IgD+CD27+, switched memory IgD-CD27+, and IgD-CD27- cells | Month 6 and 12 post -transplantation | 
| Immunoglobulin levels | focus on time needed for cessation of intravenously IgG replacement therapy | Month 6 and 12 post -transplantation | 
| Reconstitution of the NK cell | compartment (CD3-CD56dimCD16bright) | Month 6 and 12 post -transplantation | 
| Assessment of engraftment of each UCB unit over time by hematological monitoring and chimerism analysis on neutrophils, T, B, NK, pDC and macrophages at 1, 2, 3, 6 and 12 months following HSCT | To assess engraftment of each UCB unit over time by hematological monitoring and chimerism analysis on neutrophils, T, B, NK, pDC and macrophages at 1, 2, 3, 6 and 12 months following HSCT. | at 1, 2, 3, 6 and 12 months following HSCT. | 
| the graft failure/rejection rate | detected by hematological monitoring of each UCB unit | 3 months following HSCT | 
| Cumulative incidence of infections |  | 3, 6 and 12 months post- transplantation | 
| Cumulative incidence of acute and chronic episodes of GVHD and their grade | according to Glucksgberg GvHD staging | 3, 6, 12 and 24 months post-transplantation | 
| relapse rate |  | 2 years post -transplantation | 
| overall survival |  | 2 years post -transplantation | 
| Disease-free survival |  | 2 years post -transplantation | 
| Progression-free survival |  | 2 years post -transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute myeloid leukemia, minimal residual disease, hematologic malignancies, human T Lymphoid Progenitor, umbilical cord blood transplantation