Transfer of Effector Memory T Cells (Tem) Following Allogeneic Stem Cell Transplantation

Study Overview
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Brief Summary
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RATIONALE: Following stem cell transplantation, a major risk is graft-versus-host disease (GVHD). This occurs when donor immune cells that have been infused recognise the host's cells as 'foreign' and attack these cells. Prevention of GVHD relies upon depletion of donor immune T cells or drugs that block T cell function. However, these methods also increase the risk of life threatening infection. There is an important unmet need for better means of accelerating immune recovery following stem cell transplantation while avoiding GVHD. Pre-clinical studies have shown that infusion of donor CD62L- effector memory T cells (Tem) into the host improve immune recovery after allo-Stem Cell Transplant but do not cause GVHD. PURPOSE: This phase I dose escalation trial aims to determine the feasibility and safety of transfer of donor Tem following allogeneic stem cell transplantation.

Detailed Description
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Phase I study using a Bayesian Time-to-Event Continual Reassessment Method (CRM) to determine safety and maximum tolerated dose (MTD) of CD62L- Tem. Eligible patients and HLA-identical sibling donors will be registered prior to stem cell transplant (SCT). Donors will undergo an additional steady state apheresis for the collection of T cells between day -14 and day +24 of the allo-SCT according to logistics. Selection of Tem at the required dose will be performed at UCL Centre for Cell, Gene and Tissue Therapeutics (CCGTT) before distribution of the cryopreserved cells to the trial centre. Doses of Tem selected and infused will be: 1x10^5, 3x10^5, 1x10^6 or 3x10^6. Donor Tem will be infused on day 24-32 following allo-SCT. Patients will be followed-up for 12 months with specific evaluation points just prior to Tem infusion and at 3, 6, 9 and 12 months following allo-SCT.

Official Title
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Phase I Study of Transfer of Effector Memory T Cells (Tem) Following Allogeneic Stem Cell Transplantation

Conditions
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Lymphoma, Leukemia, Myeloma, Myelodysplastic Syndromes, Severe Aplastic Anemia, Primary Immune Deficiency, Graft Vs Host Disease

Intervention / Treatment
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* Biological: CD62L- Tem


Participation Criteria
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Eligibility Criteria
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Patient Registration Inclusion Criteria: Severe aplastic anaemia or Primary immune deficiency or Haematological cancer which can be ONE OF the following: Non-Hodgkin's lymphoma (NHL) in CR or PR; Hodgkin's lymphoma (HL) in CR or PR; Chronic (Pro-)lymphocytic leukaemia (CLL or PLL) in CR or PR Plasma cell myeloma (PCM) in CR, VGPR or PR; Acute myeloid leukaemia (AML) in CR; Acute lymphoblastic leukaemia (ALL) in CR; Myelodysplastic syndrome (MDS) < 10 % blasts in bone marrow; Chronic myelomonocytic leukaemia (CMML) < 10% blasts in bone marrow Suitable for HLA-identical sibling transplant using a standard alemtuzumab-based conditioning regimen with calcineurin-inhibitor based immunoprophylaxis Aged ≥ 16 years, <70 years Written informed consent Patient Registration Exclusion Criteria: Women who are pregnant or breast-feeding Life expectancy of < 8 weeks Currently taking part in any other interventional clinical research study (involving any IMP, ATMP or cellular therapy) Proposed use of any other method of GVHD prophylaxis other than alemtuzumab and calcineurin inhibitor Organ dysfunction: LVEF<45% Creatinine >200 µmol/lglomerular filtration rate (corrected) <50ml/min Bilirubin > 50 µmol/l AST or ALT >3x 2.5 x ULN (NB: If both are performed then both must be ≤3 2.5 x ULN) Patient Trial Treatment Exclusion criteria: Prior or active acute pattern GvHD of any grade Relapse or progression Primary or secondary graft failure Has received other cellular therapies Donor inclusion criteria: Aged ≥ 16 years HLA-identical sibling Have met transplant centre criteria regarding suitability for cell therapy donation Negative for HIV 1 and 2, hepatitis B, hepatitis C, HTLV-1 and 2, syphilis serology (to be confirmed before both registration and before trial treatmentat time of or up to 7 days following donation) Written informed consent Donor exclusion criteria: - Pregnant/lactating women

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Donor T cells depleted of CD62L+ cells (CD62L- Tem)<br>Donors will undergo a steady state apheresis for the collection of T cells. Selection of CD62L- Tem at the required dose will be performed at UCL Centre for Cell, Gene and Tissue Therapeutics (CCGTT). Donor Tem will be infused into patients on day 24-32 following allo-Stem Cell Transplant. | Biological: CD62L- Tem<br>* Donor memory T cells that have been depleted of CD62L+<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of dose limiting toxicity (DLT) | Occurrence of dose limiting toxicity (DLT) (defined as acute-pattern GvHD grade II-IV) | up to 72 days after Tem infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of acute GvHD | Incidence and severity of acute GvHD (whether dose limiting or not) | From date of infusion of Tem until 100 days post stem cell transplant | 
| Incidence and severity of chronic GvHD | Incidence and severity of chronic GvHD | From date of infusion of Tem up to 1 year post stem cell transplant | 
| Non-relapse mortality | Death without reoccurrence of cancer | From date of patient registration up to 1 year post stem cell transplant | 
| Overall survival | Death | From date of patient registration up to 1 year post stem cell transplant | 
| Progression-free survival | Disease progression or death | From date of patient registration up to 1 year post stem cell transplant | 
| Incidence/type of infection requiring inpatient admission | Any infection that has required an inpatient admission, incidence and type of infection | From date of infusion of Tem up to 1 year post stem cell transplant | 
| Total Number of inpatient days | Total Number of inpatient days for any reason | From date of infusion of Tem up to 1 year post stem cell transplant |