Graft Vs Host Disease, Leukemia, Lymphoma, Myelodysplastic Syndromes, Myeloma, Primary Immune Deficiency, Severe Aplastic Anemia
Conditions
Brief summary
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
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.
Interventions
BIOLOGICALCD62L- Tem
Donor memory T cells that have been depleted of CD62L+
Sponsors
Medical Research Council
University College, London
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of dose limiting toxicity (DLT) | up to 72 days after Tem infusion | Occurrence of dose limiting toxicity (DLT) (defined as acute-pattern GvHD grade II-IV) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity of chronic GvHD | From date of infusion of Tem up to 1 year post stem cell transplant | Incidence and severity of chronic GvHD |
| Non-relapse mortality | From date of patient registration up to 1 year post stem cell transplant | Death without reoccurrence of cancer |
| Overall survival | From date of patient registration up to 1 year post stem cell transplant | Death |
| Progression-free survival | From date of patient registration up to 1 year post stem cell transplant | Disease progression or death |
| Incidence/type of infection requiring inpatient admission | From date of infusion of Tem up to 1 year post stem cell transplant | Any infection that has required an inpatient admission, incidence and type of infection |
| Total Number of inpatient days | From date of infusion of Tem up to 1 year post stem cell transplant | Total Number of inpatient days for any reason |
| Incidence and severity of acute GvHD | From date of infusion of Tem until 100 days post stem cell transplant | Incidence and severity of acute GvHD (whether dose limiting or not) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Assessing the reconstitution level of virus- and bacterial-specific immunity (by measuring the levels of immune cells involved in virus- and bacterial immunity post Tem Infusion) | Day 100, 180, 270, 360 post stem cell transplant | Measuring the levels of immune cells at specific points in follow up to determine how virus- and bacterial-specific immunity recovers in patients following a stem cell transplant and Tem infusion |
| Difference between donor immune profile with number of CD62L- Tem selected | Day -14 to -7 (day of cell processing) | Analysing the donors immune profile pre and post CD62L- Tem selection (cell processing), against the cohort the patient is in (which dose of CD62L- Tem they will receive). |
| Alemtuzumab levels on the day of CD62L- Tem infusion | Day 28 post stem cell transplant | — |
| Chimerism of immune subsets (analysing the genetic profiles of recipient and donor at baseline and following stem cell transplant) | Pre-Registration and Day 100, 180, 270, 360 post stem cell transplant | Identifying the genetic profiles of the recipient and of the donor at baseline, evaluating changes in this following stem cell transplant |
| TCR repertoire analysis by deep CDR3 sequencing | Day -14 to -7 (day of cell processing) and day 100 and 360 post stem cell transplant | — |
Countries
United Kingdom
Contacts
Primary ContactToyin Adedayo
Backup ContactNadjet El-Mehidi
Outcome results
None listed