Clinical trial NCT03836690: Transfer of Effector Memory T Cells (Tem) Following Allogeneic Stem Cell Transplantation
Official title: Phase I Study of Transfer of Effector Memory T Cells (Tem) Following Allogeneic Stem Cell Transplantation
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Lymphoma
Leukemia
Myeloma
Myelodysplastic Syndromes
Severe Aplastic Anemia
Primary Immune Deficiency
Graft Vs Host Disease
Lead sponsor: University College, London
Sponsor class: OTHER
Collaborators: name: Medical Research Council
First posted: 2019-02-11
Enrollment: 18
Sex: ALL
Minimum age (years): 16
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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 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

Primary outcomes:
measure: Occurrence of dose limiting toxicity (DLT)
timeFrame: up to 72 days after Tem infusion
Secondary outcomes:
measure: Incidence and severity of acute GvHD
timeFrame: From date of infusion of Tem until 100 days post stem cell transplant
measure: Incidence and severity of chronic GvHD
timeFrame: From date of infusion of Tem up to 1 year post stem cell transplant
measure: Non-relapse mortality
timeFrame: From date of patient registration up to 1 year post stem cell transplant
measure: Overall survival
timeFrame: From date of patient registration up to 1 year post stem cell transplant
measure: Progression-free survival
timeFrame: From date of patient registration up to 1 year post stem cell transplant
measure: Incidence/type of infection requiring inpatient admission
timeFrame: From date of infusion of Tem up to 1 year post stem cell transplant
measure: Total Number of inpatient days
timeFrame: From date of infusion of Tem up to 1 year post stem cell transplant
Other outcomes:
measure: TCR repertoire analysis by deep CDR3 sequencing
timeFrame: Day -14 to -7 (day of cell processing) and day 100 and 360 post stem cell transplant
measure: Chimerism of immune subsets (analysing the genetic profiles of recipient and donor at baseline and following stem cell transplant)
timeFrame: Pre-Registration and Day 100, 180, 270, 360 post stem cell transplant
measure: 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)
timeFrame: Day 100, 180, 270, 360 post stem cell transplant
measure: Difference between donor immune profile with number of CD62L- Tem selected
timeFrame: Day -14 to -7 (day of cell processing)
measure: Alemtuzumab levels on the day of CD62L- Tem infusion
timeFrame: Day 28 post stem cell transplant
Locations:
city: London
country: United Kingdom
facility: UCLH
Study officials:
References: