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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Lymphoma; Myelodysplastic Syndromes; Leukemia; Myeloma; Graft Vs Host Disease; Severe Aplastic Anemia; Primary Immune Deficiency
• Intervention / Treatment: Biological: CD62L- Tem

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.

• Study Type: Interventional
• Enrollment (Anticipated): 18
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Toyin Adedayo; Phone Number: 0207 679 9867; Email: ctc.totem@ucl.ac.uk
• Study Contact Backup: Name: Nadjet El-Mehidi; Phone Number: 0207 679 9283; Email: ctc.totem@ucl.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom
    • Recruiting
    • UCLH
    • Contact: Ron Chakraverty, Prof

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Donor T cells depleted of CD62L+ cells (CD62L- Tem); 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; Donor memory T cells that have been depleted of CD62L+

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
TCR repertoire analysis by deep CDR3 sequencing		Day -14 to -7 (day of cell processing) and day 100 and 360 post stem cell transplant
Chimerism of immune subsets (analysing the genetic profiles of recipient and donor at baseline and following stem cell transplant)	Identifying the genetic profiles of the recipient and of the donor at baseline, evaluating changes in this following stem cell transplant	Pre-Registration and Day 100, 180, 270, 360 post stem cell transplant
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)	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	Day 100, 180, 270, 360 post stem cell transplant
Difference between donor immune profile with number of CD62L- Tem selected	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).	Day -14 to -7 (day of cell processing)
Alemtuzumab levels on the day of CD62L- Tem infusion		Day 28 post stem cell transplant

Collaborators and Investigators

• Sponsor: University College, London
• Collaborators: Medical Research Council

Study record dates

Study Major Dates

• Study Start (Actual): October 21, 2019
• Primary Completion (Anticipated): July 1, 2022
• Study Completion (Anticipated): April 1, 2023

Study Registration Dates

• First Submitted: January 10, 2019
• First Submitted That Met QC Criteria: February 8, 2019
• First Posted (Actual): February 11, 2019

Study Record Updates

• Last Update Posted (Actual): October 25, 2019
• Last Update Submitted That Met QC Criteria: October 22, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Bone Marrow Failure Disorders; Myelodysplastic Syndromes; Immunologic Deficiency Syndromes; Primary Immunodeficiency Diseases; Anemia, Aplastic; Graft vs Host Disease
• Other Study ID Numbers: UCL/13/0372; MR/R025436/1 (Other Grant/Funding Number: Medical Research Council)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No