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

Lymphoma Clinical Trial

— ToTem  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03836690
• Other study ID #: UCL/13/0372
• Secondary ID: MR/R025436/1
• Status: Recruiting
• Phase: Phase 1
• Start date: October 21, 2019
• Est. completion date: April 1, 2023

Study information

• Verified date: October 2019
• Source: University College, London
• Contact: Toyin Adedayo
• Phone: 0207 679 9867
• Email: ctc.totem[@]ucl.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 18
• Est. completion date: April 1, 2023
• Est. primary completion date: July 1, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 16 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Anemia, Aplastic
• Graft vs Host Disease
• Immunologic Deficiency Syndromes
• Leukemia
• Lymphoma
• Myelodysplastic Syndromes
• Myeloma
• Primary Immune Deficiency
• Severe Aplastic Anemia

Intervention

Biological:
• CD62L- Tem
Donor memory T cells that have been depleted of CD62L+

Locations

Country	Name	City	State
United Kingdom	UCLH	London

Sponsors (2)

Lead Sponsor	Collaborator
University College, London	Medical Research Council

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	TCR repertoire analysis by deep CDR3 sequencing		Day -14 to -7 (day of cell processing) and day 100 and 360 post stem cell transplant
Other	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
Other	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
Other	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)
Other	Alemtuzumab levels on the day of CD62L- Tem infusion		Day 28 post stem cell transplant
Primary	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	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
Secondary	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
Secondary	Non-relapse mortality	Death without reoccurrence of cancer	From date of patient registration up to 1 year post stem cell transplant
Secondary	Overall survival	Death	From date of patient registration up to 1 year post stem cell transplant
Secondary	Progression-free survival	Disease progression or death	From date of patient registration up to 1 year post stem cell transplant
Secondary	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
Secondary	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