WT1 TCR Gene Therapy for Leukaemia: A Phase I/II Safety and Toxicity Study

WT1 TCR gene therapy is a new treatment for acute myeloid leukaemia and chronic myeloid leukaemia.

Patient's white blood cells (T cells) are modified to specifically fight the leukaemia cells by transferring a gene into the T cells, which allows them to recognize fragments of a protein called WT1. This protein is present on the surface of leukaemia cells at very high levels. The gene transferred to the T cells enables them to make a new T cell receptor (TCR), which will allow them to attack leukaemia cells with high levels of WT1 on their surface.

Using this form of gene therapy the investigators can convert some of the patient's immune system's own T cells into T cells that the investigators hope will be much more effective at recognizing and killing leukaemia cells.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukaemia; Chronic Myeloid Leukaemia
• Intervention / Treatment: Genetic: WT1 TCR-transduced T cells

Detailed Description

This trial concerns a novel approach to generating leukaemia antigen-specific T cells for adoptive cellular therapy in HLA-A*0201 patients with acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML)

In this study, patient T cells will be gene-modified using a GMP grade retroviral vector containing the genes for a WT1-specific, HLA-A2-restricted T cell receptor. This ex vivo gene therapy will generate T cells expressing the WT1-specific TCR and thus able to recognise WT1-expressing target cells.

The autologous Cys1 WT1 TCR-transduced T cells will be re-infused back into adult leukaemia patients following lymphodepleting conditioning.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Bristol, United Kingdom, BS38 3AP
    • University Hospitals Bristol NHS Foundation Trust
  • London, United Kingdom, NW1 2PG
    • University College London Hospitals NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

General Inclusion Criteria:

• Age ≥ 18 years and ≤ 75 years.
• Life expectancy ≥ 16 weeks (4 months).
• World Health Organisation (WHO) performance status of 0-2
• HLA A*0201 positive
• Completed previous course of chemotherapy ≥ 4 weeks prior to commencing the initial phase of the trial (leucapheresis for collection of patient PBMC).
• Peripheral blood total lymphocyte count > 0.5x109/L.
• Informed consent in writing and ability to co-operate with treatment and follow up.
• Willing, able and available for collection of PBMC/ T cells by leucapheresis.
• Hepatitis B and C, HTLV-1, Syphilis, HIV negative.
• Free from serious concurrent illness.
• Female patients of child-bearing age must have a negative pregnancy test and agree to use reliable contraceptive methods for the duration of the therapy and for 6 months afterwards.
• Male patients must agree to use appropriate medically approved contraception during the trial and for six months afterwards.
• Haematological and Biochemical Indices:
• Haemoglobin (Hb) ≥ 7.0 g/dl; neutrophils ≥ 0.2 x 109/L; total lymphocytes > 0.5 x 109/L; platelets (Plts) ≥ 40 x 109/L
• serum bilirubin, Alanine amino-transferase (ALT) and/or aspartate amino transferase (AST) < 3 x upper normal limit
• calculated creatinine clearance ≥ 30 ml/min (uncorrected value) or isotope clearance measurement ≥ 30ml/min

Further disease specific inclusion criteria are detailed in Protocol

Exclusion Criteria:

• Age < 18 years or > 75 years.
• Patients should not receive concurrent systemic corticosteroids whilst on the study.
• Within three months of having received fludarabine (at time of leucapheresis).
• Major thoracic and/or abdominal surgery in the preceding three to four weeks from which the patient has not yet recovered.
• Patients who are high medical risks because of non-malignant systemic disease, as well as those with active uncontrolled infection.
• Patients with any other condition, which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
• Patients known to be serologically positive for Hepatitis B, C, HTLV-1 Syphilis or HIV.
• Concurrent congestive heart failure or prior history of New York Heart Association (NYHA) class III/ IV cardiac disease
• Positive pregnancy test or reluctance to use contraception.
• Pregnant and lactating women are excluded.
• History of Severe Allergy.

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: Single arm cohort study; WT1 TCR-transduced T cells	Genetic: WT1 TCR-transduced T cells; Two patient cohorts: Cohort 1 (up to 6 patients) = ≤ 2 x 107/kg WT1 TCR-transduced T cells Cohort 2 (12 patients)= ≤ 108/kg WT1 TCR-transduced T cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Identify organ toxicities and other side effects	Up to 12 months per patient
Transduction efficiency and TCR expression on TCR-transduced cells	Up to 12 months per patient

Secondary Outcome Measures

Outcome Measure	Time Frame
WT1-specific immune responses of TCR-transduced T cells	Up to 12 months per patient

Collaborators and Investigators

• Sponsor: Cell Medica Ltd
• Collaborators: University College, London; Cell Therapy Catapult
• Investigators: Principal Investigator: Emma Morris, Dr, University College, London

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): May 1, 2018
• Study Completion (Actual): May 1, 2018

Study Registration Dates

• First Submitted: March 22, 2012
• First Submitted That Met QC Criteria: June 15, 2012
• First Posted (Estimate): June 18, 2012

Study Record Updates

• Last Update Posted (Actual): October 2, 2018
• Last Update Submitted That Met QC Criteria: October 1, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: AML; CML; Gene therapy; WT1 TCR
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Other Study ID Numbers: D-00272-CT2014001

Drug and device information, study documents

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