Community Research and Development Information Service - CORDIS

Periodic Report Summary 2 - ATECT (Advanced T-cell Engineered for Cancer Therapy)

Project Context and Objectives:
Introduction: Chimeric Antigen Receptors (CARs), generated by fusing the antigen-binding region of a monoclonal antibody (mAb) to intracellular T-cell signalling domains1, hold the promise to revolutionise cancer treatment. Introduction of genes coding for CARs into T-cells using integrating vectors endow antigen recognition independent of MHC restriction. Recent clinical data leave no doubt that this new form of cancer therapy can be remarkably effective, engendering long-lived remissions in patients with refractory disease.

There are, however, considerable barriers to be overcome to take this new form of thera-py. Some of these barriers are practical – for instance can we develop ways of making such products cheaper and easier. Other barriers relate to engraftment of engineered T-cells in the face of hostile microenvironment.

Technological background: The ATECT consortium proposes to address these limitations through advanced cellular engineering. The central technological theme of this consortium is the application of gene editing strategies alongside advanced standard methods of ge-netic modification with insertional vectors, which we describe as a combination of ad-vanced “positive” and “negative” engineering
Project Results:
Considerable progress has been made during the current reporting period.

• UCART19 CAR T-cells were given to two young children with acute leukaemia which was resistant to standard treatment on a compassionate basis. These two children had complete responses to treatment and were consolidated with allogeneic haematopoi-etic stem cell transplantation (allo-HSCT). They remain in remission over a year after treatment. This is important as it represents the first use of genome-edited CAR T-cells in human subjects. This finding was just published in Science Translational Medicine.

• Partner Cellectis obtained commercial support for further development of UCART19 from Servier. Cellectis have subsequently left the ATECT consortium, but a study of UCART19 has initiated at Great Ormond Street Hospital.

• We have developed an automated CAR T-cell manufacturing process on the Miltenyi Prodigy and will run a clinical trial of 2nd party CAR T-cells using this novel technology.

• We have generated antibodies to target tumour-associated-antigens for brain tu-mours, lung cancer and paediatric cancers such as Neuroblastoma and are developing optimised chimeric antigen receptors from these.

• We have generated chimeric antigen receptors which recognise neovascular markers

• We have generated some of the first data demonstrating increased tumour infiltration by Chimeric Antigen Receptor T-cells engraftment using combination therapy with the immune-cytokine IL2-L19 developed by Philogen.

• We have demonstrated the beneficial effects of gene-editing of PD1 on adoptively transferred tumour-specific T-cells and have published this data in Cancer Research.

Potential Impact:
Clinical and research output from the ATECT consortium has the potential to develop new treatments to treat cancers which are currently very difficult to treat. Chimeric Antigen Receptor T-cells (CARTs) are showing considerable promise in the treatment of several lymphoid malignancies. Generation of CARTs is expensive and typically needs to be per-formed separately for each patient. The ATECT consortium proposes to address the chal-lenges of cost and complexity of CAR T-cell manufacture through the two clinical studies as outlined below.

The initial clinical data generated by ATECT in the context of the UCAR19 strategy/study which uses third party/healthy donor T-cell starting material paves the way for “off-the-shelf” CAR T-cell therapy. This has the potential to reduce the costs associated with CAR T-cell manufacture and to increase the availability of this novel therapy to patients.

Additionally, a second clinical study which has recently opened at UCLH will be one of the first to use an automated manufacturing platform to generate CAR T-cells. Although the products for this study will be manufactured individually for each patient, use of an auto-mated platform reduces costs and potentially increases availability of CAR T-cells to pa-tients.

CAR T-cell therapy has shown activity in lymphoid malignancies, however solid cancers are considered more challenging due to poorer T-cell engraftment and survival within the tu-mour bed. ATECT has demonstrated that combining an immunocytokine with CAR T-cells can result in increased engraftment within the tumour. Further, ATECT has demonstrated that genome editing of checkpoint blockade receptors in tumour-specific T-cells can en-hance their engraftment and survival within the tumour leading to increased activity. To-gether, these and related approaches should improve CAR T-cell efficacy in solid cancers.

List of Websites:

Reported by

United Kingdom


Life Sciences
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