ANTILEUKEMIA T CELLS · Redirecting Cytotoxic T Lymphocytes towards Leukemic antigens

Final Activity Report Summary - ANTILEUKEMIA T CELLS (Redirecting Cytotoxic T Lymphocytes towards Leukemic antigens)

We have transformed human cells specialised in the immunity against pathogens called cytotoxic T cells (CTL) so they could recognise leukemic cells. The reasons we used those specialised, anti-infectious CTL is that they appear to have strong capabilities to form so-called memory immune cells, thus potentially allowing for a long-lasting immune response. In order to transform this anti-infectious CTL into anti-leukaemia CTL, we have genetically modified the CTL using a virus in a dedicated, protected facility. The virus brought the gene sequence into the CTL that render them capable of recognising certain types of leukemic cells. Our project specifically targeted CD33, a leukaemia-associated antigen. Our principal objective was to demonstrate that CTL genetically modified to recognise this CD33 leukaemia-associated antigen were cytotoxic to human myeloid malignancies expressing this target antigen. Indeed, we demonstrated that CD33-targetted CTL were capable of killing leukaemia cells in vitro and in vivo in leukaemia-bearing mice. Because CTL usually lack enough stimulation to sustain their activity over a long period of time (thus explaining some cases of late relapse in patients with leukaemia that have come into remission), we chose to incorporate the anti CD33 chimaeric receptor into CTL specific for EBV antigens (chimaeric EBV-CTLs). EBV (or Ebstein Barr virus) is the virus responsible for mononucleosis, a usually benign infection affecting a majority of humans. EBV antigens are persistently expressed in vivo in chronically infected (albeit asymptomatic) patients, together with high levels of so-called immune costimulatory molecules. Hence, this chronic stimulation by EBV antigens usually maintains a high frequency of anti EBV CTL in normal albeit chronically EBV-infected human subjects. Thus, we hypothesised that genetically-modified CTL specific to EBV so that they could be redirected against the CD33 leukaemia-associated antigen should improve the long-lasting immunity against leukaemia as well. We showed during our project that these EBV-CTL genetically modified to recognise CD33-positive leukaemia were indeed effective at killing leukaemia cells in vitro and in vivo in mice. We tried to improve this effect by introducing another costimulatory element (aka CD28) but this turned out to somehow destroy the modified CTL, an unsuspected effect we are now exploring in an independent set of experiments. Overall, we have reached our goal of demonstrating the potency of genetically-modified CTL to redirect them against CD33, a leukaemia-associated antigen. We are now preparing a subsequent project that will focus on demonstrating that this antitumour effect is not associated with toxicity against normal bone marrow cells. If this set of experiments is consistent with good antitumour efficacy with acceptable/reversible toxicity to normal bone marrow cells, we will then seek approval to initiate a phase I/II clinical trial of chimeric CTLs in EBV-seropositive patients with relapsed or high-risk CD33+ leukaemia.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз