ICF: Chimeric antigen receptor T cells targeting CD123, CD33 and CLL1 for therapy of Acute Myeloid Leukaemia
Lead Research Organisation:
University College London
Department Name: Great Ormond St. Instit of Child Health
Abstract
Acute myeloid leukaemia (AML) is the commonest aggressive leukaemia in adults and has an increasing frequency with age. Despite advances made in treatments, in general, less than a third of adults survive long-term, though prognosis is better in younger age groups and certain subtypes. The most effective treatments are intensive chemotherapy and bone marrow transplantation which are toxic. A smaller proportion of patients do not survive because the disease does not respond to treatment (a third), a small proportion die due to toxicity and in some the disease responds but then comes back (about half). At this point, patients have often reached the ceiling of doses of certain chemotherapy agents which limits therapy options.
A new form of immune therapy for cancer called chimeric antigen receptor (CAR) T cells has been developed. This takes cells which are part of our immune system and through a form of genetic re-programming, can enable them to recognise and kill cancer cells. This is effective in another rarer form of leukaemia (acute lymphoblastic leukaemia) and we are trying to extend this approach to treat AML. This is challenging because the genetically- reprogrammed CAR T-cells also recognise and kill healthy cells such as normal bone marrow cells because they cannot distinguish these cell types. Since bone marrow transplantation is part of the standard care for a fit patient with relapsed AML, but normally involves high dose chemotherapy to clear the host bone marrow and 'make space' for the donor system to seed effectively, we propose to study CAR T cells which are effective against AML and investigate using their 'bone marrow-clearing' properties to set up an effective platform for bone marrow transplantation with lower doses of preparatory chemotherapy.
If our CAR T cell therapy works well, it will be a step forward on the path to developing effective CAR T cell treatments and making them available for patients with AML
A new form of immune therapy for cancer called chimeric antigen receptor (CAR) T cells has been developed. This takes cells which are part of our immune system and through a form of genetic re-programming, can enable them to recognise and kill cancer cells. This is effective in another rarer form of leukaemia (acute lymphoblastic leukaemia) and we are trying to extend this approach to treat AML. This is challenging because the genetically- reprogrammed CAR T-cells also recognise and kill healthy cells such as normal bone marrow cells because they cannot distinguish these cell types. Since bone marrow transplantation is part of the standard care for a fit patient with relapsed AML, but normally involves high dose chemotherapy to clear the host bone marrow and 'make space' for the donor system to seed effectively, we propose to study CAR T cells which are effective against AML and investigate using their 'bone marrow-clearing' properties to set up an effective platform for bone marrow transplantation with lower doses of preparatory chemotherapy.
If our CAR T cell therapy works well, it will be a step forward on the path to developing effective CAR T cell treatments and making them available for patients with AML
Technical Summary
Acute Myeloid Leukaemia (AML) is an aggressive haematological malignancy with approximately 3000 new UK cases annually. 60% of patients relapse or are refractory to initial therapy, , Treatment typically involves intensive salvage chemotherapy and, for the minority of these patients who enter remission and lack significant morbidities, allogeneic haematopoietic stem cell transplant (allo-SCT). This approach is associated with a low success rate and high mortality, such that long-term survival for r/r patients is 15-30%. New treatments are therefore badly needed.
Chimeric antigen receptor (CAR) T-cell therapy has been revolutionary in another acute leukaemia - acute lymphoblastic leukaemia (ALL); here, CAR T-cell therapy can engender long-term remission in patients with r/r disease. However, CAR T-cell therapy of AML is more challenging: AML arises from a diverse lineage of myeloid precursors. There is therefore much intra-patient heterogeneity in the cell-of-origin of a patient's leukaemia, resulting in a considerable targeting challenge. Further, relapse is considered to arise from a rare leukaemic stem cell (LSC) population which can differ from bulk AML. Finally, most AML and LSC targets are also expressed on HSCs, so targeting CAR T-cells would be expected to cause concomitant marrow aplasia.
We developed a Triple CAR T-cell approach which co-targets three AML antigens:CD33, CD123 and CLL1. Three separate CARs derived from camelid antibodies are co-expressed in a single vector. This approach overcomes tumour heterogeneity in most subtypes of AML and has shown potent pre-clinical activity. Given we anticipate that Triple CAR T-cells will cause marrow aplasia, the vector also co-expresses the suicide gene RQR8 to allow reduced intensity conditioning allo-SCT following CAR T-cell therapy.
We propose a phase 1, first-in-human study, in adults with r/r AML. We wish to determine feasibility, toxicity, extent of marrow aplasia, and explore early efficacy/response.
Chimeric antigen receptor (CAR) T-cell therapy has been revolutionary in another acute leukaemia - acute lymphoblastic leukaemia (ALL); here, CAR T-cell therapy can engender long-term remission in patients with r/r disease. However, CAR T-cell therapy of AML is more challenging: AML arises from a diverse lineage of myeloid precursors. There is therefore much intra-patient heterogeneity in the cell-of-origin of a patient's leukaemia, resulting in a considerable targeting challenge. Further, relapse is considered to arise from a rare leukaemic stem cell (LSC) population which can differ from bulk AML. Finally, most AML and LSC targets are also expressed on HSCs, so targeting CAR T-cells would be expected to cause concomitant marrow aplasia.
We developed a Triple CAR T-cell approach which co-targets three AML antigens:CD33, CD123 and CLL1. Three separate CARs derived from camelid antibodies are co-expressed in a single vector. This approach overcomes tumour heterogeneity in most subtypes of AML and has shown potent pre-clinical activity. Given we anticipate that Triple CAR T-cells will cause marrow aplasia, the vector also co-expresses the suicide gene RQR8 to allow reduced intensity conditioning allo-SCT following CAR T-cell therapy.
We propose a phase 1, first-in-human study, in adults with r/r AML. We wish to determine feasibility, toxicity, extent of marrow aplasia, and explore early efficacy/response.
