Abstract

Recent Advances in Adoptive Immunotherapy of Cancer

Mark Lowdell, Lead Scientist/Director, University College London

Immunotherapy of cancer has been a goal of oncologists and onco-haematologists for over 30 years but, apart from some notable exceptions, it has not been until now that great advances have been made. Immunotherapy of cancer requires the patient to overcome their immune tolerance to the tumour cells. The earliest efforts used systemic IL-2 to prime endogenous resting NK cells to target tumours; the result being unacceptable side effects from the high dose IL-2. Over 10 years ago it was demonstrated that ex-vivo priming of autologous dendritic cells (DC) with tumour lysates produced cells capable of initiating a T cell response to the tumour in vivo and, with increased understanding of DC biology new trials are underway at phase 1,2 and 3 in numerous different cancers. An autologous DC vaccine was one of the first cell therapies to become a licensed medicinal product in the US and the EU and this has driven several biopharma companies to develop new DC products which are showing promising results in clinical trials. Alternative methods of breaking T cell tolerance in clinical trial are CAR-T cells and other engineered T cells. In the first instance a murine monoclonal antibody is generated against a tumour antigen and the gene encoding the scFV region spliced to one or more T cell co-stimulatory receptor genes together with the human CD3? gene into a single construct. Autologous T cells from a patient are expanded ex-vivo and transduced to express this chimeric T/B cell receptor to for a “Chimeric Antigen Receptor” T cell – CAR-T. The outstanding success reported in the first clinical trial by Carl June’s group has lead widespread academic and industrial interest although the positive results have not been without some serious side effects which I will discuss.My group and others have shown the importance of the innate immune response to resolution of leukaemia and I will present recent data on a clinical trial of human NK cells primed to kill leukaemic blasts using a