Among these are the relatively low level of surface expression of myeloma specific antigens, and the immune suppressive factors in the myeloma microenvironment contributing to the low levels of T cell persistence compared to CD19 CARs. Chimeric antigen receptorsĭespite the initial promise of CAR T cell therapy in MM, prolonged responses are not seen and there remain challenges to the use of CAR T cell therapy in this cancer. By combining clinical, biological, genomic and immunological data from patients with SMM we hope to define better models to predict disease progression and design trials to discover new therapies to prevent the development of myeloma. We seek to understand the role of the bone marrow immune environment in regulating progression to full blown myeloma. Myeloma is preceded by presursor conditions called monoclonal gammopathy of uncertain significance (MGUS) and smouldering myeloma (SMM). These markers have application to the development of biomarkers for this disease as well as in the rational and intelligent design of immunotherapeutic strategies for this disease. Using cutting edge technologies, we are embarking on a program of detailed immune phenotyping of bone marrow cells and clinically correlating these findings in large patient cohorts.įrom these data we have identified key T cell populations present in the bone marrow of myeloma patients at diagnosis and following autologous stem cell transplant that correlate with poor patient outcomes. It is increasingly clear that disease progression couples increased tumour growth and increasing immune dysregulation in the bone marrow niche. We seek to understand the cellular and molecular bases for the protective effect of stroma, and how this can be overcome pharmacologically. Myeloma cells are especially dependent on interactions with their bone marrow environment, where soluble factors and cellular interactions promote tumour growth and reduce the effectiveness of therapeutic drugs like PIs. Our work will uncover how manipulating the autophagic process can improve responses to PIs, and identify which patient subgroups may benefit from this approach. We are working to define the role of autophagy in mediating resistance to proteasome inhibitor therapy. This is exploited by the therapeutic use of proteasome inhibitors (PIs) that have transformed the outlook for many patients, however not all patients respond and many will develop resistance. One mechanism of resistance is the utilisation of an alternate protein degradation pathway, autophagy. Myeloma cells secrete excess monoclonal immunoglobulin and are uniquely dependent on protein processing pathways. Research project examples Enhancing the anti-myeloma activity of proteasome inhibition Recent work in newly diagnosed MM patients reveal the presence of dysfunctional marrow resident effector cells that influence clinical outcomes, and we are investigating the role of changes in bone marrow immune function when patients progress from smouldering to active symptomatic multiple myeloma. Work is also focused on the role of immune dysfunction and progression of myeloma. Refinement of CAR-T approaches, and exploration of novel targets remains at the forefront of our work. Current work is focused on optimising cellular therapies through improved understanding of the marrow immune environment, by interrogating patient bone marrow, and by using immune competent murine models. The Myeloma Immunotherapy group is led by Dr Lydia Lee. We work closely with the large clinical service at UCLH, and with national NCRN studies to interrogate the drivers of disease resistance and relapse, the benefit of early stem cell transplantation and the role of immunotherapeutic strategies in deepening disease response in the Myeloma XV trial in newly diagnosed patients. Our work utilises disease models such as cellular co-cultures, ex-vivo and in-vivo models, and these are interrogated using functional assays, high dimensional flow cytometry, CyTOF, immunohistochemistry, next generation sequencing and genetic modification. Myeloma is a genomically and biologically complex tumour, and we seek to discover new biomarkers for drug sensitivity and response to novel therapies. Our research has a strong translational focus to develop new anti-myeloma therapies, including cellular immunotherapies, and to advance early detection strategies for myeloma. Our work seeks to understand the role of the bone marrow microenvironment in promoting tumour growth and drug resistance, including mechanisms of immune dysfunction. Despite considerable therapeutic advances, myeloma remains incurable and most patients will die of their cancer. Myeloma is a cancer of plasma cells that expand in the bone marrow, causing bone marrow failure and bone destruction. The Myeloma Laboratory at UCL aims to bring scientific endeavour to the clinic for patient benefit.
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