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Multiple Myeloma Lab

Group Leader: Professor Kwee Yong


Research

The Myeloma Laboratory at UCL aims to bring scientific endeavour to the clinic for patient benefit. Myeloma is a cancer of plasma cells that expand in the bone marrow, causing bone marrow failure and bone destruction. Despite considerable therapeutic advances, myeloma remains incurable and most patients will die of their cancer.

Our work seeks to understand the role of the bone marrow microenvironment in promoting tumour growth and drug resistance, including mechanisms of immune dysfunction. Our research has a strong translational focus to develop new anti-myeloma therapies, including cellular immunotherapies, and to advance early detection strategies for myeloma. Myeloma is a genomically and biologically complex tumour, and we seek to discover new biomarkers for drug sensitivity and response to novel therapies. 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.  

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. 

The Myeloma Immunotherapy group is led by Dr Lydia Lee. 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. Refinement of CAR-T approaches, and exploration of novel targets remains at the forefront of our work. Work is also focused on the role of immune dysfunction and progression of myeloma. 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.


Research project examples

Enhancing the anti-myeloma activity of proteasome inhibition

Myeloma cells secrete excess monoclonal immunoglobulin and are uniquely dependent on protein processing pathways. 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.  We are working to define the role of autophagy in mediating resistance to proteasome inhibitor therapy.  Our work will uncover how manipulating the autophagic process can improve responses to PIs, and identify which patient subgroups may benefit from this approach.    

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.  We seek to understand the cellular and molecular bases for the protective effect of stroma, and how this can be overcome pharmacologically.  
 

Immune microenvironment  

It is increasingly clear that disease progression couples increased tumour growth and increasing immune dysregulation in the bone marrow niche. 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.  

From 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. 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.  

Smouldering Myeloma

Myeloma is preceded by presursor conditions called monoclonal gammopathy of uncertain significance (MGUS) and smouldering myeloma (SMM). We seek to understand the role of the bone marrow immune environment in regulating progression to full blown myeloma.  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.

Chimeric antigen receptors

Despite 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. 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. This lab developed the first MM CAR to enter clinical trials in Europe (APRIL CAR which targets two myeloma antigens: BCMA and TACI) and in collaboration with the Pule Lab and Autolus Therapeutics continue to develop novel strategies for the optimal use of CAR T cells in multiple myeloma.


Selected Publications

Bustoros, Mark, Romanos Sklavenitis-Pistofidis, Jihye Park, Robert Redd, Benny Zhitomirsky, Andrew J. Dunford,….Yong, Kwee, Bergsagel, P. Leif, Manier, Salomon, Getz, Gad, Ghobrial, Irene. Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 38, no. 21 (20 July 2020): 2380–89.
 
Alrasheed N, Lee L, Ghorani E, Henry JY, Conde L, Chin M, Daria Galas-Filipowicz, … Quezada SA*, Yong KL* Marrow Infiltrating Regulatory T Cells Correlate with the Presence of Dysfunctional CD4+PD-1+ Cells and Inferior Survival in Patients with Newly Diagnosed Multiple Myeloma. Clinical Cancer Research 2020. *equal contribution
 
Chapman MA, Sive J, Ambrose J, Roddie C, Counsell N, Lach A, Abbasian M, Popat R, Cavenagh JD, Streetly MJ, Schey S, Koh M, Virchis AE, Crowe J, Quinn MF, D’Sa S, Cook G, Crawley CR, Pratt G, Cook M, Braganza N, Adedayo T, Smith P, Clifton-Hadley L, Owen R, Keats JF, Herrero J, Yong K. RNA sequencing of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature. Blood 2018 Nov 15;132(20):2154-2165
 
Lee L, Draper B, Chaplin N, Philip B, Chin M, Galas-Filipowicz D, Onuoha S, Thomas S, Baldan V, Bughda R, Maciocia P, Kokalaki E, Neves M, Patel D, Rodriguez-Justo M, Francis J, Yong K*, Pule M*. An APRIL Based Chimeric Antigen Receptor for Dual Targeting of BCMA and TACI in Multiple Myeloma. Blood, January 1, 2018, blood-2017-05-781351.  *equal contribution
 
Chin M, Sive JI, Allen C, Roddie C, Chavda SJ, Smith D, Blombery P, Jones K, Ryland GL, Popat R, Rismani, A, D’Sa S, Rabin N, Gale, R, Yong KL. Prevalence and Timing of TP53 Mutations in Del(17p) Myeloma and Effect on Survival. Blood Cancer Journal 7, 2017 Sep 15;7(9):e610.

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