In the summer of 2017, CLL Global Research Foundation funded an ambitious research program, the “Center of Research Excellence in Chronic Lymphocytic Leukemia at the Victorian Comprehensive Cancer Centre (VCCC)”. Headed by Dr. Constantine Tam of the Peter MacCallum (Peter Mac) Cancer Centre and the University of Melbourne, located in Melbourne, Victoria, Australia, this research program seeks to expand on the major advancements that have occurred in the treatment of CLL. The project focuses on seven research areas: 1) development of an invasive-free assay using circulating tumor DNA to track minimal residual disease; 2) understanding cardiotoxicity associated with BTK inhibitors (BTKi) such as ibrutinib; 3) understanding BTKi associated bleeding disorders; 4) investigating cellular events before and after treatment begins and at the time of relapse; 5) defining the impact of active CLL and novel therapies on host immunity; 6) expanding small molecule inhibitor combination programs, e.g. ibrutinib and venetoclax; 7) developing activated B-CLL as an antigen presenting cell for immunotherapy. Below is the press release from the VCCC announcing the award.

PRESS RELEASE
$1.5 million secured for establishment of the Centre for Chronic Lymphocytic Leukemia Research

Peter Mac, in collaboration with VCCC and other partners, has been generously awarded $1.5 million to accelerate research into improved treatments for Chronic Lymphocytic Leukemia (CLL).

The funding of $500,000 annually for three years will support an integrated clinical and scientific research program into CLL, coordinated by Associate Professor Con Tam. This grant builds upon a history of CLL breakthrough discoveries by Melbourne researchers, including key contributions to the development of two new classes of drugs: BCL2 inhibitors (e.g. venetoclax [ABT-199]) and BTK inhibitors (ibrutinib and BGB-3111). The US-based CLL Global Research Foundation is providing the funding to further accelerate the research into development of these and other new therapies.

“These are truly outstanding drugs and I think they are going to transform our whole approach to CLL,” says Professor Michael Keating of the MD Anderson Cancer Center and president of the Foundation. Professor Keating said Melbourne’s Parkville biomedical precinct has shown it is a world leader in the development of breakthrough CLL treatments and the Foundation is keen to advance this work. Key project partners include Peter Mac’s Sarah-Jane Dawson, Mark Dawson, Paul Neeson, Dennis Carney, John Seymour and Ilia Voskoboinik; Royal Melbourne Hospital’s David Ritchie, Joanne Davis and Andrew Roberts; and Baker IDI’s Julie McMullen. Peter Mac on behalf of all collaborators would like to acknowledge the generosity of Professor Keating and the CLL Global Research Foundation, noting this research program would be a further example of the trans-institutional collaboration for which the Parkville biomedical precinct was renowned.

Six Month Update:
Centre of Research Excellence in Chronic Lymphocytic Leukemia at the Victoria Comprehensive Cancer Centre

We received the generous funding from CLL Global in June 2017 and the money was put immediately to use in accelerating our research programs. New, innovative studies including the combinations of ibrutinib and venetoclax, and BGB-3111 and PD1 inhibitors, were added to our serial blood sampling studies with the aim of finding out how these drugs impact the ability of CLL to mutate and escape our treatments, and to study how these drugs may impact the normal immune system of the patient. The latter research will be conducted by Dr. Sasanka Handunnetti, who has optimized a 26 color flow cytometry panel to study in detail individual immune cell subsets in blood. The plasma DNA project is progressing well with the appointment of Dr. Kah-Lok Chan whose PhD project will revolve around the further development of this technology in CLL – our initial pilot results were very well received, being published in Nature Communications this year. With regards to cardiotoxicity of BTK inhibitors, the Foundation’s generous funding has permitted the initiation of a suite of detailed cardiac studies (including exercise MRI) in patients starting BTK inhibitor therapy, led by Dr. Chloe Tang. In the laboratory, Dr. Julie McMullen has discovered that mice predisposed to heart disease had increased rates of atrial fibrillation when given ibrutinib, mimicking the situation in humans; further experiments are currently being conducted to determine why this happens. Dr. Denise Jackson is leading our work on determining why patients taking ibrutinib are predisposed to bleeding and has made some new and exciting findings regarding the molecules that assist platelets to attach to bleeding sites; further experiments are ongoing. Collectively, the CLL research program at VCCC thanks CLL Global Foundation for its generous support and we look forward to updating the Foundation on our progress at the next meeting.

18 Month Update:

This grant has been running for approximately 18 months. In the last 6 months, we have further proven the usefulness of circulating DNA in a project involving the use of combination ibrutinib and venetoclax in patients with mantle cell lymphoma, a disease related to CLL. This project also discovered a new way cancer is able to escape combination targeted therapy. The work is now accepted for publication in Nature Medicine. Along a similar theme, analysis of samples collected and stored with support of CLL Global has identified a new mechanism of resistance to venetoclax in patients with CLL. This work is currently under peer review. Finally, Dr Thompson at MD Anderson and our group have established a collaborative research project extending the circulating DNA technology to patients treated with novel combination treatments for CLL at MD Anderson. In the work on BTKi related heart toxicity, we have now recruited 32 (of a target 40) patients for our clinical study of heart function before and during BTKi therapy. In the work on BTKi-associated bleeding, Professor Jackson is extending her studies to larger numbers of patients starting BTKi at our hospital to confirm her preliminary findings of differential platelet effects between ibrutinib and zanubrutinib, which is a more targeted version of ibrutinib with potential for reduced side-effects. Other projects including analyses of serial genomic and immunological changes during novel agent therapy continue to progress on track.