Clinician-researcher focuses on patients with rare lymphoma

Haematologist, Dr Colm Keane, has a clear focus on improving patient outcomes through his lymphoma research program at the Translational Research Institute (TRI).

Dr Keane splits his time evenly between treating lymphoma patients at the Princess Alexandra Hospital and searching for better treatments in his laboratory next door at the TRI, where he is an NHMRC Early Career Fellow with Mater Research (University of Queensland).

Dr Keane is particularly interested in harnessing the immune system to help improve patient outcomes, with a particular interest in rare lymphomas.

“I am interested in some of the rare lymphomas as they are very poorly understood, and many patients with these lymphomas have poor outcomes, and we need to identify novel strategies to improve outcomes for these patients,” says Dr Keane.

By concentrating on the biology of lymphomas, Dr Keane is also aiming to identify more tailored treatment options for patients that improve outcomes and reduce toxic side effects.

He says that while numerous new therapeutics have emerged for blood cancers such as lymphoma, in the past decade, more research is needed to ensure patients receive the best possible treatment regimens at the right time in their treatment journey.

“In the disease groups I treat, the breakthroughs are incredible, but we have so much still to learn so we can pick the best therapy for each individual patients tumour at the time of initial diagnosis. There are so many exciting new treatment options for lymphomas. Some are quite standardised, but for the most part we don’t know where the treatments fit in and which patients will respond the best.

“Through my research, I’m investigating the immune system and translating this into a better understanding of the biology of the tumour and how it manages to avoid detection by our immune system in the first place. It’s a very structured approach so that we can understand how drugs impact the disease.”

Primary Central Nervous System Lymphoma (PCNSL)

Dr Keane was awarded a $1.39 million Investigator Grant in the 2020 Medical Research Future Fund (MRFF) Priority Round to run a clinical trial for an immune checkpoint therapy in patients with the rare brain cancer, PCNSL.

The cancer accounts for less than five per cent of all lymphomas and four per cent of brain cancers, according to Dr Keane.

“It’s rare, but not uncommon, we’d see between five and 10 patients each year at the Princess Alexandra Hospital, for example. The issue for clinicians is that this cancer is very challenging to treat, and patients have a poor outcome.

“The standard treatment for this cancer is intensive chemotherapy treatment and whole-of-brain radiation but, the intensity of treatment required invariably leads to significant side-effects.

“Many patients who are cured from the cancer will have significant long term effects from therapy, Most never go back to work after treatment.”

In a bid to improve patient outcomes, Dr Keane is leading a new clinical trial to test an ‘immune checkpoint’ therapy already being used to successfully treat people with melanoma and lung cancer.

This brain lymphoma seems to be unique as immune evasion appears key to progression of the disease, says Dr Keane.

“We suspect the immune checkpoint therapy may help the immune system’s ability to eradicate PCNSL tumour cells, which are somehow managing to evade the immune system in the brain.

“Our clinical trial using this therapeutic is novel, but just as importantly we are also hoping to understand the biology of what happens in patients’ brains and in their blood when they receive the treatment.

“To do this, we will be collecting both tumour and blood samples from patients. Internationally, there are astonishingly few tumour samples of this particular cancer available, so it’s going to be an important resource for ongoing research.”

The trial is scheduled to start in late 2020, with up to 15 Australian hospitals taking part in the study through the Australasian Leukaemia & Lymphoma Group (ALLG) clinical trial research group. They are hoping to recruit 48 PCNSL patients into the study.

Diffuse large B-cell lymphoma (DLBCL)

DLBCL is the most common form of lymphoma: an aggressive type of non-Hodgkin lymphoma that develops from the B-cells in the lymphatic system.

Dr Keane is looking at changes in patients’ immune system after relapse (when the cancer returns following treatment). He is also interested in why immune checkpoint inhibitor therapies have so far been ineffective for this group of patients.

“Immune checkpoint therapies don’t work very well with this type of cancer, but in theory they should, so I’m trying to work out what’s happening,” said Dr Keane.

“I suspect we may be using the therapy too late in the treatment process, when the patient’s immune system is just too depleted to respond.”

Dr Keane has been able to collect important patient samples from sites around Australia for this study, which he says will give his team a big advantage in their work.

The outcomes from this study will potentially assist in the rational design of novel combination checkpoint-blockade therapies that may improve results for patients. 

Clinical trials

Dr Keane works as part of a larger team at TRI, overseen by the internationally renowned haematologist, Professor Maher Gandhi. The collaboration has allowed Dr Keane to be involved in several clinical trials running at the Princess Alexandra and Mater hospitals, including a current trial for Epstein-Barr Virus (EBV) positive lymphoma and another trial using an upfront treatment for Primary Refractory Aggressive Lymphoma.

Having such close ties between his laboratory and hospitals is very helpful for his research says Dr Keane.

“Obviously having a clinical link is really good for us to be able to translate our laboratory findings into the clinic as well as to get access to patients samples. The expertise across the different institutes is also very helpful when doing these projects,” he said.

“Clinical trials are vital part of the process required to improve the standards of care for our patients. It’s also incredibly important that we get Queensland patients, both in Brisbane and regionally, access to clinical trials. Institutes like TRI are helping us change this dynamic.”

Dr Keane says it’s also important to acknowledge the critical role his clinical colleagues and everyone in the Mater Research lymphoma research group at TRI for their contribution to his work as well as his MRFF rare cancer research grants, which are allowing him to “compete on a global stage”.

About Dr Colm Keane MB BCh, BAO, MSc, MBA, PhD, MRCPI, FRCPath FRCPA 

Born in Ireland, Dr Colm Keane studied Medicine at University College, Dublin. After completing his medical training in Ireland and England, he moved to Australia, where he has practised as a haematologist at the Princess Alexandra Hospital in Brisbane since 2007.

Dr Keane has a Masters in Haematopathology from the University of York and an MBA from Griffith University. He also competed his PhD in lymphoma research with Griffith in 2015. While undertaking his PhD, he held a Research Fellowship at the QIMR Berghofer Medical Research Institute, before taking up a joint position with Mater Research and The University of Queensland.

Dr Keane won the prestigious Princess Alexandra Hospital Young Clinician Award and ASCO Young Investigators Award in 2014 for his work on tissue based biomarkers in aggressive lymphoma. In 2016, Dr Keane was awarded an NHMRC Early Career Fellowship. He has received research grants from the NHMRC and the MRFF as well as from Cure Cancer and the Leukaemia Foundation in partnership with Bridgestone.

Research projects

• Immuno-genetic biomarkers of response in a prospective study of immune checkpoint therapy in primary CNS lymphoma
• Investigation of the key immuno-genetic drivers of Primary Central Nervous System Lymphoma that occurs in patients with HIV infection
• An Open Label, Multicentre, Phase One Study Incorporating Early Application of CAR T cells for Primary Refractory Aggressive Lymphoma
• An Open label, Multicentre, Phase I study of Ibrutinib, Rituximab and EBV specific T-cells in Patients with EBV-positive Primary or Secondary CNS Lymphoma unsuitable for standard therapies
• Investigation of unique immune microenvironment of Primary CNS Lymphoma

Recent journal publications

• Keane, Colm, Law, Soi C., Gould, Clare, Birch, Simone, Sabdia, Muhammed B., Merida de Long, Lilia, Thillaiyampalam, Gayathri, Abro, Emad, Tobin, Joshua W., Tan, Xiaohong, Xu-Monette, Zijun Y., Young, Ken H., Gifford, Grace, Gabreilli, Sara, Stevenson, William S., Gill, Anthony, Talaulikar, Dipti, Jain, Sanjiv, Hernandez, Annette, Halliday, Sarah-Jane, Bird, Robert, Cross, Donna, Hertzberg, Mark and Gandhi, Maher K. (2020). LAG3: a novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma. Blood Advances, 4 (7) 1367-1377. doi:10.1182/bloodadvances.2019001390
• Tobin, Joshua W.D., Keane, Colm, Gunawardana, Jay and Gandhi, Maher K. (2020). Reply to M. Sorigue. Journal of Clinical Oncology, 38 (6) 648-649. doi:10.1200/JCO.19.02935
• Cristino, Alexandre S., Nourse, Jamie, West, Rachael A., Sabdia, Muhammed Bilal, Law, Soi C., Gunawardana, Jay, Vari, Frank, Mujaj, Sally, Thillaiyampalam, Gayathri, Snell, Cameron, Gough, Madeline, Keane, Colm and Gandhi, Maher K. (2019). EBV-microRNA-BHRF1-2-5p targets the 3'UTR of immune-checkpoint ligands PD-L1 and PD-L2. Blood, 134 (25) 2261-2270. doi:10.1182/blood.2019000889
• Wight, Joel C., Yue, Mimi, Keane, Colm, Johnston, Anna, Linton, Kim, Chin, Collin, Wai, Shin Hnin, Talaulikar, Dipti, Gasiorowski, Robin, Yoon Cheah, Chan, Gregory, Gareth P., Dickinson, Michael, Minson, Adrian, Coombes, Caitlin, Ku, Matthew, Lam, Stephanie and Hawkes, Eliza A. (2019). Outcomes of synchronous systemic and central nervous system (CNS) involvement of diffuse large B-cell lymphoma are dictated by the CNS disease: a collaborative study of the Australasian Lymphoma Alliance. British Journal of Haematology, 187 (2) bjh.16064, 174-184. doi:10.1111/bjh.16064
• Keane, Colm, Tobin, Joshua, Gunawardana, Jay, Francis, Santiyagu, Gifford, Grace, Gabrielli, Sara, Gill, Anthony, Stevenson, William, Talaulikar, Dipti, Gould, Clare, Jain, Sanjiv, Birch, Simone, Hertzberg, Mark and Gandhi, Maher K. (2019). The tumour microenvironment is immuno‐tolerogenic and a principal determinant of patient outcome in EBV‐positive diffuse large B‐cell lymphoma. European Journal of Haematology, 103 (3) ejh.13274, 200-207. doi:10.1111/ejh.13274
• Tobin, Joshua W. D., Keane, Colm, Gunawardana, Jay, Mollee, Peter, Birch, Simone, Hoang, Thanh, Lee, Justina, Li, Li, Huang, Li, Murigneux, Valentine, Fink, J. Lynn, Matigian, Nicholas, Vari, Frank, Francis, Santiyagu, Kridel, Robert, Weigert, Oliver, Haebe, Sarah, Jurinovic, Vindi, Klapper, Wolfram, Steidl, Christian, Sehn, Laurie H., Law, Soi-Cheng, Wykes, Michelle N. and Gandhi, Maher K. (2019). Progression of disease within 24 months in follicular lymphoma is associated with reduced intratumoral immune infiltration. Journal of Clinical Oncology, 37 (34) 3300-3309. doi:10.1200/JCO.18.02365
• Lees, Charlotte, Keane, Colm, Gandhi, Maher K. and Gunawardana, Jay (2019). Biology and therapy of primary mediastinal B-cell lymphoma: current status and future directions. British Journal of Haematology, 185 (1) 25-41. doi:10.1111/bjh.15778
• Law, Soi Cheng, Haigh, Oscar L., Walpole, Carina M., Keane, Colm, Miles, John, Gandhi, Maher K., Radford, Kristen J. and Steptoe, Raymond J. (2019). Simple, rapid and inexpensive typing of common HLA class I alleles for immunological studies. Journal of Immunological Methods, 46572-76. doi:10.1016/j.jim.2018.12.002
• Keane, Colm and Yoon Cheah, Chan (2019). Designing optimal prognostic models for diffuse large B-cell lymphoma. Leukemia and Lymphoma, 60 (8) 1-3. doi:10.1080/10428194.2019.1599117