Introduction
In this feature on page 45 of this Issue 6, 2020 of UPDATE (Journal of Oncology and Haematology) Austin Duffy, Professor of Translational Oncology, Mater University Hospital and UCD, reflects back on an experimental treatment (immune checkpoint inhibitor) his patient with advanced liver cancer received at the NIH (National Institute of Health) when Prof Duffy was working there in 2013.
Prof Duffy’s disease area of interest is hepatocellular carcinoma (HCC) where immunotherapy has been paradigm-changing, especially since the recent landmark publication in NEJM demonstrating the clear superiority of an immune based (atezolizumab and bevacizumab) approach over sorafenib (the previous standard and only drug available in Ireland for this cancer).
But when Prof Duffy returned to Ireland in 2017, he was struck by the lack of access Irish patients had to these new treatments, that were readily available in the US. In this feature Prof Duffy tells us about opening the innovative and ‘science heavy’ NIH study in Dublin, to provide access to immunotherapy for Irish patients with liver cancer and to hopefully provide real and lasting benefit to Irish patients diagnosed with this difficult and intransigent cancer, with UCD as sponsor and study approval by HPRA and IRB. The study also allows linkages with the Biden Cancer Moonshot Initiative – giving patients access to the deep immunogenetic technologies available in the NIH.
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CASE-STUDY
In 2013, talking to one of my patients through an interpreter, I felt sure that we were making the wrong decision even as we were making it. My colleague Tim Greten and I, flanked by our research team, sat in front of our patient who was himself surrounded by his devoted family. There was no tension, just sadness, we were like two entourages hoping to come to terms on an agreement that neither side wanted. The gentleman had advanced liver cancer – caused by the hepatitis B virus he had probably picked up at birth – and he was taking part in an immunotherapy clinical trial that Tim and I had spent the previous two years developing. (He had already received all the standard treatments for his liver cancer – ablation, resection, followed upon relapse by several TACE procedures and sorafenib.) We were in one of the clinic rooms on the 12th floor of Building 10, in the heart of the National Institutes of Health, just outside Washington DC. Our patient, a lovely man originally from South East Asia, was 8 weeks into the experimental treatment but things weren’t looking so good. In the previous week he’d felt the need, reluctantly, to start taking oxycontin for his liver pain and – for probably the first time in his life – sick days from his physically demanding factory job. Talking to him, looking at him, it seemed pretty clear that hospice care was the next step and this was what we advised him. Through the interpreter he asked if there was any way he could stay on the protocol. He and his family wanted to give the treatment more time to work. We advised against it. While yes, it was true that there had been reports of what is termed ‘pseudoprogression’ on immunotherapy – where tumours worsen before eventually shrinking – the reality was that this was quite a rare phenomenon. Most likely his disease was simply getting worse. We didn’t want to waste any of the time he had left, he would be better off at home. The patient and his family looked at us. The counter argument was that he was tolerating the treatment remarkably well – not a single side-effect – and his laboratory parameters were all fine. Also, it was only a monthly infusion so the travel was not onerous. Our protocol did allow for continuing treatment a little longer given the possibility of a delayed response. After much discussion, we reluctantly agreed to give him the benefit of the doubt, proceeding with another dose of the treatment. He and his family were pleased but, leaving the room, both Tim and I felt like we had been out-negotiated somehow. A few weeks later, in our team meeting, our research nurse casually mentioned that she had spoken to our patient over the phone and he had stopped his pain medication. He was a stoical man, so perhaps this wasn’t such a surprise. He’s also back at work, she said. Ok, that was something. Sure enough, when we saw him again our patient looked better - more able to hop up onto the examination table, more conversant, our conversation far more routine than the previous one. Interestingly, his aFP tumour marker was in the thousands and continued to climb, but he was clinically so much better we had no qualms about continuing his treatment, at least until his restaging visit a few weeks later. When that came around we eagerly waited for the CT images to appear on the screen in our clinic room. Gathered at the computer we were amazed when we saw them. His liver tumours were all smaller, some of them had disappeared.
IMMUNOTHERAPY FOR LIVER CANCER
The experimental treatment our patient received was a form of immunotherapy. This is a broad term which encompasses a range of modalities – drugs, vaccines, cellular treatments, even viruses – united by a common underlying principle: manipulating a patient’s own immune system to attack their cancer, (as opposed to directly assaulting the dividing cells with cytotoxic chemotherapy or signal transduction inhibitors). The idea of immunotherapy has a long and colourful history, dating back to ‘Coley’s toxins’ in the late 1800s, when William Coley, a surgeon in New York, began administering – with apparently mixed results – direct intratumoral injections of bacteria in the hope of producing an inflammatory reaction against the cancer. Much of the subsequent century was spent elucidating a basic understanding of the immune system itself and it is perhaps surprising to see how recently this began to come together. (The T-cell receptor wasn’t identified until the early 1980s). The current era of clinical breakthroughs in immunotherapy has been built on the back of these and many other basic science discoveries, mapped out in increments by scientists working in largely neglected fields. The field of immunotherapy has exploded over the past decade – resulting in much hope (and no little hype). The breakthroughs seem to be coming thick and fast with barely a week going by without a new drug approval or indication. When I returned to Ireland in 2017 (after 11 years in the US) one of the first things that struck me was the lack of access Irish patients had to these new treatments which were readily available in America. It’s not a simple issue of course. These drugs are expensive and the fact that they don’t work for everyone’s cancer (perhaps not even for the majority) – but work spectacularly for some – only complicates things.
In my disease area of interest - hepatocellular carcinoma (HCC) - immunotherapy has been paradigm-changing. Historically, conventional drug treatment in HCC has been difficult due to the frequent co-existence of cirrhosis and hepatic dysfunction (impairing drug metabolism). Immunotherapy largely bypasses this, and is conceptually attractive for another reason: given that an immune process (inflammation) is commonly the underlying reason for liver cancer, an immune-based solution makes sense. Several immunotherapy drugs have been available for liver cancer for several years, but the standard of care definitively changed a few weeks ago with a landmark publication in the New England Journal of Medicine demonstrating the clear superiority (in any category you care to mention: responses, survival, quality of life measures) for an immune-based approach (atezolizumab and bevacizumab) over sorafenib (the previous standard and still the only drug available in Ireland for this cancer). The Food and Drug Administration in the US approved the new combination at the time of publication. Most likely it will be several years before Irish patients with liver cancer can be prescribed this treatment. In the meantime the only way for a patient here to access these new drugs is through a clinical trial. Of course, clinical trials shouldn’t really be a means of covering deficits in a country’s ability to provide the international standard of care but, practically speaking, they are the only means for patients to access new treatments. This was our motivation in wanting to take the clinical trial that Tim and I developed at the NIH and open it here in Dublin.
NIH CLINICAL TRIAL
The experimental treatment our patient received at the NIH was an immune checkpoint inhibitor combined with a more traditional HCC treatment: an ablative procedure directed at his tumour (or part of it). The rationale for the study was based on the work of numerous investigators in the ‘pre-immune checkpoint’ era who had noticed that when a liver tumour was either burnt or frozen (or had its blood supply interrupted), some tumour cell death occurred which led to a relatively weak (in clinical terms) systemic activation of the immune system. This effect could, in theory, be amplified (and rendered clinically relevant) if combined with immune checkpoint inhibitors whose main effect is to
exaggerate an immune response that has been already set in motion. At the time Tim and I designed our study there was little information on the safety of immunotherapy in patients with liver cancer, who tend to have significant associated conditions (viral hepatitis, for example). Therefore we had to proceed incrementally, with safety being our primary concern. We published our initial findings in 2016 before proceeding to ‘double up’ on the immune activation by adding a second immune checkpoint inhibitor. This second iteration of the study opened in 2016 but suffered a little in terms of accrual – ironically – because of the increased availability of immunotherapy drugs in the US as part of the evolving standard of care. (This meant that patients didn’t need to enrol on a clinical trial in order to access immunotherapy.) We don’t have the same problem here of course so opening the NIH study here in Dublin made sense all round: we could help with accrual while at the same time provide access to immunotherapy for Irish patients with liver cancer. Turning this relatively simple quid pro quo into a reality has been a challenge and has required a team effort. Clinical trials are (appropriately) highly regulated and monitored. It is not straightforward to take an experimental protocol which has evolved in one regulatory environment and transplant it into another, especially a fairly innovative, ‘science-heavy’ study such as this. Huge acknowledgement to Peter Doran and his staff at UCD Clinical Research Centre for accomplishing this, in particular Rabia Hussein and Anna Malara who managed to negotiate the fraught terrain of GDPR and regulatory compliance, not to mention the various contractual issues at play when several parties are involved. We also of course required the full backing of Tim and his colleagues at the NIH as well as the approval and funding support of AstraZeneca (who make and own the immune checkpoint inhibitors). Clinical colleagues (Ray McDermott, Diarmaid Houlihan, Ronan Ryan) have been enthusiastic about opening the study and collaborating on it. UCD have taken on the role of sponsorship and the study was approved by the HPRA and local IRB. On July 8 we initiated the trial in St Vincent’s Hospital – perhaps the main site for liver cancer in the country – and hope to enrol our first patient very soon. The trial will help us develop scientific links with the NIH by taking advantage of the local immunology expertise in Dublin. (Professor Cliona O’Farrelly of Trinity College Dublin is a co-investigator on the study). Excitingly, the study will also allow us to link in with the Biden Cancer Moonshot Initiative – thus giving our patients access to the deep immunogenetic technologies available in the NIH – and making us the only non-US/Canadian site to be added to the Moonshot as an adjunct site. Most importantly though, the study will hopefully provide real and lasting benefit to Irish patients diagnosed with this difficult and intransigent cancer.