Cancer Research Wales

The New Year started on a high with the publication, in prestigious journals, of two research articles that has resulted from Cancer Research Wales (CRW) funded projects. The closely related papers report how malignant cells in both colorectal cancer (CRC) and Chronic Lymphoblastic Leukaemia (CLL) are able to manipulate the immune system and induce a state of ‘immuno-suppression’. This phenomenon effectively allows the cancer to take a firmer hold in the body, thus impacting upon the clinical course of the disease.

The first study led by Dr Andrew Godkin (pictured) at the Heath Hospital in Cardiff examined the impact of T-regulatory cells (T-regs) in colon cancer patients, both before and following surgical removal of the tumour. T-reg cells, which as their name suggests, normally function to stringently regulate and suppress the activity of key modulators in the immune system in order to prevent inappropriate over-stimulation of the immune system which can lead to the destruction of healthy tissue and autoimmune disease. The main physiological target of T-reg cells are T-effector cells, a vital cell of the immune system whose role is to keep the body free of disease through the killing and removal of cancerous cells and cells infected with invading microbes. Dr Godkin and his team have revealed that the blood and tumours of colon cancer patients harbour increased numbers of T-reg cells, which in line with their function, invoke an immuno-suppressive trait within the immune system. These alterations skew the overall immune response in favour of the tumour, thus allowing the cancer to grow, unrestrained by the T-effector cells which set out to eliminate the cancer. The work published in the leading journal Gut, also went on to show that following surgery, the number of T-reg cells in the blood of patients decreased to levels of that observed in healthy subjects. Importantly, this reduction was accompanied by an improvement in the ability of patients T-effector cells to recognise and mount an immune response against tumour-associated molecules they recognise as foreign. Collectively, these findings strongly implicate the tumour as the causal factor for the increased T-reg number and the accompanying immuno-suppression observed in colon cancer patients.

The above findings have a number of therapeutic implications, including the use of vaccines in cancer. The concept of using vaccination strategies to eradicate tumours is appealing, although the reality is more sobering, given that many clinical trials involving cancer vaccines have met with limited success. One significant factor is the inability of patients’ immune system to mount an effective response and produce cells and antibodies that will home in and attack the cancer. Indeed, T-reg cells are considered the most potent inhibitors of anti-tumour immunity and the greatest obstacle to effective cancer vaccines. However, insights gained from studies such as the one described above provide new information and clues of how to use such therapeutic modalities more effectively. To this end, Dr Godkin is currently undertaking a CRW sponsored Phase II cancer vaccine clinical trial in patients with advanced colon cancer. The trial will incorporate the use low dose cyclophosphamide, a conventional chemotherapeutic agent that has the ability to selectively deplete the number of immuno-suppressive T-reg cells in the blood and tumours of colon cancer patients. Following depletion of T-reg cells, a cancer vaccine will be administered so that a more effective immune response can be invoked toward the modified colon cancer molecules contained within the vaccine design. The expected boost in anti-tumour immunity will hopefully result with increased elimination of cancerous colon tissue in these patients. The sequential series images (right) illustrate how activated T cells can home in (panel1) and kill cancer cells through the release of immune mediators as depicted by increased cancer cell blebbing and lysis (panels 2 and 3). The trial called TaCTiCC represents one of the first bench-to-bedside studies of its nature in Wales and is a great example of how, with research, better use can be made of existing anti-cancer agents such as cyclophosphamide.

The second study was a collaborative venture involving five CRW supported scientists who together investigated whether immune dysfunction could play a significant role in clinical outcome of early stage Chronic Lymphocytic Leukemia (CLL). CLL, a chronic B-cell leukaemia is the most common form leukaemia in the UK and predominantly affects people over the age of 50. Most people with early stage CLL exhibit little if any symptoms and is often only detected incidentally following routine blood tests for other purposes. In the early stages of the disease most patients remain well for long periods of time and do not require any form of treatment. Instead they are continually monitored over years for evidence of disease progression, a process known as ‘watchful waiting’. It can frequently take over 12 years for people with early stage CLL to develop a level of advanced disease that will require therapeutic intervention. However, not an insignificant number of patients, particularly those of younger age, have a more rapid onset of disease progression and will require treatment sooner. For these patients, disease markers are needed that can identify those at high risk, given that the conventional pathological parameters currently used have their limitations. The group led by Drs Steve Man (pictured) and Chris Pepper found that the ratio of two molecules expressed on the surface of T cells in the blood of patients with early stage CLL, known as CD4 and CD8 can accurately determine those who have a significantly shorter lead in time to treatment. Specifically, a higher proportion of CD8 positive T cells relative to CD4 positive T cells (termed an inverted ratio), indicate that these patients required therapy between 3-5 years earlier than those patients with a normal CD4:CD8 ratio. The investigators also went on to show in the same paper, published in Clinical Cancer Research, that T cells in patients with an inverted ratio displayed markers of ‘exhaustion’. In other words, the very cells responsible for keeping tumour B cells in check had literally become ‘worn out’, resulting in a loss of immunological control of the cancer, paralleled with the onset of aggressive disease. With further work, the ability to pinpoint such high risk subgroups using such findings as described above may very well allow treating clinicians to better determine the exact course of treatment best suited for individual patients with early CLL.

Links to the detailed papers are as follows

Nunes T, Wong R, Mason M et al. Expansion of a CD8+PD-1+ replicative senescence phenotype in early stage CLL patients is associated with inverted CD4 :CD8 ratios and disease progression. Clinical Cancer Research (2012) Jan 20. http://www.ncbi.nlm.nih.gov/pubmed/22190592

Betts G, Jones E, Junaid S et al. Suppression of tumour-specific CD4+ T cells by regulatory T cells is associated with progression of human colorectal cancer. Gut (2011) Dec 29. http://www.ncbi.nlm.nih.gov/pubmed/22207629

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Andrew Godkin, antitumour immunity, Cancer Research Wales, cancer vaccines, chronic lymphoblastic leukemia, clinical trial, colon cancer, cyclophosphamide, immune system, Steve Man