Combating a vicious disease

C&I Issue 22, 2011

The recent deaths from pancreatic cancer of Apple’s former ceo Steve Jobs and this year’s Nobel medicine laureate Ralph Steinman, as well as the actor Patrick Swayze in 2009, have highlighted a disease that has a dismal prognosis.

Pancreatic cancer is the fifth most common cause of cancer death in the UK but has the lowest survival rate of any common cancer. Most patients are expected to live between three and six months, while only 3% of those diagnosed survive more than five years – and survival rates have not improved in the last 40 years.

With current treatments lacking, hope is turning to biological therapies in development to significantly improve the outlook of pancreatic cancer patients.

About 8,000 patients in the UK, and 29,000 in the EU, develop pancreatic cancer each year – and about the same number die of it each year. It is an aggressive disease that occurs deep inside the body and produces non-specific symptoms in its early stages. This means it is usually detected at an advanced stage, when the cancer has already spread to other organs and surgery is not an option.

‘Unless a patient has extremely early disease that can be completely removed by surgery, the outlook is bleak because this type of cancer responds poorly to conventional chemotherapy and is resistant to radiotherapy,’ says Nicholas Lemoine, director of Barts Cancer Institute and chair of the Pancreatic Cancer Research Fund’s scientific advisory panel (www.pcrf.org.uk). ‘The unmet clinical need is huge.’

Currently, the most ‘effective’ chemotherapy combinations are GemCap, consisting of gemcitabine and capecitabine (Xeloda) and Folfirinox (oxaliplatin, irinotecan, fluorouracil and leucovorin), but even with these the time before the disease starts to progress again is only six or seven months, and half the patients will have died by one year, says Lemoine.

‘Recently it has been recognised that one of the characteristic features of the pancreatic cancer – an intense fibrous reaction that impedes the blood supply around the tumour deposits – actually stops drugs getting through. So even if the chemotherapies worked better at killing pancreatic cancer cells, not enough would reach the tumour to be effective,’ adds Lemoine.

The reign of Gemzar (gemcitabine) as the gold standard treatment in metastatic pancreatic cancer is in flux, at least as a monotherapy, says Sophia Walker, senior analyst, advanced markets, healthcare and pharma, at IHS Global Insight. She says research has now turned to evaluating Gemzar with other therapies, including targeted ones.

For example, the combination of Gemzar and Roche’s Xeloda (capecitabine), an EGFR inhibitor that slows tumour growth by inhibiting DNA synthesis CK, was approved in the US in 2005 and the EU in 2007 and is one of the first examples of a ‘successful’ combination therapy, says Walker. ‘Although “successful” needs to be used lightly because, despite the approvals, the combination therapy has only shown a modest extension in survival and had trouble receiving reimbursement as a result,’ she says.

And, although the results of a Phase III trial of Folfiriniox in combination with Gemzar, (New England Journal of Medicine, 2011, 364, 1817) demonstrated the most promising survival data yet for a combination therapy, those results are overshadowed by concerning safety data, which demonstrate more severe adverse events for the combination therapy than Gemzar alone, adds Walker.

Meanwhile, current pancreatic cancer research – like cancer research in general – is focusing on evaluating cancer vaccines and immunotherapies.

For example, Iowa-based NewLink Genetics is developing HyperAcute Pancreas, a cancer immunotherapy currently in Phase III trials for the treatment of surgically-resected pancreatic cancer. HyperAcute Pancreas, which has received fast track status from the US Food and Drug Administration (FDA), consists of two types of pancreatic cancer cell lines that have been engineered to express molecules that encourage a response from the immune system – a response that should also destroy the patient’s tumour. NewLink is currently planning a Phase I trial of the treatment.

Colorado-based GlobeImmune is developing GI-4000, a treatment that kills cells containing the ras oncogene. Ras mutations occur in about 90% of pancreatic cancers, and tumours caused this way may be resistant to current therapies, according to the company.

GI-4000 is a yeast genetically modified to express protein targets that stimulate the immune system against ras-containing diseased cells. A Phase I study of 33 patients with advanced colorectal and pancreas cancer treated with GI-4000 over 29 days showed that GI-4000 was well-tolerated and prompted an antigen-specific T-cell response in 90% of patients.

One patient with stage IV pancreatic cancer was clinical stable for eight months after treatment, and five patients lived between one and two-and-a-half years. GI-4000 is currently in Phase II trials.

In August 2011, the FDA granted orphan drug status to Merrimack Pharmaceuticals’ MM-398 for the treatment of pancreatic cancer. Such status is given to companies developing promising drugs for diseases that affect fewer than 200,000 people in the US.

MM-398 is a nanotheraputic encapsulation of the marketed chemotherapy drug irinotecan. A recent phase II study involved 40 metastatic pancreatic cancer patients who had previously failed treatment with gemcitabine. Patients treated with MM-398 survived on average over 22 weeks, while 20% lived for more than a year. Merrimack plans to start a Phase III trial by the end of 2011.

Amgen and Takeda are developing Ganitumab (AMG 479), a monoclonal antibody that targets type 1 insulin-like growth factor receptor, blocking two growth hormones (IGF-1 and IGF-2) to slow the growth of pancreatic tumour cells. Phase II results have shown that patients given a combination of Ganitumab and gemcitabine survived 8.7 months, compared with only 5.9 months for those given gemcitabine alone. Results of Amgen’s Phase III study are expected in October 2013.

Researchers in the US have shown that a combination of gemcitabine chemotherapy and a CD40 antibody, manufactured by Pfizer, shows promise in treating pancreatic cancer. Tests in a small group of patients who had surgically incurable pancreatic cancer showed that treatment appeared to halt progression of the cancer for an average of 5.6 months, with some tumours shrinking substantially (Science, 2011, 331, (6024) 1539).

The researchers found that the antibody activated CD40, promoting macrophages, which suppressed the tumours by depleting the structural/supporting stroma around them.  ‘Until this research, we thought the immune system needed to attack the cancer directly in order to be effective,’ said senior author Robert Vonderheide, an associate professor of medicine in the division of haematology/oncology and the Abramson Family Cancer Research Institute. ‘Now we know that isn’t necessarily so.

These results provide fresh insight to build new immune therapies for cancer.’

‘Within metastatic pancreatic cancer, the most vicious of cancers, there is much hope for these new developments as either a replacement for, or as means to increase the efficacy of Gemzar,’ says Walker, ‘however, despite a bustling pipeline, no cancer vaccine has been approved yet for pancreatic cancer. But vaccines have been showing some promise and one such vaccines, GV1001 has been garnering a lot of attention lately.’

GV1001 is a peptide vaccine being developed by Korean company Kael-GemVax. It is a 16 amino acid-long sequence containing two different types of epitopes that activate two types of immune responses to attack cells expressing the telomerase enzyme, which is expressed in large amounts in tumour cells.

Results of the Phase III TeloVac trial, which is testing the cancer vaccine in combination with Gemzar and Xeloda, are expected by 2012. ‘These results are highly anticipated as early phase data showed much promise,’ says Walker.

‘The new biological approaches to pancreatic cancer are really exciting as they target the disease in a completely different way to chemotherapy and so are not affected by the same mechanisms of resistance,’ says Lemoine. ‘Using techniques that stimulate a powerful immune response and mobilise lymphocytes and natural killer cells that can actively force their way through the fibrous network that surrounds these tumours is really attractive. So the vaccine and antibody approaches look good for this, but also really interesting is the use of cancer-targeted viruses that trigger powerful immune effects against the infected tumour cells.’

One example of this is Jennerex Biotherapeutics’ efforts in developing JX-929 for treating pancreatic cancer. JX-929 is a vaccinia virus that has had two genes removed so that it only replicates in cancer cells: cells with large nucleotide pools and cells with an active EGFR-Ras pathway, a common mutation in many cancers.

In addition, a modification means that JX-929 contains an enzyme that can convert a subsequently administered nontoxic prodrug to a chemotherapy drug. So as well as a viral attack, chemotherapy is selectively activated in cancer tissue – markedly increasing potency while decreasing side effects. JX-929 is currently in Phase I trials.

Most of these potential treatments are in the very early stages of development.  Nevertheless, says Walker, pancreatic cancer, with its desperate need for new therapies which show an increase in survival, remains a hotly watched area.

Emma Dorey is a science writer based in Brighton, UK.

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