Monday, July 18, 2011

Breakthrough therapy for pancreatic cancer?

A potential new therapy that targets not the ‘bricks’ but the ‘mortar’ of pancreatic cancer may offer new hope to patients. The research is led by an Irish doctor, writes Eimear Vize.
With less than 5% of pancreatic cancer patients surviving the first five years after diagnosis, this notoriously aggressive disease typically has a very poor prognosis. So when news was released earlier this year about the discovery of a novel immune therapy for pancreatic cancer, the medical world sat up and took note.

Researchers, led by an Irish doctor Peter O’Dwyer, not only found that an experimental antibody caused pancreatic tumours to shrink significantly in a small cohort of patients, they also believe their findings - and the novel way in which they uncovered them - could lead to quicker, less expensive cancer drug development.

Until now, it was assumed that the immune system needed to attack the cancer cells directly in order to be effective, however, this new research from the University of Pennsylvania's (Penn) Abramson Cancer Center revealed that CD40 antibodies could trigger the patient’s own immune system into shredding the structural “scaffolding” that holds tumours together.

And they made this groundbreaking discovery by happy accident.

In the clinical trial, led by Prof Peter O'Dwyer, professor of medicine at Penn, and Dr Gregory Beatty, instructor in medicine, 21 patients with surgically incurable pancreatic ductal adenocarcinoma (PDA) were treated with standard gemcitabine chemotherapy as well as an agonist CD40 antibody - an experimental antibody manufactured by Pfizer Corporation.

“The micro-environment of the pancreatic tumour is a hostile and inflammatory environment, fuelling the malignant process and preventing access of anti-cancer drugs to the tumour cells,” explains Prof O’Dwyer. “The essence of using an antibody such as CD40 is to engage the immune system and try to activate one’s normal immune responses to recognise the tumour cell as something that ought not be there and eliminate it.

“Our hypothesis was that the antibody would bind and stimulate a cell surface receptor called CD40, which is a key regulator of T-cell activation. The CD40 antibodies would then turn on the T cells and allow them to do their job and attack the tumour. That was our theory, anyway.”

In a departure from the usual sequence of experiments, a unique mouse model of pancreatic cancer - developed at Penn - was used concurrently by Prof O’Dwyer and his colleagues to fully understand the human response to the immune therapy.

Unlike older mouse models that were simplistic models of human disease, these genetically engineered mice develop spontaneous cancers that are very close reproductions of human tumours.

Prof Peter O'Dwyer
“This model recapitulates the process by which most pancreatic cancers seem to occur in people. Even though it’s a very difficult model to work with, it’s a much more reliable model to mimic what’s going on in people. It means we can perform preclinical trials in these mice with the same principles we use in our patients,” Prof O’Dwyer adds.

The research team found that the experimental treatment appeared to work, with some patients' tumours shrinking substantially and the vast majority of tumours losing metabolic activity after therapy, although all of the responding patients eventually relapsed.

However, the real surprise came when investigators examined post-treatment tumour samples from the mouse models, which had been treated with the identical regimen. They expected to find swarming T cells busy doing their job but there were no T cells to be seen. Instead, they discovered an abundance of another white blood cell known as macrophages, which usually get co-opted into helping the tumours.

Closer inspection revealed that the macrophages had turned traitor and were attacking the tumour stroma - the supporting tissue around the tumour.

Pancreatic tumours secrete chemical signals that draw macrophages to the tumour site, but if left to their own devices, these macrophages would protect the tumour. The Penn researchers found that treating the mice (or patients) with CD40 antibodies seems to flip that system on its head.

"It is something of a Trojan horse approach," remarks senior author Dr Robert Vonderheide, an associate professor of medicine at Penn. "The tumour is still calling in macrophages, but now we've used the CD40 receptor to re-educate those macrophages to attack - not promote - the tumour."

While the current focus of immunotherapy is to strengthen the immune response to launch a direct attack on tumour cells, this new research suggests that attacking the dense tissues surrounding the cancer is another approach.

Dr Vonderheide says this tactic is “similar to attacking a brick wall by dissolving the mortar in the wall”.

He continues: “Ultimately, the immune system was able to eat away at this tissue surrounding the cancer, and the tumours fell apart as a result of that assault. These results provide fresh insight to build new immune therapies for cancer."

Prof O’Dwyer agrees that their research highlights the importance of designing treatments that focus not just on tumour cells but also on the neighbouring tissue that helps them survive and grow. This hold particularly relevance in pancreatic tumours as the surrounding tissue is very dense, fibrotic, and hostile, which is one of the main reasons standard therapies for this disease often work so poorly.

“There was evidence of response in most of the patients, which you wouldn’t ordinarily see in this cohort,” he notes. “The study is very preliminary, and it’s important not to over interpret results from a relatively small clinical trial, which this was, but I would say that these results are promising and interesting and they need to be verified by additional studies.”

Prof O’Dwyer and colleagues are now working on ways to capitalise on their novel information, testing ways to super-charge the macrophage response and to get the T cells into the tumour micro-environment.

It is also possible they may be able to speed up clinical research by running pilot trials in the mice to test potential therapeutics. Once they understand responses in the mice, then they can use that information to design better human trials.

Beyond the current research conclusions relating to pancreatic tumours, the Penn investigators believe these findings point to a new approach for drug development in cancer - one where state-of-the-art mouse models are used for preclinical trials to guide which trials should be carried out next in patients. This approach could prove faster and cheaper, giving researchers a head start in the clinical trials.

Prof O’Dwyer is naturally excited about the study results; it’s implications for the development of immunotherapy in treating pancreatic cancer as well as other cancers, potentially.

“Our trial was the first round of human tests. It was really designed to figure out the dose that we could safely administer this antibody along with standard doses of gemcitabine. In fact, there was a very small range of doses; almost everyone on the trial received doses that we thought were going to be effective and well tolerated.

“The CD40 antibodies appear not to be terribly toxic; the patients did not have much more in the way of side effects than they would have had from the chemotherapy by itself,” he notes.

The big question is whether the results in this preliminary trial in pancreatic cancer patients could be reproduced across the cancers. “The answer should be yes but we don’t know. Those studies have to be done,” says Prof O’Dwyer.

“With regard to pancreatic cancer, a number of exciting changes in how we treat this disease have emerged in the last two years or so. Some of the chemotherapy treatments have changed and become more effective, and others are in the pipeline. Also, targeted compounds are being investigated in patients with pancreatic cancer. It seems likely to me that the standard treatments for this disease are going to change fairly markedly in the next five years, with significant improvement in patient outcome,” predicts Prof O’Dwyer.

“I believe that activating the immune system, if it really is going to work, is going to be a part of a multi-dimensional approach to the management of this disease; chemotherapy will be important, as will targeted therapies, perhaps by attacking the tumour’s blood vessels or the growth signalling pathways within the tumour. The combined use of these with immunostimulatory approaches is likely to be the most fruitful in combating this disease and the best tolerated by the patient.”

The research paper - CD40 Agonists Alter Tumour Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans - was published in the journal Science (25 March 2011: 1612-1616).

Clinical trials in Ireland

Professor Peter O’Dwyer, who co-led groundbreaking research in the US on a novel immune therapy that targeted tumour stroma in the treatment of pancreatic cancer, says Ireland offers an attractive potential location for further research on the experimental CD40 antibody.

The Irish doctor, who is vice-chairperson of Eastern Co-operative Oncology Group (ECOG) in the US, is working closely with members of the All-Ireland Cooperative Oncology Research Group (ICORG) on a number of other clinical trials in Ireland.

“There are several cancer trials ongoing at the Irish research sites that are being conducted through ECOG. We have been building a strong relationship with ICORG members for three or four years now and we are hoping to expand this activity significantly over the next two years.

“There are no immediate plans to involve ICORG in a further study of the CD40 antibody but it would be our goal,” he says.

He pointed out that ICORG is the only full European member of ECOG.

Prof O’Dwyer serves as Professor of Medicine in the Haematology-Oncology division at the University of Pennsylvania and Director and Program Leader of the Experimental Therapeutics Program in the Abramson Cancer Center of the University of Pennsylvania.