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FDA Grants Orphan Status for the CRS-207 Vaccine with GVAX Immunotherapy for Pancreatic Cancer

In an interesting step with intriguingly complex promise, the Office of Orphan Products Development of the U.S. Food and Drug Administration recently designated the immunotherapy CRS-207 as having orphan drug status for use in sequential combination with the GVAX Pancreas biologic for the treatment of pancreatic cancer (ductal adenocarcinoma of the pancreas). Both of these immunotherapeutic agents are owned by Aduro BioTech Inc. of Berkeley, California.

This move by the FDA coincides with Aduro having recently completed a randomized controlled Phase II clinical trial of patients with metastatic pancreatic cancer with this regimen (as yet unpublished), and appears to have sprung from the earlier work of Laheru and colleagues at Johns Hopkins University pursuant to a study published in the February 2012 issue of Clinical Cancer Research, the official journal of the American Association For Cancer Research. In this earlier Phase I research study, three of the patients with pancreatic cancer who had been earlier treated with GVAX appeared to show disease stability after the addition of further immunotherapy that included CRS-207.

Although vaccines and immunotherapies have been an interesting concept in theory generally in cancer and specifically in pancreatic cancer – there have been no clear breakthroughs.

CRS-207 is a live but attenuated Listeria monocytogenes strain that is aimed to induce an immunologic response specific to the antigen: mesothelin – which tends to be over-expressed in pancreatic cancer.  GVAX is a biologic that stimulates “granulocyte-macrophage colony-stimulating factor” (GM-CSF), boosting white cells including monocytes that roam and can mature into macrophages and dendritic cells – which augment the immune system’s ability to fight cancer.

In February 2013, Aduro purchased GVAX from BioSante Pharmaceuticals, Inc.  Drew Pardoll, MD, PhD of Johns Hopkins University is the Chairman of the Scientific Advisory Board of Aduro BioTech. He and other researchers from Johns Hopkins have been involved in research with GVAX and pancreatic cancer for over a decade.

This 1-2 punch (CRS-207 / GVAX) at different areas of the immunologic / inflammatory cascade is a clever and promising idea for the treatment of pancreatic cancer.  It will be interesting to see the results of the Phase II work, and to follow the results of this novel and creative line of study.

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Dale O’Brien, MD

FOLFIRINOX (Minus Irinotecan) for Gemcitabine-refractory Pancreatic Cancer

Since the promising article on the 4-drug 5-FU led FOLFIRINOX regimen for metastatic pancreatic cancer (ductal adenocarcinoma of the pancreas) per the May 12, 2011 article in the New England Journal of Medicine, this treatment approach has emerged as a solid first-line option.  In the ensuing months there have been a number of studies exploring further options with this 4-drug combination, including for other stages in cancer of the pancreas.

Now comes interesting research by Wahba and El-Hadaad of Mansoura University, Egypt as published in the September 2013 issue of the Journal of Gastrointestinal Cancer looking at a somewhat truncated version of this regimen in patients whose advanced pancreatic cancer showed progression after treatment with gemcitabine.

In a phase 2 clinical trial, the authors treated thirty such patients with a regimen that included 5-FU (fluorouacil), folinic acid, and oxaliplatin (the FOLFIRINOX regimen without irinotecan) with tolerable (adjudged) side-effects and a median overall survival of 22 weeks, and a six-month survival rate of 30%. They conclude that this regimen is active and in need of further study.

We concur. Very interesting work – that would benefit by follow-up research.

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Dale O’Brien, MD

Microwave “Surgery” for Pancreatic Cancer

Studies involving the thermal (heating) mode for the treatment of pancreatic cancer (ductal adenocarcinoma of the pancreas) have generally concentrated on radio waves. This form of “surgery” is called ablation – and of course is not surgery at all, but the destruction of tumor tissue by heating it to levels that cause cell death.  Generally, the range of 120 to 140 degrees (Fahrenheit) will cause coagulation and then cell death in a matter of minutes. Temperatures above this will cause immediate tissue death.

Radio waves and microwaves can each heat tissues to these levels, but their mechanisms are quite different. Radiofrequency ablation (RFA) relies on electrical current running through the tissue in the form of a complete circuit.  It works because ion rich fluid permeates the human body.  And as body tissue is not a perfect electrical conductor, a resistive rise in temperature occurs.

Microwave ablation is a form of dielectric heating based on an alternating electromagnetic field, and in which the tissue itself is the dielectric material. Water molecules in the tissue are forced to oscillate, with some bound molecules oscillating out of phase – causing energy to be converted to heat.

Thus microwave heating tends to occur in the space around the applicator wand, while radio frequency heating is limited to specific areas created by high electrical current. Radiofrequency ablation (RFA) has increasingly been shown to be an effective modality in the treatment of tumors in such organs as the liver, lung and kidney.  But due to its reliance on tissue properties, RFA can be somewhat limiting. Microwaves are less effected by tissue properties and offer very good penetration. However, there has not been a long history with commercial or academic microwave systems, and correspondingly there have been less studies involving microwave ablation for the treatment of cancer.

So it is with great interest that we read the recent research by Carrafiello and colleagues from the Division of Interventional Radiology, Department of Radiology at the University of Insubria in Varese, Italy as published in the October 2013 issue of the Journal of Vascular and Interventional Radiology which reports on microwave ablation for pancreatic cancer.

The researchers treated ten patients who had adenocarcinoma located in the head of the pancreas with a microwave generator for ten minutes at intermittent intervals for up to 12 months.  The tumor response was measured, and the safety and effectiveness of the procedure was evaluated.

The authors report that the procedure was feasible in all of the patients.  They indicate that there was one major complication which occurred but was resolved.  That the patients quality of life tended to improve after the microwave applications, but that this tended to revert to pre-procedure levels in weeks to months after the intervention. They conclude the microwave ablation appears to be encouraging and feasible in the palliative care of pancreatic cancer.

This is an interesting study of an under-studied intervention.  Microwave ablation in the treatment of pancreatic cancer deserves further inquiry.

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Dale O’Brien, MD