An experimental vaccine aimed at a key genetic driver of pancreatic cancer has begun to produce promising early results in people at elevated risk for the disease. The so-called off-the-shelfKRAS vaccine successfully triggered long-term immune responses in most of the volunteers, offering optimism that cancer vaccines may one day provide a means to pre-empt pancreatic cancer.
The results are from a first-in-man Phase 1 trial in 20 people with a familial predisposition to pancreatic cancer and a previous abnormality on pancreatic imaging. The investigational agent, mKRAS-VAX, is aimed at the six most common mutations of the KRAS gene, which is mutated in many pancreatic ductal adenocarcinomas and their precursor lesions.
One of the hardest cancers to detect and treat is pancreatic cancer. It is asymptomatic in its early stages and is usually diagnosed at an advanced stage. Much research has been done to allow for the earlier detection and intervention in those with a hereditary risk to develop pancreatic cancer.
This is where the concept of this vaccine becomes fascinating. Instead of targeting a large, invasive tumor, the investigators are designed to educate the immune system to detect abnormal KRAS mutations much earlier in the disease process. Pancreatic precursor lesions can develop over years, if not decades, of evolving molecular aberrations providing an opportunity for immune intervention.
The vaccine is claimed to be “off-the-shelf” since it is not made individually for each patient. Instead, the vaccine consists of synthetic peptides for six of the most prevalent KRAS mutations in pancreatic cancer which is perhaps easier to produce than very individualised cancer vaccine, which usually involves analyzing the individual’s tumor and producing a personalized vaccine. The subjects were given 4 different doses of the vaccine, over an approximately 13-week period.
They were then monitored by blood sampling and follow-up examinations to assess safety and activity. The initial findings were remarkable. 18 out of 20 patients (or 90%) tested developed a substantial mutant KRAS-specific T-cell response. The median fold-increase was 18.
2, reflecting the ability of the vaccine to stimulate the expansion of the immune cell population that would be expected to recognize the tumor-specific mutant product of the Kras gene mutation. Both CD4-positive and CD8-positive T cells were recruited, indicating that the vaccine stimulated a whole immune cell response. There was also evidence of persistence of immune response in the study.
The group using T-cell receptor sequencing revealed that vaccine-induced KARS-specific immune-cell clones remained present for even up to two years post-vaccination. This is of great value as an abstraction or good would be to be able to generate a lasting immune memory which could identify abnormal cells after being vaccinated. After a median follow up of 16.
5 months, none of the 20 patients developed pancreatic cancer or a high risk pancreatic lesion necessitating surgery. Though, investigators are cautious about claiming this as evidence that the vaccine prevented cancer. The trial was very small, had no control arm, and was designed as a phase I trial to assess safety and immune response and not efficacy.