Progress in the Creation of a Neoantigen Cancer Vaccine

Targeting therapies to some combination of neoantigens, distinctive markers on the surface of cancerous cells that the immune system learns to recognize, and which vary from patient to patient, represents an advance in the specificity of targeted cancer immunotherapy. It should, in principle, better rouse the immune system to attack cancerous cells, while producing fewer side-effects. Researchers here report on an early human trial of this sort of approach; the initial results look promising, certainly from the perspective of an absence of serious side-effects, though a more robust demonstration of the ability to reduce tumor burden is still needed.

A personal cancer treatment vaccine that targets distinctive "neoantigens" on tumor cells has been shown to stimulate a potent, safe, and highly specific immune anti-tumor response in melanoma patients. Antigens are molecules that are displayed on the surface of cells and stimulate the immune system. Neoantigens are molecules on cell's surfaces that are produced by DNA mutations that are present in cancer cells but not in normal cells, making neoantigens ideal targets for immune therapy against cancer. The vaccines used in the phase I trial contained up to 20 neoantigens, derived from an individual patient's tumor. The vaccines were administered to patients to train their immune system to recognize these neoantigens, with the goal of stimulating the immune system to destroy the cancer cells that display them.

While other immunotherapies, such as checkpoint inhibitor drugs, also trigger immune responses against cancer neoantigens, they are not designed to be specific. They can also induce responses against normal tissue antigens, leading the immune system to attack normal tissues and cause toxicity in a subset of patients. The researchers found that the personal vaccine induced a focused T cell response against several tumor neoantigens, beyond what is normally seen in response to existing immunotherapies.

The vaccine was administered to six patients with melanoma whose tumors had been removed by surgery and who were considered at high risk for recurrence. The vaccinations were started at a median of 18 weeks after surgery. At a median of 25 months after vaccination, four of the six patients showed no evidence of cancer recurrence. In the other two patients, whose cancer had spread to their lungs, the disease recurred after vaccination. At that point, they began treatment with the drug pembrolizumab, which inhibits the PD-1 immune checkpoint. Both patients had complete resolution of their tumors and remain free of disease according to imaging scans.

The study results suggest, that a personalized neoantigen vaccine can potentially overcome two major hurdles in cancer therapy. One is the heterogeneity of tumors - the fact that they are made up of cells with a variety of different traits, which often allows cancers to evade drugs targeted to malignant cells having a single genetic abnormality. The vaccine, because it contains many different neoantigens from the tumor, targets multiple genetic types of tumor cells. A second hurdle in cancer is to generate an immune response sharply focused on cancer cells while avoiding normal cells and tissues. This aim was achieved by the vaccine, which appeared to have few "off-target" effects, causing only flu-like symptoms, fatigue, rashes, and irritation at the site of the vaccine injection, according to the report.



It would be interesting to see this technology combined with some of the oncoming improved vaccine technologies such as high density lipoprotein nanodisks:

""Thanks to their ultrasmall size (around 10 nm in diameter), the nanodiscs efficiently drain through lymphatic vessels after being injected into the body," explains Schwendeman, "thereby significantly improving delivery of antigen peptides and adjuvants to lymphoid tissues." And that is not all: compared with other HDLs (produced from purified human plasma, for example), the new HDLs do not trigger autoimmunity.

The nanodiscs can be used to deliver antigens to draining lymph nodes in the body and stimulate the activity of anti-tumour T-cells that significantly inhibit tumour growth. "They can also eradicate established tumours when combined with so-called immune checkpoint inhibitors (that work by removing the 'brakes' in immunosuppressed T-cells)," Moon tells "And in experiments on mice, they even protect the animals from tumour recurrence."

Posted by: Jim at July 8th, 2017 10:28 AM

Purine deficient bacteria as a means of more selectively delivering checkpoint blockade or immunostimulatory drugs to tumours are also a developing technology that would be interesting to see in combination with neoantigen vaccines.

"To use these common intestinal bacteria as tumor-seeking missiles, Lyon and Bellamkonda, working with lead co-author Nalini Mehta, selected a detoxified strain of S. typhimurium that was also deficient in a crucial enzyme called purine, forcing the bacteria to seek supplies elsewhere.
Tumors just so happen to be an excellent source of purine, causing the bacteria to flock to them in droves.

Then, the Duke engineers made a series of genetic tweaks so that the bacteria would produce two compounds called Azurin and p53 that instruct cells to commit suicide-but only in the presence of low levels of oxygen. And since cancerous cells are multiplying so energetically, the environment around and within tumors has unusually low oxygen."

Posted by: Jim at July 8th, 2017 10:40 AM

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