Personalized bacterial vaccine shows promise as cancer immunotherapy

Columbia researchers have engineered probiotic bacteria that teach the immune system to destroy cancer cells, opening the door to a new class of cancer vaccines that take advantage of the bacteria’s natural tumor-targeting properties. These microbial cancer vaccines can be personalized to attack each individual’s primary tumor and metastases, and may even prevent future recurrences.

In studies using mouse models of advanced colorectal cancer and melanoma, the bacterial vaccine supercharged the immune system to suppress the growth of — or in many cases, eliminate — primary and metastatic cancers. While leaving healthy parts of the body alone.

The results were published on October 16 in Nature in an article titled “Probiotic Neoantigen Delivery Vectors for Precision Cancer Immunotherapy.”

The bacterial vaccine was found to be notably more effective than the peptide-based therapeutic cancer vaccines that have been used in many previous cancer clinical trials.

“The important advantage of our system is its unique ability to coordinately restructure and activate all arms of the immune system to induce a productive anti-tumor immune response. We believe this is why the system works so well in advanced solid tumor models that have been particularly difficult to achieve. treat with other immunotherapies,” says Andrew Redenti, MD/Ph.D. student at Columbia University’s Vagelos College of Physicians and Surgeons who helped lead the study.

“The net effect is that the bacterial vaccine is able to control or eliminate the growth of advanced primary or metastatic tumors and prolong the survival of mouse models,” says Jongwon Im, a Ph.D. student at Columbia University who helped lead the bacterial engineering aspects of the study.

The bacterial vaccine is personalized for each tumor.

“Every cancer is unique: tumor cells harbor distinct genetic mutations that distinguish them from normal healthy cells. By programming bacteria that direct the immune system to target these cancer-specific mutations, we can design more effective therapies that stimulate a patient’s immune system to detect and kill their cancer cells,” says Nicholas Arpaia, Ph.D., associate professor of microbiology and immunology at Columbia University’s Vagelos College of Physicians and Surgeons, who led the research with Tal Danino, Ph.D., associate professor of biomedical sciences at Columbia’s School of Engineering.

“As we continue to incorporate additional safety optimizations through further genetic programming, we get closer to the point of testing this therapy in patients,” he adds.

Bacteria as a treatment for cancer

Bacteria have been used in the treatment of cancer since the late 19th century, when Dr. William Coley, a surgeon at New York Hospital, observed tumor regression in a subset of patients with inoperable tumors who received a injection of bacteria. The bacteria are still used today as a therapeutic in patients with early-stage bladder cancer.

Researchers now know that certain bacteria can naturally migrate to and colonize tumors, where they can thrive in an often oxygen-deprived environment and locally provoke an immune response.

But used in this way, bacteria generally do not precisely control or direct the immune response to attack cancer. “These qualities alone generally do not give bacteria enough power to stimulate immune responses capable of destroying a tumor, but they are a good starting point for building a new therapeutic area against cancer,” explains Nicholas Arpaia, Ph. .D..

Stimulate several parts of the immune system, safely

The new system starts with a probiotic strain of the E. coli bacteria. The researchers then carried out multiple genetic modifications to precisely control how the bacteria interact with and educate the immune system to induce tumor destruction.

The modified bacteria encode protein targets, called neoantigens, specific to the cancer being treated. These neoantigens delivered by bacteria train the immune system to target and attack cancer cells that express the same proteins.

Neoantigens are used as tumor targets so that normal cells, lacking these cancer-marking proteins, are left alone. Due to the nature of the bacterial system and additional genetic modifications designed by scientists, these bacterial cancer therapies also simultaneously overcome the immunosuppressive mechanisms that tumors use to block the immune system.

These genetic modifications also aim to block the bacteria’s innate ability to evade immune attacks against themselves. As a safety measure, this means that the modified bacteria can be easily recognized and eliminated by the immune system and are quickly eliminated from the body if they do not find the tumor.

When tested in mice, researchers found that these finely programmed bacterial cancer vaccines recruit a wide range of immune cells that attack tumor cells, while preventing responses that would normally suppress directed immune attacks. against the tumor.

The bacterial vaccine also reduced cancer growth when given to mice before they developed tumors, and prevented the same tumors from regrowing in mice that had been cured, suggesting that the vaccine could have the ability to prevent cancer from returning in patients who have suffered. discount.

Personalization

In humans, the first step in creating these microbial vaccines would be to sequence a patient’s cancer and identify its unique neoantigens using bioinformatics. Next, the bacteria would be engineered to produce large quantities of the identified neoantigens, as well as other immunomodulatory factors.

When infused into the patient whose tumors are to be treated, the bacteria travel to the tumors, take up residence in them, and regularly produce and deliver their “drug” payload.

Once activated by the bacterial vaccine, the immune system would be prompted to eliminate cancer cells that have spread throughout the body and prevent metastatic development.

Since each tumor has its own set of neoantigens, immunotherapy will be personalized for each patient. “The processing time will first depend on the time needed to sequence the tumor. Then we will just have to produce the bacterial strains, which can be quite rapid. The bacteria may be simpler to manufacture than some other vaccine platforms,” Danino explains.

The bacteria are also designed to thwart the cancer’s ability to mutate quickly and escape treatment. “As our platform allows us to deliver a large number of different neoantigens, it theoretically becomes difficult for tumor cells to lose all of these targets at once and avoid the immune response,” says Arpaia.

The researchers believe their approach could succeed where previous cancer vaccines have failed. In the latter case, although immune responses against tumor neoantigens can be induced, direct modulation of the tumor’s immunosuppressive environment is not achieved to such a degree.

Arpaia adds: “Bacteria allow the delivery of a higher concentration of drugs than can be tolerated when these compounds are administered systemically throughout the body. Here we can confine the delivery directly to the tumor and locally modulate how we stimulate the immune system. “