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In-situ vaccine may enhance immunotherapy response in resistant cancers, study shows.
A novel approach to cancer immunotherapy injects immune stimulants directly into a tumor to “teach,” induce the immune system to destroy the cancer and other tumor cells throughout the body. The three-step approach works as an in-situ cancer vaccine, researchers said.
A preliminary study could point to a new way of making immunotherapy more effective in cancers that have proven to be resistant to treatment and also enhance the effects of checkpoint blockade.
“The in-situ vaccine approach has broad implications for multiple types of cancer,” the study’s lead author, Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai in New York City, told the Reading Room. “This method could also increase the success of other immunotherapies, such as checkpoint blockade. The in-situ vaccine has multiple benefits: it’s simple, more practicable, costs a fraction of a personalized vaccine [does], and lets us optimize therapy.”
So far, Brody and colleagues have treated 11 patients, median age of 54, with indolent non-Hodgkin lymphoma (NHL), a cancer that, in general, does not respond to immunotherapy. Of the 11 patients who received the experimental therapeutic vaccine, one had a complete remission, two had partial remissions, and six had stable disease.
“This adds a new way to make anti-programmed death-1 (PD-1) agents effective in tumors where they are generally not effective,” Brody said. “PD-1 blockers help 20% of NHL patients, but that leaves the other 80% without effective immunotherapy. This is a novel solution to fix that problem. We have seen dramatic results in the laboratory to make PD-1 blockers more effective, and the vaccine induces systemic clinical remissions that can last for months.”
As immunotherapy continues to benefit from novel approaches to cut immune brake pedals, such as anti‐PD-1 and anti‐cytotoxic T-lymphocyte antigen 4 antibodies, there will be an increasing need to develop immune “steering wheels,” such as vaccines to guide the immune system specifically toward tumor-associated antigens, he noted. One hurdle in cancer vaccines has been the identification of universal antigens to be used in “off‐the‐shelf” vaccines for common cancers. Another hurdle is production of individualized whole tumor cell vaccines.
The new vaccine essentially turns the tumor into cancer vaccine factories by teaching the immune cells to recognize the cancer cells, said Brody. Once identified, the immune cells actively seek out all the cancer cells of the body and kill them. The three-step approach consists of (1) recruiting dendritic cells, (2) loading dendritic cell tumor antigens, and (3) activating the antigen-loaded dendritic cells.
The treatment consists of administering a series of immune stimulants directly into one tumor site. In the first step, a human protein form of FMS-like tyrosine kinase-3 ligand (FLT3L) recruits dendritic cells, which are important immune cells that act like generals of the immune army, Brody explained.
In the second step, low-dose radiation therapy activates the dendritic cells, which then instruct T cells, the immune system’s soldiers, to kill cancer cells and spare non-cancer cells.
In the third step, a toll-like receptor-3 agonist activates the dendritic cells and stimulates the immune army to recognize features of the tumor cells so it can seek them out and destroy them throughout the body.
In laboratory tests in mice, the vaccine drastically increased the success of checkpoint blockade immunotherapy. PD-1 blockade didn’t cure any large tumors, but after adding the vaccine, the cure rate increased to 75%. Side effects were grade 1 or 2 flu-like symptoms and muscle aches that last for a day. “We did not see any autoimmune adverse events,” said Brody.
Clinical Trial Ongoing
A clinical trial for lymphoma, breast, and head and neck cancer patients opened in March 2019 to test the vaccine with checkpoint blockade. The in-situ vaccine is also being tested in the laboratory in liver and ovarian cancers.
“Literally hundreds of immunotherapy trials are accruing thousands of patients each year to understand how to better whip T cells into shape and to get immune soldiers to do their job harder,” said Brody. “Clinical oncologists are frustrated that the majority of patients don’t respond to PD-1 blockers. We may be able to potentiate PD-1 blockade with this in-situ vaccine.”
In a 2018 review of in-situ vaccination, Mee Rie Sheen, PhD, of Harvard Medical School in Boston, and Steven Fiering, PhD, of the Geisel School of Medicine at Dartmouth in Hanover, New Hampshire, noted that local administration of immunostimulatory reagents into a recognized tumor by in-situ vaccination can generate systemic antitumor immunity to fight metastatic disease. “Conventional vaccines contain antigens and immune adjuvants. With in-situ vaccination, the tumor itself supplies the antigen, and the treatment only applies immune adjuvant directly to the tumor,” the authors stated.
They explained that current immunotherapy often fails to eliminate cancer because of local immunosuppression mediated by tumors. In-situ vaccination, in effect, “changes the tumor microenvironment from immunosuppressive to immunostimulatory, stimulates presentation of tumor antigens by antigen‐presenting cells to T cells, and generates systemic antitumor immunity that promotes antigen‐specific effector T‐cell attack of both treated and importantly, untreated metastatic tumors.”
Sheen and Fiering concurred with Brody about the advantages of in-situ vaccination — i.e., that it:
Is simple and cost‐effective
Has minimal systemic side effects
Is a feasible and flexible adjuvant delivery system
Exploits all tumor antigens in the tumor to avoid the need to identify antigens
Utilizes all antigens in the tumor to minimize immune escape
Has potential synergy when combined with other therapies