Novel two-drug combo teaches immune system to attack cancer

Human T cell
A two-drug combo being tested at Mount Sinai is designed to teach the immune system's T cells to kill cancer cells. (NIAID)

The idea of training the immune system to hunt down cancer cells and kill them has been borne out in two FDA-approved CAR-T treatments for lymphoma, Novartis’ Kymriah and Gilead’s Yescarta, both of which involve removing T cells from patients and engineering them to be able to recognize cancer. But what if an effective immune attack against lymphoma could be achieved by injecting drugs directly into tumors?

Researchers at Mount Sinai School of Medicine in New York have promising early evidence that this approach, called “in situ vaccination,” could be effective in fighting lymphoma. Their results were so encouraging that they’ve opened a clinical trial not only in lymphoma but also in breast cancer and head and neck cancer, Mount Sinai said in a statement.

The vaccine consists of two drugs that are administered to tumor sites. The compounds work together to instruct the immune system’s T cells to kill cancer cells throughout the body, according to the statement.

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In mouse models, the vaccine produced remissions in 40% of the animals. When the treatment was combined with drugs that block the immune “checkpoint” PD-1, 80% of the mice had durable remissions.

The Mount Sinai researchers went on to test the vaccine in 11 patients with advanced non-Hodgkin lymphoma. Eight patients showed partial or complete responses in the tumor sites that were treated, and three went into remission. The results were published in the journal Nature Medicine.    

RELATED: Tumor ‘vaccine’ clears several cancer types in mice

The Mount Sinai approach relies on a process they refer to as “cross-priming.” First, they recruited dendritic cells in the immune system using Fms-like tyrosine kinase 3 ligand (Flt3L). Then they activated the dendritic cells using radiation and a drug called a TLR3 agonist. Once activated, the dendritic cells teach T cells how to seek out tumor cells throughout the body and kill them.

“We expected that direct-priming would account for the rapid … tumor clearance, but were surprised to see that tumor clearance was completely dependent on cross-priming,” the authors wrote in the study.

Among the organizations that provided support for the research were immuno-oncology drug developer Celldex Therapeutics and Merck, which makes the PD-1 inhibitor Keytruda. Celldex, currently regrouping following several disappointments in its pipeline, provided Flt3L for the study.

Injecting immune-boosting agents directly into tumors is an idea that’s being pursued by several researchers who are searching for ways to improve the effectiveness of immuno-oncology treatments. Last year, Stanford University opened a clinical trial of a tumor vaccine that combines a short stretch of DNA with an antibody that binds to the protein OX40, stimulating T cells to eradicate cancer cells.

Startup Elicio Therapeutics recently raised $30 million to pursue its approach of delivering anti-cancer vaccines via the lymph nodes. Gilead-backed Hookipa Pharma is seeking more than $86 million in an initial public offering to develop its platform, which uses viruses to stimulate immune responses from dendritic cells.

Although Mount Sinai’s initial small trial of the in situ vaccine in people was not designed to test a combination of the vaccine with PD-inhibiting drugs, the results in mice strongly suggest that doing so might improve the effectiveness of checkpoint inhibitors, the authors wrote. The newly opened clinical trial will test a combination of the vaccine with Keytruda, Mount Sinai said.

“Here we demonstrate that increasing and activating cross-presenting [dendritic cells] at the tumor site can prime tumor-specific [T cells], restore efficacy of checkpoint blockade and yield superior anti-tumor immunity,” the authors wrote.

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