Use one type of immune cell to target another

Researchers at the Icahn School of Medicine at Mount Sinai in New York say a new cancer immunotherapy that uses one immune cell to kill another cell, rather than directly attacking cancer, will stimulate a powerful anti-tumor immune response to shrink ovarian, lung and pancreatic tumors
in preclinical disease models.
The findings were published in the October 11, 2022, issue of
the journal Cancer Immunology Research.

The research involves a therapy
that uses immune cells called CAR-T cells.
CAR-T cells are designed to directly recognize cancer cells in current clinical applications and have successfully treated several blood cancers
.
But in many solid tumors, there are still some challenges
that prevent their effective application.

Most solid tumors are heavily infiltrated
by another type of immune cell called macrophages.
Macrophages help tumors grow by preventing T cells from entering the tumor tissue, thereby preventing CAR-T cells and the patient's own T cells from destroying cancer cells
.

To address this immunosuppression problem at its source, the researchers engineered T cells to make a "chimeric antigen receptor" (CAR) that recognizes a molecule
on the surface of macrophages.
When these CAR-T cells encounter tumor macrophages, the CAR-T cells are activated and kill tumor macrophages
.

Targeting CAR-T cells with these macrophages to treat mice with ovarian, lung, and pancreatic tumors reduced the number of tumor macrophages, shrunk tumors, and prolonged their survival
.

Killing tumor macrophages allows the mice's own T cells to enter and kill cancer cells
.
The researchers further demonstrated that this anti-tumor immunity is driven by cytokine interferon-γ released by CAR-T cells, a molecule
involved in regulating inflammatory responses γ.

"Our initial goal was simply to use CAR-T cells to kill immunosuppressive macrophages, but we found that they also boost tumor immunity by releasing this powerful immune-boosting molecule," said senior author Brian D.
Brown, PhD, director of the Icahn Genome Institute and associate director
of the Mark and Jennifer Lipschultz Institute for Precision Immunology (PrIISM) in Mount Icahn Sinai.
"It's a two-pronged approach
to treatment.
"

Shifting the sight of CAR-T cells from cancer cells to tumor macrophages may address another key obstacle to
CAR-T cells successfully eliminating solid tumors.
Only a few proteins are found only in cancer cells and not in healthy tissue, and can be used to directly target cancer cells in solid tumors without harming healthy tissue
.

Immunosuppressive macrophages found in tumors are very similar in different types of cancer and very different from
macrophages in healthy tissue.
This has sparked interest in macrophage depleting agents for cancer treatment, but the methods developed so far have had limited
success in clinical trials.

"Our molecular study of human tumors found that macrophage subsets are present in human tumors, not in normal tissue, and are similar
between tumors and patients.
Therefore, macrophages targeting CAR-T cells may be a broad way to target different types of solid tumors and improve immunotherapy," said Miriam Merad, PhD, co-senior author
of the study.

Next, the researchers are studying tumor macrophages-specific CAR-T and generating humanized genetic instructions to introduce them into
cancer patients' own T cells.

Alfonso R.
Sá nchez-Paulete, Jaime Mateus-Tique, Gurkan Mollaoglu, Sebastian R.
Nielsen, Adam Marks, Ashwitha Lakshmi, Jalal A.
Khan, C.
Matthias Wilk, Luisanna Pia, Alessia Baccarini, Miriam Merad, Brian D.
Brown.
Targeting Macrophages with CAR T Cells Delays Solid Tumor Progression and Enhances Antitumor Immunity.
Cancer Immunology Research, 2022; OF1