Researchers at the Icahn School of Medicine (Mount Sinai, New York) have found that macrophage-targeted CAR T cells are capable of provoking a strong anti-tumour response in preclinical cancer models. The paper, published in Cancer Immunology Research, offers new hope for immunotherapy treatments that have traditionally had limited success in clinical trials.
The trouble with CAR T
Typically, CAR T cells have a chimeric antigen receptor that is engineered to recognise cancer cells directly. These cells have been used to treat varying blood cancers successfully, but they have been less successful in treating solid tumours that are heavily infiltrated by tumour-promoting macrophages. Tumour-associated macrophages (or TAMs) tend to block the entry of T cells into tumour tissues and protect the cancer cells from being destroyed.
To overcome this, Brian Brown (Director of the Icahn Genomics Institute and Associate Director of the Marc and Jennifer Lipschultz Precision Immunology Institute (PrIISM) at Icahn Mount Sinai) and his team decided to engineer their own CAR T cells that recognised surface molecules on macrophages. Therefore, when these cells came across a macrophage displaying this specific surface molecule, they would become activated and kill it.
The proof is in the punch
To validate their potential new approach, the team created mouse models of ovarian, lung, and pancreatic tumours. They then watched as their new CAR T cells managed to reduce the number of tumour macrophages, shrink the size of the tumours, and extend the survival of the mice. It appears that by killing the tumour macrophages, the body’s own T cells were then better able to access and kill cancer cells as well.
In addition, the team demonstrated that anti-tumour activity is driven by the release of the cytokine interferon-gamma (involved in regulation of inflammatory responses) from CAR T cells. “Our initial goal was just to use the CAR T cells to kill the immunosuppressive macrophages, but we discovered they were also boosting tumour immunity by releasing this powerful immune-boosting molecule,” said senior author Brian Brown. “It was a one-two punch from this single treatment.”
A new era for immunotherapy?
The highlight of this research is what it could mean for future cancer therapy approaches. One of the difficulties with developing immunotherapies is that there are very few proteins unique to cancer cells – most are also found on healthy cells. This, of course, can cause challenges as healthy tissue can sometimes get caught in the crossfire.
However, tumour-specific macrophages are very different from those found in healthy tissues, and they are also highly conserved across different types of cancer. This means macrophage-depleting agents, especially those as successful as in this study, could offer new hope for cancer therapy.
“Our molecular studies of human tumours have revealed macrophage subsets present in human tumours and not in normal tissues and are similar across tumours and across patients,” said Miriam Merad, co-senior author of the study, and Director of PrIISM. “Macrophage-targeting CAR T cells could be a broad way to target different types of solid tumours and improve immunotherapy.”
The next step for the team is to generate human versions of the genetic code so this treatment can be studied in patients.
