Training the innate immune system to fight cancer

Mouse
A research team led by scientists at the Icahn School of Medicine successfully used a tiny biologic drug to train the innate immune system to clear cancer cells in mice. (Pixabay)

Existing immuno-oncology therapies primarily leverage one branch of our immune system—adaptive immunity—by recruiting T cells to fight cancer. A research team led by scientists at the Icahn School of Medicine at Mount Sinai has now found a possible way to tap into the other branch, the innate immune system.

In a study published in Cell, the team described a "nanobiologic," which they designed with tiny materials engineered from a natural molecule and then paired with a therapeutic. The nanobiologic targets the bone marrow, a factory of immune cells. In mice, adding the drug to medicines that block PD-1 and CTLA-4 significantly shrank tumors that were refractory to those checkpoint inhibitors.

A startup called Trained Therapeutix Discovery, or TTxD, is testing the nanobiologic treatment to treat cancer and serious infections, with the goal of moving them into human studies in two to four years.

While the adaptive immune system can target specific antigens once it memorizes them on first encounter, the innate immune system, which acts as the body’s first line of defense, was long believed to lack such memory. But a recent discovery showed that the innate immune system can be “trained.” This so-called trained immunity works by manipulating progenitor cells in the bone marrow, which can later develop into mature immune cells.

The Mount Sinai-led team set out to find out whether bone marrow-aimed materials bearing trained immunity-inducing components can elicit a durable anti-cancer innate immune response. The researchers screened a library of nanobiologics and came up with a lead candidate, dubbed MTP10-HDL, which they determined possessed the best combination of stability and immunity-promoting capacity at a relatively low dose.

In mouse models of melanoma, the drug inhibited tumor growth better than a placebo did. At the most effective dosing tested, the mean tumor volume among treated mice was about half of that in the control group.

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The scientists then set out to determine whether MTP10-HDL can boost the effect of PD-1 and CTLA-4 inhibitors, which work by removing tumors' suppressive signals to cancer-killing T cells in the adaptive immune system.

Neither PD-1/CTLA-4 monotherapy nor the combination of both had any anti-tumor effects on a melanoma type that’s known to be resistant to the checkpoint inhibitors. But pairing MTP10-HDL with either drug led to a significantly lower tumor growth rate, and combining all three together “strongly suppressed tumor growth rate,” the team reported.

Further analysis revealed that MTP10-HDL reshaped the immune cell populations in the bone marrow and the spleen. The trained cells also changed the tumor microenvironment, priming the immune system in a way that allowed checkpoint inhibitors to work better.

Many anti-cancer researches have shifted their focus to the innate immune system. For example, companies such as Artiva Biotherapeutics are working on natural kill cell therapies. While T-cell therapies need priming to attack specific antigens on tumor cells, NK cells, as part of the innate immune system, don’t need such preparation.

Researchers at Mount Sinai are working with their collaborators to develop nanobiologics for human testing. "Our study is a significant advancement for both trained immunity and cancer treatment, with real potential to move quickly into use in patients," said lead author Willem Mulder, Ph.D., a professor at the Icahn School of Medicine there, in a statement