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New T cell immune response discovery points to 'out-of-box' cancer therapy options

April 20, 2022 01:33 PM EDT Updated 01:45 PM Discovery Pharma

https://endpts.com/new-t-cell-immune-response-discovery-points-to-out-of-box-cancer-therapy-options/

Researchers have identified a class of T cells with an unconventional tumor-homing mechanism that could point the way to new types of cancer immunotherapies.

In immune checkpoint therapy, monoclonal antibodies prevent PD-1, a “checkpoint protein” on certain tumors from binding to the T cell and turning the T cell off. The T cells can thus remain on and destroy cancerous cells presenting with certain tumor antigens.

However, T cells are part of the adaptive immune system, which means they can only be reactive: They need to see specific foreign proteins or other molecules before they attack.

But these recently discovered innate-like T cells (ILTCKs) act as if they are part of a person’s innate immune system and don’t require the typical priming process with foreign antigens in order to react to cancers, according to the research team led by Ming Li from Memorial Sloan Kettering.

In their study published in Nature, the researchers found that these ILTCKs reacted to unmutated antigens from cancer cells that came from different mice, as opposed to conventional T cells, which only reacted to individual antigens from specific tumors.

“The discovery of ILTCKs provides a new paradigm for cancer immunotherapy,” Li told Endpoints News. “Current cancer immunotherapy programs are centric on conventional T cells, including immune checkpoint blockade therapies as well as cell therapies. However, these programs have limited efficacy in solid tumors, particularly in tumors with low mutation burden.”

According to a 2018 study, only 12% of US cancer patients were eligible and responsive to immune checkpoint drugs.

The reasons patients don’t respond vary widely, but one major reason is that, as Li said, some tumors have a “low mutation burden” — they just aren’t weird enough for a conventional T cell to react to them.

Harnessing ILTCK cells might offer a path to treating those patients.

What sets ILTCKs apart? Conventional T cells are activated against foreign and mutated antigens. If they react to the body’s own proteins, the body destroys them. But ILTCKs are activated against the body’s own proteins. They’re the rare autoimmune cell that doesn’t get destroyed.

That “endows them with unique tumor-homing and cancer cell-sensing properties,” Li said.

That selection process makes them similar to invariant natural killer T cells (iNKT), which have been the launching pad for more than one startup.

“Normally, developing T cells that react strongly to self-antigens are proactively killed off by the body to prevent autoimmune reactions,” Li said. “But ILTCK progenitors escape that fate.”

Instead, they have reduced T cell receptor signaling, making them harmless to normal cells, Li noted. Despite that diminished signaling, ILTCKs can still “robustly sense alarming molecules” like the cytokine IL-15, which is present in high levels in cancer cells, Li said.

Li and his team took their study a step further by demonstrating the potential for ILTCK therapy in a mouse model. From a previous study, they knew that ILTCK activity was dependent on IL-15. In tumor-bearing mice in which IL-15 was activated, tumor growth was “significantly deterred” compared to controls.

When they gave mice cell therapy with ILTCKs, they showed diminished tumor growth compared to those who received CD8-positive T cells.

“It is important to think out-of-box in terms of understanding the immune system function in cancer,” Li said, “so that we can not only optimize therapeutics within the current tumor immunology paradigm, but also explore novel therapeutic approaches.”

Memorial Sloan Kettering, where Li and his team are based, has filed a patent application for using ILTCKs in cancer immunotherapy.