Several drugs that block the immune checkpoints PD-1 and PD-L1 have been approved to treat non-small cell lung cancer (NSCLC), but their efficacy in the disease is estimated to be well under 50%. Scientists at the Massachusetts Institute of Technology (MIT) say they’ve uncovered a mechanism of resistance to immuno-oncology drugs in NSCLC patients—and a potential avenue for addressing it.
The MIT team explored the phenomenon known as T cell exhaustion, in which a subset of immune cells stop working, leading to resistance to checkpoint inhibitors. The problem has long been believed to occur within tumors, but the MIT team’s research suggests that a subset of the cells become resistant to immune-checkpoint blockade before they even reach the cancer. They become dysfunctional because of changes in gene expression that occur while they’re being activated in the lymph nodes, the researchers explained in Science Immunology.
The MIT team made the discovery by studying mouse models of NSCLC. They sequenced messenger RNA (mRNA) from both functional and crippled T cells, which allowed them to scrutinize gene expression patterns. They believe the differences in gene expression may be the underlying cause of immunotherapy resistance in NSCLC.
“We show that this state is actually a preset condition, and that the T cells are already non-responsive to therapy before they enter the tumor,” said senior author and MIT Professor Stefani Spranger, Ph.D., in a statement. “If T cells are rendered dysfunctional early on, [checkpoint inhibition] is not going to be effective, and we need to think outside the box,” she added.
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So how can dysfunctional T cells be reactivated so they can kill cancer? To find an answer, Spranger’s team analyzed gene expression in the nonresponsive T cells and discovered low expression of immune-controlling small proteins known as cytokines.
They went on to treat the mouse models of NSCLC with the cytokines interleukin-2 (IL-2) and IL-12. They observed that non-responsive T cells came back to life and attacked the tumors, they reported.
Problem is, cytokine therapy is not safe to administer to people as a systemic therapy, because it can cause a dangerous over-activation of the immune system. Several research groups have experimented with safe alternatives, including a University of Washington team, which designed a synthetic protein that looks like IL-2 but doesn’t trigger dangerous side effects.
Bristol Myers Squibb is working with Dragonfly Therapeutics to develop DF6002, a modified IL-12 fusion protein. The drug is currently in early-stage trials in patients with multiple solid tumor types.
The MIT researchers cited ongoing efforts to determine whether cytokines can be injected directly into tumors to enhance immunotherapy. They suggested that with further research, such a therapy could be used in combination with immune checkpoint inhibitors to improve responses in NSCLC patients.