Victorian researchers have discovered an intracellular immune checkpoint that may be targeted to enhance responses to anti-PD-1 therapy and allow CAR T-cell therapies to work against solid tumours.
A study led by the Monash Biomedicine Discovery Institute (BDI) has identified the protein tyrosine phosphatase 1b (PTP1B) as an integral negative regulator of T-cell function and an intracellular T-cell checkpoint that limits the antitumour immunity of tumour-infiltrated CD8+ T cells.
In a paper published in Cancer Discovery the researchers report results from animals studies showing that the inhibition of PTP1B in cancer could enhance endogenous T cell–mediated antitumour immunity, “akin to that seen by targeting the cell-surface checkpoint PD-1 that has revolutionised cancer therapy.”
“Furthermore, the inhibition or genetic deletion of PTP1B can overcome a major hurdle that has thus far limited the effectiveness of CAR T cells against solid tumours,” they wrote.
In their paper, the researchers from Monash BDI noted that the development of anticancer therapies directed against cell-surface checkpoints such as PD-1 stemmed from decades of research focused on understanding T-cell biology and mechanisms governing T-cell tolerance.
However, not all patients respond to these therapies and the development of resistance was common, so approaches that could enhance the effectiveness or extend the utility of PD-1 checkpoint blockade were needed, they said.
In mice studies, the Monash scientists working in conjunction with colleagues at the Peter MacCallum Cancer Centre in Melbourne and Cold Spring Harbor Laboratory in New York, showed that PTP1B was of fundamental importance in coordinating JAK/STAT5 signalling in T cells and thereby the activation, expansion, and cytotoxic activity of T cells.
They showed that the expression of PTP1B was increased in effector/memory CD8+ T cells that infiltrate tumours in mice, or in effector and exhausted CD8+ T cells that infiltrate melanomas in humans. Induction of PTP1B in intratumoural CD8+ T cells could limit T-cell expansion and cytotoxicity, and thereby facilitate tumour growth.
And notably, deletion or inhibition of PTP1B could overcome such inhibitory constraints, they reported, to enhance the antitumour activity of T cells, and the efficacy of adoptively transferred CAR T cells, without promoting autoimmunity and systemic inflammation.
Using a drug candidate molecule MSI-1436 , the team showed that pharmacologic inhibition of PTP1B recapitulated the T cell–mediated repression of tumour growth and enhanced the response to PD-1 blockade.
“Furthermore, the deletion or inhibition of PTP1B enhanced the efficacy of adoptively transferred CAR T-cells against solid tumours,” the investigators said.
“Although further studies are required to explore such possibilities, targeting PTP1B with specific inhibitors stands to transform CAR T-cell therapy and readily extend the utility of CAR T cells to the effective therapy of recalcitrant solid tumours,” they concluded.
Senior author Professor Tony Tiganis, Professor of Biochemistry and Molecular Biology at the Monash BDI, said the next step would be to further define the impact of PTP1B deletion in CAR T and conventional T cells in humans. Professor Tiganis said the team would continue to collaborate with Cold Spring Harbor Laboratory and DepYmed Inc., a US-based company developing PTP1B inhibitors, to test in their preclinical models orally bioavailable PTP1B inhibitor drug candidates as novel checkpoint inhibitors.