New drug could help overcome tumour resistance to treatment

T cells attack cancer cell

New study results have demonstrated the potential of a new drug to reprogramme the immune profile in the tumour microenvironment (TME) and convert resistant tumours to responders to Immune Checkpoint Blockage (ICB) therapies.

Purple Biotech shared the new results at the American Association for Cancer Research (AACR) Annual Meeting 2023 in Florida, US.

The study was led by researchers at The University of Texas MD Anderson Cancer Center. The results showed NT219 induced significant PDL1 expression in melanoma cells in-vitro and showed a synergistic effect with anti-PD1 therapy in tumour growth inhibition in-vivo.

The induction of PDL1 by NT219 was much higher in the ICB-resistant melanoma strain as compared to ICB-sensitive cells, suggesting the potential to re-sensitise refractory tumours to anti-PD1 therapy.

“These results suggest that combining ICB with NT219 may be a promising strategy to reprogramme the immune profile of the TME to enhance anti-tumour immunity, turning ‘cold’ tumours ‘hot’ and re-sensitizing resistant tumours to anti-PD1 therapy”, said Hadas Reuveni, VP R&D at Purple Biotech.

“The insidious process by which tumours become resistant to so many of our most promising cancer drugs robs patients of hope and of time with their families. Lengthening the duration of treatment as well as broadening the patient population that may benefit from these treatments address the highest obstacles of ICB therapies today.”

Activating the tumours

Treatment of immunocompetent mice bearing ICB-resistant tumours with NT219 in combination with either anti-PD1 or anti-CTLA4 therapies showed a significant increase in activated CD8 cytotoxic T cells and NK cells in the TME.

This effect was seen in parallel with a significant decrease in the infiltration of immunosuppressive populations, including regulatory T cells, and myeloid-derived suppressor cells, and M2 macrophages. No such effects were detected with either therapy alone.

Similarly, NT219 in combination with anti-PD1 showed synergistic effects inducing significant tumour growth inhibition of ICB-resistant tumours, while each therapy alone had no effect.

The ICB-resistant clone showed higher levels of both IRS1 and STAT3 activation in comparison with the ICB-sensitive clone of the same origin melanoma cells.

Treatment with NT219 diminished both IRS1 and STAT3 phosphorylation in both cloned cell lines and showed a durable effect on these target proteins, which are known to be involved in drug resistance.

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