A new publication from our group

We are happy to share our new publication about a modified version of PD-1 receptor, or how to turn something negative to an enhancing molecule. There have been a few reports this year showing technologies similar to ours, suggesting that interest for associated molecules to increase the binding might represent a solution to improve cell -based therapy. We thank all co-authors and of course our support: Helse Sør Øst, The Research Council of Norway and The Norwegian Cancer Society

“Built-in” PD-1 blocker to rescue NK-92 activity from PD-L1–mediated tumor escape mechanisms

Nadia Mensali, Pierre Dillard, Artem Fayzullin, Hakan Köksal, Gustav Gaudernack, Gunnar Kvalheim, Else Marit Inderberg, Sébastien Wälchli

Success of adoptive cell therapy mainly depends on the ability of immune cells to persist and function optimally in the immunosuppressive tumor microenvironment. Although present at the cancer site, immune cells become exhausted and/or inhibited, due to the presence of inhibitory receptors such as PD-L1 on malignant cells. Novel genetic strategies to manipulate the PD1/PD-L1 axis comprise (i) PD-1 reversion where the receptor intracellular domain is replaced with an activating unit, (ii) the use of anti-PD-L1 CAR or (iii) the disruption of the PD-1 gene. We here present an alternative strategy to equip therapeutic cells with a truncated PD-1 (tPD-1) to abrogate PD-1/PD-L1 inhibition. We show that engagement of tPD-1 with PD-L1-positive tumor unleashes NK-92 activity in vitro. Furthermore, this binding was sufficiently strong to induce killing of targets otherwise not recognized by NK-92, thus increasing the range of targets. In vivo treatment with NK-92 tPD-1 cells led to reduced tumor growth and improved survival. Importantly, tPD-1 did not interfere with tumor recognition in PD-L1 negative conditions. Thus, tPD-1 represents a straightforward method for improving antitumor immunity and revealing new targets through PD-L1 positivity.