Daniela Thommen: We are excited to share our new work in Cancer Discovery AACR Journals, in which we explore a CD8-targeted IL2 to revive dysfunctional T cells in anti-PD1 resistant human cancers

Daniela Thommen, Group Leader (Associate professor) at The Netherlands Cancer Institute, made the following post on LinkedIn:

“Right in time to celebrate the lab’s 4 yr anniversary, we are excited to share our new work in Cancer Discovery AACR Journals, in which we explore a CD8-targeted IL2 to revive dysfunctional T cells in anti-PD1 resistant human cancers.

This study was led by the fantastic Paulien Kaptein with help from many other lab members, with wonderful collaborators Kelly Moynihan and Ivana Djuretic, Asher Biotherapeutics, and Ton Schumacher, The Netherlands Cancer Institute, and with critical financial support from Melanoma Research Alliance.

Many anti-PD1 resistant tumors contain substantial T cell infiltrates suggesting additional barriers limiting T cell function. IL2 is a potent activator of T cells, but its clinical use has been challenging due to its pleiotropic effects causing tox and immunosuppression. We here explored a novel IL2 molecule cis-targeted to CD8 developed by AsherBio enabling the selective stimulation of CD8 T cells (check out their back-to-back study).

Utilizing patient-derived tumor fragments, we found that CD8-IL2 broadly rewires intratumoral CD8 T cells with an effector program, preparing them for optimal function. More importantly, it specifically reinvigorates dysfunctional T cells to become potent functional effectors upon antigen encounter. By comparing CD8-IL2 and anti-PD1 treatment within the same tumor samples, we found that CD8-IL2 induces a broader and qualitatively superior reinvigoration of the tumor-reactive dysfunctional T cell pool as compared to PD1 blockade. Of clinical relevance, we observed that targeting of IL2 to CD8 T cells induces immunological responses also in anti-PD1 resistant tumors, suggesting the presence of a tumor-reactive T cell pool that is not susceptible to reinvigoration by PD1 blockade (alone).

Altogether, our study provides critical mechanistic insights into how IL2 rewires the CD8 T cell landscape in human cancers, and reveals a pivotal role of the tumor-specific dysfunctional T cell pool in mediating local immune reactivation upon both CD8-IL2 and PD1 blockade.
This study adds to recent studies bringing IL2 back into the spotlight and further highlights precision targeting of immunostimulatory signals to specific immune cell populations as a promising therapeutic strategy.”

Source: Daniela Thommen/LinkedIn