A novel tumor targeted 4-1BB agonist amplifies intra-tumor T cell effector functions in fresh human tumor lesions from patients
F. Uhlenbrock1*, D.S. Thommen1, M. Thelen1, P. Herzig1, C. Claus2, C. Ferrara2, V. Karanikas2, M. Bacac2, M. Amann2, C. Klein2, P. Umana2, A. Zippelius1
1University of Basel, Department of Biomedicine, University Hospital, Hebelstrasse 20, CH-4031 Basel, Switzerland; 2Roche Innovation Center Zurich, Wagistrasse 18, CH-8952 Schlieren, Switzerland
* Corresponding author
The costimulatory receptor 4-1BB plays an important role in sustaining effective T cell immune responses and in generating immunological memory. As 4-1BB signalling has been shown to potentiate robust effector responses in lymphocytes critical for anti-tumor immunity, 4-1BB is considered as an interesting target for immunotherapy. Non-tumor targeted 4-1BB directed therapies showed, however, side effects including liver toxicity and cytokine release syndrome due to Fc gamma receptor related off-target immune activation.
Using tumor infiltrating lymphocyte (TIL) suspensions obtained from patients with non-small cell lung cancer (NSCLC) and epithelial ovarian cancer (EOC), we here dissect the immunomodulatory capacity of a novel tumor targeted 4-1BB agonist in vitro. Treatment with the latter combined with anti CD3 stimulation induced the upregulation of T cell activation markers such as CD25, OX40 and 4-1BB, enhanced proliferation of intra-tumoral CD4 and CD8 T cells and production of inflammatory cytokines such as IFN-gamma, IL-2 and TNF-alpha. Of note, 4-1BB co-stimulation induced a strong secretion of IL-13 preferentially by intra-tumoral CD8 T cells, which further augmented T cell proliferation. The observed immune activation of TILs was restricted to tumors expressing the target antigen and 4-1BB co-stimulation had no effect on the activation of Treg cells. Interestingly, the targeted 4-1BB agonist showed the capacity to activate T cells with a PD-1high phenotype representing a terminal exhausted effector stage.
These data provide a strong rationale to assess targeted 4-1BB agonists in early clinical trials.