Cancer therapy has experienced a paradigm shift due to the clinical success of immune checkpoint inhibitors (ICI) such as anti-PD-L1 antibodies, yet ICI benefits remain limited to a minority of patients. On top of the resistance mechanisms limiting their efficacy, ICI are causing auto-immune side effects related to the activation of self-directed CD8 T cells. We propose a new approach using antitumoral T cells as vehicles to deliver anti-PD-L1 nanobodies specifically at the tumor site. Compared to antibodies, nanobodies offer the advantage of a good penetration ability in tissues while displaying a very short half-life in the blood stream. We evaluated whether this approach could improve efficacy and reduce toxicity compared to classical anti-PD-L1 antibody treatment.
Ovalbumin-specific OT-I T cells were engineered to secrete an anti-PD-L1 blocking nanobody. In MC38 Ova murine colon carcinoma model, adoptive transfer of nanobody-secreting T cells was compared with wildtype T cells alone or wildtype T cells in combination with an anti-PD-L1 antibody given by intraperitoneal injection. Treatment efficacy was assessed by measuring tumor growth over time. Flow cytometry and immuno-histochemistry (IHC) analysis on tumor, lymph nodes and spleen samples were performed to compare the distribution of the anti-PD-L1 treatment across different tissues.
Intratumoral delivery of anti-PD-L1 nanobody improved tumor rejection compared to systemically given anti-PD-L1 antibody. According to flow cytometry and IHC analysis, anti-PD-L1 nanobody was enriched in the tumor compared to spleen and lymph nodes, while anti-PD-L1 antibody was rather enriched in spleen and lymph nodes and weakly detected in the tumor. This low systemic exposure to the nanobody could minimize the risk of developing auto-immune side effects.
Our study points out the poor penetration of anti-PD-L1 antibody in established tumors as a limitation factor for its efficacy in treating MC38 Ova tumors. Local delivery of an anti-PD-L1 nanobody could both overcome this limitation and reduce the risk of side effects as the nanobody is enriched in the tumor compared to the periphery.
Legal entity responsible for the study
Ludwig Cancer Research, Brussels Branch - De Duve Institute.
F.N.R.S. (Fonds National pour la Recherche Scientifique).
B.J. van den Eynde: Advisory/Consultancy: iTEOS therapeutics. All other authors have declared no conflicts of interest.