Development of an in vitro hot tumor model for immunotherapeutic drug screening

Description

Immunotherapy using monoclonal antibodies targeting regulatory immune checkpoints (ICPs) hold promise for the treatment of various cancer types. Especially monoclonal antibodies targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1 transformed the field of onco-immunology and became standard of care for many malignancies. Unfortunately, not all patients benefit from ICP therapy as some tumors find ways to disguise themselves from the immune system and thereby escape antitumor immune responses. These unresponsive tumors like prostate, breast and pancreatic cancer are also referred to as ‘cold tumors’. Previously we developed a three dimensional model containing a solid eGFP⁺ melanoma spheroid surrounded by primary peripheral blood lymphocytes (PBLs). This model allows high-throughput screening of onco-immunological therapeutics by evaluating immune cell activation and composition and by measuring tumor cell killing in real time. When evaluating PD-L1 blocking antibody-fragments, we found that these tumor spheroids resemble cold tumors and therefore needed preactivated PBLs before measuring tumor lytic activity. In order to refine this model, we genetically modified the melanoma cells to express interleukin (IL-)15, a pleiotropic cytokine that binds to the common γ-chain on cells of the innate and adaptive immunity. When these cells were used as target cells, PBLs were significantly activated, resulting in immune cell expansion and tumor cell killing. Next we evaluated whether transgenic IL-15 expression enables the evaluation of immunoglobulin (Ig)G1 based anti-PD-L1 single domain antibody fragments. We demonstrated that the anti-PD-L1 antibodies could significantly improve tumor cell killing through IgG1-Fc effector functions. Altogether, we developed a 3D melanoma model with inherent immunogenicity that can be used for the evaluation of ICP drugs and IgG1-based therapeutics.

Period	21 Sept 2022
Event title	IC-3Rs Symposium 2022: MORE SCIENCE, MORE CARE, LESS ANIMALS
Event type	Conference
Location	Brussels, BelgiumShow on map
Degree of Recognition	International