Abstract 4196: A controlled drug release device facilitates the identification of favorable combinations of immune-oncology drugs with targeted or cytotoxic drugs in a patient-derived humanized mouse model of renal cancer
Authors: Jonas Oliver , Oswald Eva , Lashuk Kanstantsin , Ahn Sebastian , Schüler Julia 
Published: June 2022

Identifying how to optimally combine immunotherapies with other available anti-cancer therapies is a major challenge in oncology. We have utilized an implantable microdevice performing cassette microdosing that measures intratumor drug responses and anti-tumor immunity for eleven agents in parallel. Local tumor response is measured by cyclical immunofluorescence for deep cellular response phenotyping. This approach is combined with the systemic administration of checkpoint inhibitors to examine whether local immunogenic cell death (ICD) induced by a given drug microdose potentiates the immunotherapy’s anti-tumor effect. The measurements were performed in a humanized mouse model of clear cell renal cancer, patient derived xenograft (PDX) RXF488. RXF488 was implanted subcutaneously in 30 NSG mice. Animals were stratified into 6 groups with n= 4-6. Humanization was performed by the intravenous injection of 5x10e6 human peripheral blood mononuclear cells prior to the first treatment. Systemic anti-PD1 treatment was applied in the presence and absence of the microdevice loaded with eleven different drugs. Control groups received the empty microdevice in the presence or absence of PBMC. Beside the histological examination of the tumor tissue, flow cytometry (FC) was performed on bone marrow, spleen and tumor tissue to determine infiltration of human immune cells. FC analyses revealed no influence of the treatment on the human immune cells in bone marrow and spleen. The anti-PD1 treatment induced an increase in huCD45+ cells specifically in the tumor tissue only 48h after treatment. Several agents showed a significant increase in apoptosis induction when nivolumab was added: The largest increase was observed for the panRAF inhibitor LXH254, Sorafenib, Oxaliplatin and Doxorubicin. The increased efficacy from immunotherapy administration has a strong positive correlation with increased induction of ICD in the tumor microenvironment determined by CD11b, ICAM-1 and MHC-II expression: drugs that showed the highest increase in apoptosis when combined with aPD-1 showed an increased likelihood for markers associated with ICD, namely Oxaliplatin and LXH254. We were able to verify the results of the screening experiment in a conventional setting with systemic combination treatment arms in the same PDX model. Our results demonstrate that local tumor response signatures of ICD can be used to systemically identify synergistic combinations of a range of drugs with immunotherapy on a tumor specific basis. The approach may represent a new paradigm for efficient in vivo screening of novel combinations, particularly with combinations involving immunotherapies.

Citation Format: Oliver Jonas, Eva Oswald, Kanstantsin Lashuk, Sebastian Ahn, Julia Schüler. A controlled drug release device facilitates the identification of favorable combinations of immune-oncology drugs with targeted or cytotoxic drugs in a patient-derived humanized mouse model of renal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4196.