Abstract 4442: Drug resistant humanized PDX platform: Clinically relevant <i>in vivo</i> modeling of innate and acquired resistance within human immune environment

Abstract Cancer treatment has been facing many hurdles, drug resistance is one of the most significant one among them. Over the years, treatment strategies have been evolving. A complex interaction between intrinsic (innate) and extrinsic (acquired) factors enables the survival of selected cancer cells, through progression under unfavorable conditions, ultimately develop resistance. Although numerous prospective drugs against cancer have been shown promising therapeutic efficacy on preclinical in vitro and in vivo models, only a few have been proven safe and effective in clinical validations. These problems are largely due to the lack of precise research tools to reveal the genuine status of cancer especially to recapitulate cancer resistance development in real-world patients. Patient derived xenograft (PDX) models have been shown superiority in reflecting the characteristics of cancer patients by retaining genomic information, diversified treatment backgrounds and clinical behaviors, all of these features make PDX an excellent in vivo system to study drug resistance, evaluate drug sensitivity and better treatment regimens. However, due to the low tumor engraftment rate and difficulty to reconstitute proper human immune system, only a few studies published about drug resistant humanized PDX model. The current study describes the successful establishment and validation of two drug-resistant humanized PDX models: a HER2 ADC resistant gastric PDX demonstrating clear innate resistance, and a multidrug resistant (MDR) melanoma PDX showing acquired resistance to targeted therapies, immune check point inhibitors (ICIs) and ionizing radiation. The gastric PDX model with HER2 expression confirmed by IHC (2+) shown limited response (TGI &amp;lt;10%) to trastuzumab deruxtecan and no response to Dxd, demonstrating a clear intrinsic resistance. In a separate study in hPBMC mice, significant tumor growth inhibition was achieved (TGI &amp;gt; 60%) when treating with anti-hPD1, implicating the clinical benefit of combining ICIs with ADC treatments. The MDR melanoma PDX model was derived from a patient with treatment history of initial surgical resections, followed by targeted therapies (VEM+COB) then ICIs when recurrence happened. The tumor shown limited response to BRAF inhibitor (TGI &amp;lt;15%) and completely abolished response to anti-hPDL1, anti-hPD1 and ionizing radiation in humanized mice with averaged hCD45% &amp;gt; 30%. We have successfully established and characterized several drug resistant PDX models particularly in humanized mice, making it possible to study interactions between human tumors and immune system, identify biomarkers and better clinical strategies to overcome drug resistance. This platform can be used to achieve personalized medication management, which is the ultimate translational goal. Citation Format: Jie Wen, Hao Cheng, Cheng Zhang, Bingrui Han. Drug resistant humanized PDX platform: Clinically relevant in vivo modeling of innate and acquired resistance within human immune environment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4442.