Generation of Orthotopic Patient-Derived Xenografts in Humanized Mice for Evaluation of Emerging Targeted Therapies and Immunotherapy Combinations for Melanoma
Year: 2023
Type: article
Abstract: Current methodologies for developing PDX in humanized mice in preclinical trials with immune-based therapies are limited by GVHD. Here, we compared two approaches for establishing PDX tumors in humanized mice: (1) PDX are first established in immune-deficient mice; or (2) PDX are initially established in humanized mice; then established PDX are transplanted to a larger cohort of humanized mice for preclinical trials. With the first approach, there was rapid wasting of PDX-bearing humanized mice with high levels of activated T cells in the circulation and organs, indicating immune-mediated toxicity. In contrast, with the second approach, toxicity was less of an issue and long-term human melanoma tumor growth and maintenance of human chimerism was achieved. Preclinical trials from the second approach revealed that rigosertib, but not anti-PD-1, increased CD8/CD4 T cell ratios in spleen and blood and inhibited PDX tumor growth. Resistance to anti-PD-1 was associated with PDX tumors established from tumors with limited CD8+ T cell content. Our findings suggest that it is essential to carefully manage immune editing by first establishing PDX tumors in humanized mice before expanding PDX tumors into a larger cohort of humanized mice to evaluate therapy response.
Source: Cancers
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,892
Funders: U.S. Department of Defense, U.S. Department of Veterans Affairs, Melanoma Research Alliance, Vanderbilt University, Vanderbilt-Ingram Cancer Center, Pelotonia, National Institutes of Health, National Cancer Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1188393146, G1243813451, G1280513408, G1300984159, G1388609297, G153582612, G1683023738, G2006259475, G2367676916, G2600212515, Leica Bond RX, G2761330696, G3152736877, G3428023363, G3433274139, New Strategies for Treatment of NRAS Mutant Melanoma after Progression on Immune Checkpoint Inhibitors, G359867969, G36614667, G4334524930, G4513176822, G4923790243, G5562593068, Training Program in Stem Cell and Regenerative Developmental Biology, G5853943267, Chemokine Signals in the Premetastatic Niche Inhibit Metastasis, G6537411040, G6983782547, HARNESSING INNATE IMMUNITY TO IMPROVE METASTATIC BREAST CANCER THERAPY. THE ASSISTANT SECRETARY OF DEFENSE FOR HEALTH AFFAIRS THROUGH THE BREAST CANCER RESEARCH PROGRAM, ENDORSED BY THE DEPARTMENT OF DEFENSE. THE ASSISTANT SECRETARY OF DEFENSE FOR HEALTH AFFAIRS THROUGH THE BREAST CANCER RESEARCH PROGRAM, ENDORSED BY THE DEPARTMENT OF THE ARMY., G8113317439, G818418256, G8516375048, VOLT (Vanderbilt Oncology Training Program), G9000081609, G9000130502, G9000266250, G9000270150, G9000285544, G9000312249, Cancer Center Support Grant, Cancer Center Support Grant, Combining senescence-inducing and senolytic agents to improve melanoma therapy, G946322834
OpenAlex ID: W4385068898