Mouse Models & CRISPR: Revolutionizing Cancer Immunotherapy

‍Immunotherapy has transformed cancer treatment, and mouse models have been pivotal in this progress. Recent advancements in cancer research utilizing genetically modified mouse models have illuminated novel disease mechanisms and furthered the development of therapeutic strategies. CRISPR technology, in particular, has been instrumental in creating more targeted mutations that better replicate human cancer biology. 

Precision CRISPR Models Reveal Tumor Evolution

Notably, researchers employed CRISPR/Cas9 to induce controlled Kras and Trp53 mutations in somatic cells of mice, generating more relevant in vivo cancer models that closely mimic the progression of lung and liver cancers. These sophisticated models enable real-time tracking of tumor evolution and clonal diversity, offering unprecedented insights into cancer biology. The enhanced precision of these mouse models has significantly improved our understanding of cancer initiation, progression, and treatment response. By more accurately replicating human cancer characteristics, these models provide a robust platform for testing novel therapeutic approaches and predicting their efficacy in human patients. This progress in model development is expected to accelerate the translation of laboratory findings into clinical applications, potentially leading to more effective and personalized cancer treatments in the near future ,. 

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Air Pollution Accelerates Oncogenesis in Lung Cancer

‍One notable study focused on lung adenocarcinoma, where researchers explored how exposure to fine particulate matter (PM2.5) from air pollution promotes tumorigenesis in EGFR-mutant lung cancers. Using genetically engineered mouse models, such as the Rosa26LSL-tTa/LSL-tdTomato; TetO-EGFRL858R model, researchers induced the expression of oncogenic human EGFRL858R in lung cells. Upon exposure to PM2.5, these mice showed a significant increase in tumor burden, reinforcing the notion that environmental pollutants can exacerbate pre-existing oncogenic mutations in lung tissues. This study exemplified how environmental factors, when coupled with genetic predispositions, can accelerate cancer progression in mice.

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CRISPR-Edited CD45 Enhances CAR T Cell Therapy Safety

‍Preclinical research conducted at the University of Pennsylvania has paved the way for safer and more broadly applicable cancer treatments. This groundbreaking study enhanced the effectiveness of CAR T cells in treating various hematologic malignancies while protecting healthy tissues. Researchers explored how CRISPR adenine base epitope editing of CD45 in hematopoietic cells enabled the safe application of CD45-directed CAR T cells for blood cancer therapy. The study utilized mice as crucial experimental tools to demonstrate that edited CD45 cells could protect healthy hematopoietic stem cells from on-target/off-tumor effects. This breakthrough showed the feasibility of universal CAR T therapy for blood cancers while maintaining the integrity of the immune system. The findings represent a significant step forward in the development of more targeted and effective cancer treatments, potentially revolutionizing the field of immunotherapy.

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STING Pathway and Immune Surveillance in Metastatic Dormancy

‍Another recent impactful study from MSKCC explored lung adenocarcinoma metastasis and how the immune system regulates the dormancy and reactivation of metastatic cells. Specifically, two mouse models of tumor metastasis, H2087-LCC (​​Foxn1nu athymic nude mice, lacking T cells) and KPad1 (developed from KrasLSL-G12D/+; Trp53 flox/flox (KP) mice) were used to study cancer progression, focusing on how the STING pathway influences immune surveillance. These models simulated dormancy by allowing disseminated lung adenocarcinoma cells to remain quiescent for extended periods before some reawaken, leading to metastasis. Mouse models provided invaluable insights into immune regulation, genetic factors, and the ability of therapeutic agents to target dormant cancer cells.

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Microbiota Modulate Chemotherapy Response in Pancreatic Cancer

‍In another report, humanized gnotobiotic (germ-free) mice were crucial for studying the role of microbiota in human patients with pancreatic ductal adenocarcinoma, one of the most lethal cancers currently with the poorest prognosis. Mice enabled researchers to investigate how differences in the microbiota from chemotherapy responders and non-responder patients influenced tumor growth and treatment response. The mice were orthotopically injected with PDAC cells and treated with FIRINOX chemotherapy. Mice colonized with microbiota from responding patients showed smaller tumor sizes when treated with chemotherapy, while mice with microbiota from non-responsive patients did not. The study also identified the impact of a microbiota-derived tryptophan metabolite, 3-indole acetic acid (3-IAA), on chemotherapy efficacy in pancreatic cancers.

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Additionally, mouse models were instrumental in evaluating new immune checkpoint inhibitors. Key genetically modified mouse models, such as the MISTRG, NSG-SGM3, and Hu-SRC, which provide fully functional aspects of the human immune system, have been crucial for studying human immune cell interactions and tumor responses in immunotherapy research. The findings from these genetically modified mouse models are being translated into clinical trials, leading soon to the development of more effective immunotherapeutic strategies.

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