Related Experiment Video
Updated: Nov 12, 2025
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
The KRASG12C Inhibitor MRTX849 Reconditions the Tumor Immune Microenvironment and Sensitizes Tumors to Checkpoint
David M Briere1, Shuai Li2, Andrew Calinisan1
1Mirati Therapeutics, Inc., San Diego, California.
Abstract:
KRASG12C inhibitors, including MRTX849, are promising treatment options for KRAS-mutant non-small cell lung cancer (NSCLC). PD-1 inhibitors are approved in NSCLC; however, strategies to enhance checkpoint inhibitor therapy (CIT) are needed. KRAS mutations are smoking-associated transversion mutations associated with high tumor mutation burden, PD-L1 positivity, and an immunosuppressive tumor microenvironment. To evaluate the potential of MRTX849 to augment CIT, its impact on immune signaling and response to CIT was evaluated. In human tumor xenograft models, MRTX849 increased MHC class I protein expression and decreased RNA and/or plasma protein levels of immunosuppressive factors. In a Kras -mutant CT26 syngeneic mouse model, MRTX849 decreased intratumoral myeloid-derived suppressor cells and increased M1-polarized macrophages, dendritic cells, CD4+, and CD8+ T cells. Similar results were observed in lung Kras -mutant syngeneic and a genetically engineered mouse (GEM) model. In the CT26 Kras model, MRTX849 demonstrated marked tumor regression when tumors were established in immune-competent BALB/c mice; however, the effect was diminished when tumors were grown in T-cell-deficient nu/nu mice. Tumors progressed following anti-PD-1 or MRTX849 single-agent treatment in immune-competent mice; however, combination treatment demonstrated durable, complete responses (CRs). Tumors did not reestablish in the same mice that exhibited durable CRs when rechallenged with tumor cell inoculum, demonstrating these mice developed adaptive antitumor immunity. In a GEM model, treatment with MRTX849 plus anti-PD-1 led to increased progression-free survival compared with either single agent alone. These data demonstrate KRAS inhibition reverses an immunosuppressive tumor microenvironment and sensitizes tumors to CIT through multiple mechanisms.
Insights
KRAS inhibitors like MRTX849 can improve immunotherapy for KRAS-mutant lung cancer by reducing immunosuppression and enhancing T-cell responses. Combination therapy shows durable responses and adaptive immunity.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- KRAS mutations drive non-small cell lung cancer (NSCLC) and are linked to an immunosuppressive tumor microenvironment.
- While PD-1 inhibitors are used in NSCLC, enhancing checkpoint inhibitor therapy (CIT) is crucial.
- KRAS inhibitors, such as MRTX849, offer a promising therapeutic avenue.
Purpose of the Study:
- To investigate the potential of MRTX849 to enhance anti-PD-1 checkpoint inhibitor therapy (CIT) in KRAS-mutant cancers.
- To evaluate the impact of MRTX849 on immune signaling and the tumor microenvironment.
- To assess the efficacy of combining KRAS inhibition with CIT.
Main Methods:
- Evaluation of MRTX849's effects on MHC class I expression and immunosuppressive factors in human tumor xenografts.
- Analysis of immune cell populations (MDSCs, macrophages, dendritic cells, T cells) in Kras-mutant mouse models treated with MRTX849.
- Assessment of tumor regression, complete responses (CRs), and adaptive immunity in syngeneic and genetically engineered mouse models.
- Comparison of single-agent treatments (MRTX849 or anti-PD-1) versus combination therapy.
Main Results:
- MRTX849 increased MHC class I expression and reduced immunosuppressive factors.
- In Kras-mutant models, MRTX849 modulated the tumor microenvironment, decreasing myeloid-derived suppressor cells and increasing beneficial immune cells.
- Combination therapy of MRTX849 and anti-PD-1 achieved durable complete responses and induced adaptive antitumor immunity.
- Combination treatment improved progression-free survival compared to single agents in a GEM model.
Conclusions:
- KRAS inhibition effectively reverses the immunosuppressive tumor microenvironment.
- MRTX849 sensitizes tumors to checkpoint inhibitor therapy through multiple immune-modulating mechanisms.
- Combining KRAS inhibitors with PD-1 blockade represents a promising strategy for KRAS-mutant NSCLC.
More Related Videos
09:29Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
06:51Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
Related Concept Videos
01:27Tumor Immunotherapy
02:17The Tumor Microenvironment