University of Pittsburgh researchers have developed a novel therapy for KRASG12C cancers. Using a combination regimen consisting of a small molecule inhibitor of KRASG12C driver oncoprotein, an oncolytic virus (OV), and immune checkpoint blockade therapy, complete tumor regression in KRASG12C can be selectively achieved through a combination of cytotoxicity and antitumor immunity. The development and optimization of this regimen could revolutionize the treatment of KRASG12C cancers improving outcomes in patients with these difficult-to-treat cancers.
A novel triple combination regimen consisting of an IL-36g-armed OV, a covalent inhibitor for KRASG12C, MRTX1257, and anti PD-1 medication. Treatment of LLC, a KRASG12C lung cancer cell line, led to decreased tumor size within three weeks.
Description
The oncogenic driver mutation KRASG12C is linked to many cancers including lung, colorectal, and pancreatic cancers. Researchers have long struggled to target this mutation, and these cancers are often considered “undruggable”. OV-mediated cancer immunotherapy is a growing area of cancer treatment where OVs selectively infect cancer cells, inducing cell death and antitumor immunity. In this novel approach, a combination of an IL-36-armed OV and a covalent inhibitor for KRASG12C, MRTX1257, together with anti-PD-1 to block immune checkpoint proteins, can effectively treat murine KRASG12C tumor models. This first-of-a-kind triple combination regimen specifically targets KRASG12C cancers, inhibiting growth. The therapy could provide hope to tens of thousands of patients leading to improved survival rates and patient outcomes with the possibility of developing lifelong cures for KRASG12C cancers.
Applications
• Lung cancer
• Colorectal cancer
• Pancreatic cancer
Advantages
KRASG12C-containing cancers are viewed as one of the most challenging targets in cancer. A small molecule, MRTX1257, has previously demonstrated selective inhibition of the KRASG12C oncoprotein. This novel approach combined inhibition of KRASG12C oncoprotein with OV and anti-PD-1 treatments to treat KRASG12C-containing cancers using a multitude of overlapping and complementary mechanisms. Treatment with this triple regimen led to increased T cells including CD8+, CD4+, and tumor-reactive tumor-infiltrating lymphocytes (TILs). This novel approach could have applications beyond KRASG12C-containing cancers and potentially lead to adoptive T cell therapy in other poorly immunogenic tumors.
Invention Readiness
Selective cytotoxicity of MRTX1257 in KRASG12C cancers was confirmed. Co-treatment with an IL-36-armed OV enhanced the antitumor activity of both treatments. It was observed that dual treatment led to enhanced PD-1+CD8+ T cells, and subsequent experiments confirmed that treatment with PD-1 significantly improved efficacy compared to dual therapy alone. In animal models of lung and mesothelioma KRASG12C-containing cancers, this treatment regimen improved survival.
IP Status
https://patents.google.com/patent/US20230338384A1Related Publications
Zhu, Z., McGray, A. J. R., Jiang, W., Lu, B., Kalinski, P., & Guo, Z. S. (2022). Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways. Molecular Cancer, 21(1). https://doi.org/10.1186/s12943-022-01664-z
Yang, M., Giehl, E., Feng, C., Feist, M., Chen, H., Dai, E., Liu, Z., Ma, C., Ravindranathan, R., Bartlett, D. L., Lu, B., & Guo, Z. S. (2021). IL-36γ-armed oncolytic virus exerts superior efficacy through induction of potent adaptive antitumor immunity. Cancer Immunology, Immunotherapy, 70(9), 2467–2481. https://doi.org/10.1007/s00262-021-02860-4
