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Intratumoral IL12 mRNA administration activates innate and adaptive pathways in checkpoint inhibitor resistant tumors
Jayalakshmi Lakshmipathi1, Sreevidya Santha1, Man Li1
1Yale School of Medicine.
Abstract:
Despite the proven clinical activity of checkpoint inhibitors (ICIs) in several cancer indications, frequent occurrence of primary and secondary resistance reduces their overall effectiveness. Development of ICI resistance has been attributed mainly to genetic or epigenic alterations that affect the tumor antigen presentation machinery leading to diminished anti-tumor immune responses. There is an urgent need for new approaches which can either re-sensitize resistant tumors to the ICIs or engage alternate immune pathways to inhibit tumors. Intratumoral delivery of nanoparticle encapsulated murine IL-12 (mIL-12) mRNA induces powerful anti-tumor immune responses in murine tumor models and the human version of this drug results in objective responses in patients with advanced disease. Here, we tested the efficacy of mIL12 mRNA as a single agent and in combination with anti-PD-L1 antibodies in ICI sensitive Yummer1.7 melanoma and MC38 colorectal murine tumors and in ICI resistant, β2-microglobulin (B2M) knockout versions of these models. mIL12 mRNA monotherapy was sufficient to cause complete responses (CRs) in ≥ 60% of both ICI sensitive or resistant Yummer1.7 melanoma and MC38 colorectal carcinoma tumors. The mIL12 mRNA treatment resulted in potent upregulation of TH1 type cytokines and chemokines. A reduction in number of Tregs, increase in numbers and activation state of both cytotoxic T cells (CTLs) as well as tumor associated macrophages (TAMs) was observed indicating enhanced anti-tumor, cell-based immune responses in the tumor microenvironment. This mIL-12 induced concerted immune activation was associated with a robust killing and phagocytosis of tumor cells resulting in durable CRs. These observations suggest that intratumoral IL12mRNA therapy may benefit patients with ICI resistant cancers.
Insights
Intratumoral interleukin-12 (IL-12) mRNA therapy effectively treats both sensitive and resistant cancers by boosting anti-tumor immunity. This approach shows promise for patients unresponsive to current immune checkpoint inhibitors (ICIs).
Area of Science:
- Immunology
- Oncology
- Nanotechnology
Background:
- Immune checkpoint inhibitors (ICIs) show clinical activity but face resistance, limiting their effectiveness in cancer treatment.
- Resistance to ICIs is often linked to tumor antigen presentation defects, impairing anti-tumor immune responses.
- Novel strategies are needed to overcome ICI resistance or activate alternative immune pathways against tumors.
Purpose of the Study:
- To evaluate the efficacy of intratumoral interleukin-12 (IL-12) mRNA as a single agent and in combination with anti-PD-L1 antibodies.
- To assess IL-12 mRNA's effectiveness in both ICI-sensitive and ICI-resistant murine tumor models, including those with beta-2-microglobulin (B2M) knockout.
Main Methods:
- Treatment with mIL-12 mRNA alone or combined with anti-PD-L1 antibodies in Yummer1.7 melanoma and MC38 colorectal murine models.
- Utilized both ICI-sensitive and ICI-resistant (B2M knockout) tumor variants to test therapeutic response.
- Analyzed immune cell populations (Tregs, CTLs, TAMs) and cytokine/chemokine profiles within the tumor microenvironment.
Main Results:
- mIL-12 mRNA monotherapy achieved complete responses (CRs) in over 60% of both ICI-sensitive and resistant Yummer1.7 and MC38 tumors.
- Treatment significantly upregulated TH1 cytokines and chemokines, reduced regulatory T cells (Tregs), and increased cytotoxic T cells (CTLs) and tumor-associated macrophages (TAMs).
- Enhanced immune cell activity led to robust tumor cell killing and phagocytosis, resulting in durable complete responses.
Conclusions:
- Intratumoral IL-12 mRNA therapy demonstrates potent anti-tumor activity, inducing significant immune responses in the tumor microenvironment.
- This approach is effective as a single agent in both ICI-sensitive and resistant murine cancer models.
- Intratumoral IL-12 mRNA therapy holds potential for treating patients with ICI-resistant cancers.
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