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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 Center for Precision Cancer Modeling, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
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 IL12 (mIL12) 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 Yummer 1.7 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 Yummer 1.7 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 mIL12-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 (IL12) mRNA therapy shows promise for overcoming resistance to immune checkpoint inhibitors (ICIs). This novel approach effectively eliminates tumors and enhances anti-tumor immune responses, offering hope for patients with advanced cancers.
Area of Science:
- Immunology
- Oncology
- Gene Therapy
Background:
- Immune checkpoint inhibitors (ICIs) show clinical activity but are limited by primary and secondary resistance.
- Resistance to ICIs is often linked to impaired tumor antigen presentation and reduced anti-tumor immunity.
- Novel strategies are needed to re-sensitize tumors to ICIs or activate alternative immune pathways.
Purpose of the Study:
- To evaluate the efficacy of intratumoral interleukin-12 (IL12) mRNA as a single agent and in combination with anti-PD-L1 antibodies.
- To assess the effectiveness of IL12 mRNA in both ICI-sensitive and ICI-resistant murine tumor models (melanoma and colorectal carcinoma).
- To investigate the immune mechanisms underlying IL12 mRNA's anti-tumor activity.
Main Methods:
- Intratumoral delivery of nanoparticle-encapsulated murine IL12 (mIL12) mRNA.
- Testing mIL12 mRNA monotherapy and combination therapy with anti-PD-L1 antibodies.
- Utilizing ICI-sensitive (Yummer 1.7 melanoma, MC38 colorectal) and ICI-resistant (B2M knockout) murine tumor models.
- Analysis of immune cell populations (Tregs, CTLs, TAMs) and cytokine/chemokine profiles within the tumor microenvironment.
Main Results:
- mIL12 mRNA monotherapy achieved complete responses (CRs) in ≥60% of both ICI-sensitive and ICI-resistant tumors.
- Treatment led to significant upregulation of TH1 cytokines and chemokines.
- Observed reduction in regulatory T cells (Tregs) and increased numbers/activation of cytotoxic T cells (CTLs) and tumor-associated macrophages (TAMs).
- mIL12 mRNA induced robust tumor cell killing and phagocytosis, resulting in durable CRs.
Conclusions:
- Intratumoral IL12 mRNA therapy is a potent single agent capable of inducing complete and durable responses in both ICI-sensitive and resistant tumors.
- IL12 mRNA effectively reshapes the tumor microenvironment to enhance anti-tumor immune responses.
- Intratumoral IL12 mRNA therapy holds potential for treating patients with ICI-resistant cancers.
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