Vector Aided Microenvironment programming (VAMP): reprogramming the TME with MVA virus expressing IL-12 for effective...

Area of Science:

• Immunology
• Oncology
• Gene Therapy

Background:

• The tumor microenvironment (TME) suppresses antitumor immunity, posing a challenge for cancer immunotherapy.
• Cytokine-based therapies aim to modify the TME and enhance antitumor responses.
• Interleukin-12 (IL-12) shows potent anti-tumor effects but causes systemic toxicity upon administration.

Purpose of the Study:

• To evaluate the efficacy of intratumoral administration of a modified Vaccinia Ankara (MVA) vector carrying IL-12 (MVA-IL-12) for cancer immunotherapy.
• To investigate the impact of MVA-IL-12 on reprogramming the tumor microenvironment (TME) and T-cell receptor repertoire.

Main Methods:

• Cloning of IL-12 into the MVA genome for intratumoral delivery.
• Preclinical evaluation of MVA-IL-12 in murine tumor models.
• RNA sequencing (RNA-Seq) analysis to assess TME and T-cell receptor repertoire changes.

Main Results:

• MVA-IL-12 demonstrated significant antitumor activity, leading to complete tumor remission in various models, including those resistant to checkpoint inhibitors.
• Treatment resulted in minimal circulating cytokine levels.
• MVA-IL-12 effectively reprogrammed the TME by reducing M2 macrophages, increasing M1 macrophages, and recruiting dendritic cells, thereby promoting CD8 T cell priming and expansion.

Conclusions:

• Intratumoral MVA-IL-12 therapy effectively converts immunologically 'cold' tumors into 'hot' tumors.
• This approach overcomes resistance to programmed cell death protein-1 (PD-1) blockade, offering a promising strategy for cancer immunotherapy.