A Novel Engineered AAV-Based Neoantigen Vaccine in Combination with Radiotherapy Eradicates Tumors

Area of Science:

• Immunology
• Oncology
• Gene Therapy

Background:

• Tumor-specific antigen (TSA) vaccines, including neoantigen (neoAg) vaccines, face challenges from host immune checkpoints like PD-1/PD-L1.
• These checkpoints inhibit neoAg presentation on dendritic cells (DCs) and reduce T cell cytotoxicity, limiting vaccine efficacy.

Purpose of the Study:

• To develop a novel modified adeno-associated virus (meAAV) neoAg vaccine to overcome PD-1/PD-L1 mediated immune suppression.
• To evaluate the therapeutic potential of this enhanced vaccine, alone and in combination with radiotherapy, against colorectal and breast cancers.

Main Methods:

• Development of a meAAV neoAg vaccine incorporating TLR9 inhibitory fragments, PD-1 trap, and PD-L1 miRNA.
• Assessment of vaccine persistence, neoAg-specific T-cell responses, and cytotoxic T lymphocyte (CTL) activity in murine models.
• Evaluation of the combination therapy with radiotherapy in terms of antigen presentation, CTL responses, tumor microenvironment modulation, and anti-tumor efficacy.

Main Results:

• The meAAV neoAg vaccine demonstrated extended persistence and activated neoAg-specific T-cell responses in colorectal and breast cancer models.
• Combination with radiotherapy enhanced antigen presentation and maintained neoAg-specific CTL responses, overcoming PD-1/PD-L1 inhibition.
• The combined therapy significantly boosted CTL responses, increased CTL infiltration, reduced tumor immunosuppression, leading to complete colorectal tumor elimination and delayed breast tumor growth.

Conclusions:

• The developed meAAV neoAg vaccine effectively overcomes host immune checkpoint inhibition.
• Combining this novel vaccine with radiotherapy represents a promising strategy to enhance anti-cancer therapeutic efficacy against colorectal and breast cancers.