Eliminating mesothelioma by AAV-vectored, PD1-based vaccination in the tumor microenvironment
Zhiwu Tan1, Mei Sum Chiu1, Chi Wing Yan1
1AIDS Institute and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China.
Abstract:
The potency of cancer vaccines is often compromised by a variety of immunoinhibitory mechanisms, including stimulation of the programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint pathway. Here, to overcome inhibition, we determined the potential of recombinant adeno-associated virus (rAAV)-vectored, PD1-based vaccination in the tumor microenvironment (TME) to activate antigen-specific T cell responses in the immune-competent murine mesothelioma model. We found that our rAAV-soluble PD1 (sPD1)-TWIST1 vaccine elicited and maintained TWIST1-specific cytotoxic T lymphocyte (CTL) responses and the PD-1 blocker systemically against lethal mesothelioma challenge after intramuscular injection, which was more effective than rAAV-TWIST1 or rAAV-sPD1 alone. More importantly, intratumoral injection of rAAV-sPD1-TWIST1 significantly enhanced immune surveillance by inducing TWIST1-specific CTL responses against vaccine-encoded TWIST1 and bystander gp70-AH1 epitopes, increasing CTL infiltration into the TME and decreasing tumor-associated immunosuppression, leading to complete elimination of established mesothelioma in 5 of 8 tumor-bearing mice. In addition, direct oncosuppression synergized with recruitment of T cells after localized rAAV-sPD1-TWIST1 treatment in a humanized mouse model to inhibit growth of REN human mesothelioma. Our results warrant clinical development of the rAAV-sPD1-TWIST1 vaccine to enhance immunotherapy against a wide range of TWIST1-expressing tumors.
Insights
This study developed a novel cancer vaccine using recombinant adeno-associated virus (rAAV) to target TWIST1 and PD-1. The vaccine effectively activated T cells and eliminated mesothelioma tumors in mice, showing promise for cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Gene Therapy
Background:
- Cancer vaccine efficacy is limited by immune checkpoints like PD-1/PD-L1.
- Overcoming tumor-associated immunosuppression is crucial for effective cancer immunotherapy.
Purpose of the Study:
- To evaluate a novel recombinant adeno-associated virus (rAAV)-vectored vaccine encoding soluble PD-1 (sPD1) and TWIST1.
- To assess the vaccine's ability to activate antigen-specific T cell responses and overcome immune inhibition in a mesothelioma model.
Main Methods:
- Development of an rAAV-sPD1-TWIST1 vaccine.
- Intramuscular and intratumoral administration in immune-competent murine mesothelioma models.
- Evaluation of TWIST1-specific cytotoxic T lymphocyte (CTL) responses, T cell infiltration, and tumor elimination.
- Assessment in a humanized mouse model for direct oncosuppression.
Main Results:
- The rAAV-sPD1-TWIST1 vaccine induced and maintained TWIST1-specific CTL responses.
- Intratumoral injection led to enhanced immune surveillance, increased CTL infiltration, and reduced immunosuppression.
- Complete elimination of established mesothelioma was observed in 5 of 8 treated mice.
- Localized treatment inhibited human mesothelioma growth in a humanized model.
Conclusions:
- The rAAV-sPD1-TWIST1 vaccine demonstrates significant potential in overcoming tumor immune evasion.
- This approach warrants clinical development for enhancing immunotherapy against TWIST1-expressing tumors.
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