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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Synergy of Immune Checkpoint Blockade with a Novel Synthetic Consensus DNA Vaccine Targeting TERT
Elizabeth K Duperret1, Megan C Wise2, Aspen Trautz1
1Vaccine Center, The Wistar Institute, Philadelphia, PA 19104, USA.
Abstract:
Immune checkpoint blockade antibodies are setting a new standard of care for cancer patients. It is therefore important to assess any new immune-based therapies in the context of immune checkpoint blockade. Here, we evaluate the impact of combining a synthetic consensus TERT DNA vaccine that has improved capacity to break tolerance with immune checkpoint inhibitors. We observed that blockade of CTLA-4 or, to a lesser extent, PD-1 synergized with TERT vaccine, generating more robust anti-tumor activity compared to checkpoint alone or vaccine alone. Despite this anti-tumor synergy, none of these immune checkpoint therapies showed improvement in TERT antigen-specific immune responses in tumor-bearing mice. αCTLA-4 therapy enhanced the frequency of T-bet+/CD44+ effector CD8+ T cells within the tumor and decreased the frequency of regulatory T cells within the tumor, but not in peripheral blood. CTLA-4 blockade synergized more than Treg depletion with TERT DNA vaccine, suggesting that the effect of CTLA-4 blockade is more likely due to the expansion of effector T cells in the tumor rather than a reduction in the frequency of Tregs. These results suggest that immune checkpoint inhibitors function to alter the immune regulatory environment to synergize with DNA vaccines, rather than boosting antigen-specific responses at the site of vaccination.
Insights
Combining a TERT DNA vaccine with immune checkpoint inhibitors like CTLA-4 blockade enhanced anti-tumor activity. This synergy improved effector T cells within tumors, not antigen-specific responses.
Area of Science:
- Immunology
- Oncology
- Vaccinology
Background:
- Immune checkpoint blockade antibodies represent a new standard of care in cancer therapy.
- Evaluating novel immune-based therapies alongside immune checkpoint blockade is crucial.
Purpose of the Study:
- To assess the synergistic effects of combining a TERT DNA vaccine with immune checkpoint inhibitors (CTLA-4 and PD-1).
- To investigate the impact of this combination on anti-tumor activity and immune responses.
Main Methods:
- Utilized a synthetic consensus TERT DNA vaccine designed to overcome tolerance.
- Administered combination therapy with CTLA-4 or PD-1 blockade in tumor-bearing mice.
- Analyzed TERT antigen-specific immune responses and immune cell populations within tumors and peripheral blood.
Main Results:
- Blockade of CTLA-4, and to a lesser extent PD-1, synergized with the TERT vaccine, increasing anti-tumor activity.
- No improvement in TERT antigen-specific immune responses was observed with checkpoint blockade.
- αCTLA-4 therapy increased effector CD8+ T cells and decreased regulatory T cells within tumors, but not in peripheral blood.
Conclusions:
- Immune checkpoint inhibitors synergize with DNA vaccines by altering the tumor's immune regulatory environment.
- The primary mechanism appears to be the expansion of effector T cells within the tumor, rather than a reduction in regulatory T cells or enhanced antigen-specific responses at the vaccination site.
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