Heterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy
Background The clinical benefit of immune checkpoint blockade (ICB) therapy is often limited by the lack of pre-existing CD8+ T cells infiltrating the tumor. In principle, CD8+ T-cell infiltration could be promoted by therapeutic vaccination. However, this remains challenging given the paucity of va...
| Κύριοι συγγραφείς: | , , , , , , , , , , , |
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| Μορφή: | Journal article |
| Γλώσσα: | English |
| Έκδοση: |
BMJ Publishing Group
2021
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| _version_ | 1826289260108447744 |
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| author | McAuliffe, J Chan, HF Noblecourt, L Ramirez-Valdez, RA Pereira-Almeida, V Zhou, Y Pollock, E Cappuccini, F Redchenko, I Hill, AV Leung, CSK Van den Eynde, BJ |
| author_facet | McAuliffe, J Chan, HF Noblecourt, L Ramirez-Valdez, RA Pereira-Almeida, V Zhou, Y Pollock, E Cappuccini, F Redchenko, I Hill, AV Leung, CSK Van den Eynde, BJ |
| author_sort | McAuliffe, J |
| collection | OXFORD |
| description | Background The clinical benefit of immune checkpoint blockade (ICB) therapy is often limited by the lack of pre-existing CD8+ T cells infiltrating the tumor. In principle, CD8+ T-cell infiltration could be promoted by therapeutic vaccination. However, this remains challenging given the paucity of vaccine platforms able to induce the strong cytotoxic CD8+ T-cell response required to reject tumors. A therapeutic cancer vaccine that induces a robust cytotoxic CD8+ T-cell response against shared tumor antigens and can be combined with ICB could improve the outcome of cancer immunotherapy.
Methods Here, we developed a heterologous prime-boost vaccine based on a chimpanzee adenovirus (ChAdOx1) and a modified vaccinia Ankara (MVA) encoding MAGE-type antigens, which are tumor-specific shared antigens expressed in different tumor types. The mouse MAGE-type antigen P1A was used as a surrogate to study the efficacy of the vaccine in combination with ICB in murine tumor models expressing the P1A antigen. To characterize the vaccine-induced immune response, we performed flow cytometry and transcriptomic analyses.
Results The ChAdOx1/MVA vaccine displayed strong immunogenicity with potent induction of CD8+ T cells. When combined with anti-Programmed Cell Death Protein 1 (PD-1), the vaccine induced superior tumor clearance and survival in murine tumor models expressing P1A compared with anti-PD-1 alone. Remarkably, ChAdOx1/MVA P1A vaccination promoted CD8+ T-cell infiltration in the tumors, and drove inflammation in the tumor microenvironment, turning ‘cold’ tumors into ‘hot’ tumors. Single-cell transcriptomic analysis of the P1A-specific CD8+ T cells revealed an expanded population of stem-like T cells in the spleen after the combination treatment as compared with vaccine alone, and a reduced PD-1 expression in the tumor CD8+ T cells.
Conclusions These findings highlight the synergistic potency of ChAdOx1/MVA MAGE vaccines combined with anti-PD-1 for cancer therapy, and establish the foundation for clinical translation of this approach. A clinical trial of ChadOx1/MVA MAGE-A3/NY-ESO-1 combined with anti-PD-1 will commence shortly.
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| first_indexed | 2024-03-07T02:26:11Z |
| format | Journal article |
| id | oxford-uuid:a5b0ce21-1c08-4742-9224-748335a0e1da |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:26:11Z |
| publishDate | 2021 |
| publisher | BMJ Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:a5b0ce21-1c08-4742-9224-748335a0e1da2022-03-27T02:42:08ZHeterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapyJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a5b0ce21-1c08-4742-9224-748335a0e1daEnglishSymplectic ElementsBMJ Publishing Group2021McAuliffe, JChan, HFNoblecourt, LRamirez-Valdez, RAPereira-Almeida, VZhou, YPollock, ECappuccini, FRedchenko, IHill, AVLeung, CSKVan den Eynde, BJBackground The clinical benefit of immune checkpoint blockade (ICB) therapy is often limited by the lack of pre-existing CD8+ T cells infiltrating the tumor. In principle, CD8+ T-cell infiltration could be promoted by therapeutic vaccination. However, this remains challenging given the paucity of vaccine platforms able to induce the strong cytotoxic CD8+ T-cell response required to reject tumors. A therapeutic cancer vaccine that induces a robust cytotoxic CD8+ T-cell response against shared tumor antigens and can be combined with ICB could improve the outcome of cancer immunotherapy. Methods Here, we developed a heterologous prime-boost vaccine based on a chimpanzee adenovirus (ChAdOx1) and a modified vaccinia Ankara (MVA) encoding MAGE-type antigens, which are tumor-specific shared antigens expressed in different tumor types. The mouse MAGE-type antigen P1A was used as a surrogate to study the efficacy of the vaccine in combination with ICB in murine tumor models expressing the P1A antigen. To characterize the vaccine-induced immune response, we performed flow cytometry and transcriptomic analyses. Results The ChAdOx1/MVA vaccine displayed strong immunogenicity with potent induction of CD8+ T cells. When combined with anti-Programmed Cell Death Protein 1 (PD-1), the vaccine induced superior tumor clearance and survival in murine tumor models expressing P1A compared with anti-PD-1 alone. Remarkably, ChAdOx1/MVA P1A vaccination promoted CD8+ T-cell infiltration in the tumors, and drove inflammation in the tumor microenvironment, turning ‘cold’ tumors into ‘hot’ tumors. Single-cell transcriptomic analysis of the P1A-specific CD8+ T cells revealed an expanded population of stem-like T cells in the spleen after the combination treatment as compared with vaccine alone, and a reduced PD-1 expression in the tumor CD8+ T cells. Conclusions These findings highlight the synergistic potency of ChAdOx1/MVA MAGE vaccines combined with anti-PD-1 for cancer therapy, and establish the foundation for clinical translation of this approach. A clinical trial of ChadOx1/MVA MAGE-A3/NY-ESO-1 combined with anti-PD-1 will commence shortly. |
| spellingShingle | McAuliffe, J Chan, HF Noblecourt, L Ramirez-Valdez, RA Pereira-Almeida, V Zhou, Y Pollock, E Cappuccini, F Redchenko, I Hill, AV Leung, CSK Van den Eynde, BJ Heterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy |
| title | Heterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy |
| title_full | Heterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy |
| title_fullStr | Heterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy |
| title_full_unstemmed | Heterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy |
| title_short | Heterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy |
| title_sort | heterologous prime boost vaccination targeting mage type antigens promotes tumor t cell infiltration and improves checkpoint blockade therapy |
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