Additional expression of T-cell engager in clinically tested oncolytic adeno-immunotherapy redirects tumor-infiltrated, irrelevant T cells against cancer cells to enhance antitumor immunity
Background Oncolytic adenoviruses (OAds) are the most clinically tested viral vectors for solid tumors. However, most clinically tested “Armed” OAds show limited antitumor effects in patients with various solid tumors even with increased dosages and multiple injections. We developed a binary oncolyt...
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BMJ Publishing Group
2024-12-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/12/e009741.full |
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| author | Bora Lim Caroline Porter Mae Woods Masataka Suzuki Daisuke Morita Amanda Rosewell Shaw Greyson Biegert Spyridoula Vasileiou |
| author_facet | Bora Lim Caroline Porter Mae Woods Masataka Suzuki Daisuke Morita Amanda Rosewell Shaw Greyson Biegert Spyridoula Vasileiou |
| author_sort | Bora Lim |
| collection | DOAJ |
| description | Background Oncolytic adenoviruses (OAds) are the most clinically tested viral vectors for solid tumors. However, most clinically tested “Armed” OAds show limited antitumor effects in patients with various solid tumors even with increased dosages and multiple injections. We developed a binary oncolytic/helper-dependent adenovirus system (CAdVEC), in which tumors are coinfected with an OAd and a non-replicating helper-dependent Ad (HDAd). We recently demonstrated that a single low-dose CAdVEC expressing interleukin-12, programmed death-ligand 1 blocker, and HSV thymidine kinase safety switch (CAdTrio) induces significant antitumor effects in patients, including complete response. Similar to previous OAd studies, all patients primarily amplified Ad-specific T cells after treatment however, CAdVEC was still able to induce clinical responses even given at a 100-fold lower dose.Methods To address the mechanisms of CAdTrio-mediated antitumor effect in patients, we analyzed patients’ samples using Enzyme-linked immunosorbent spot (ELISpot) to measure T-cell specificity and quantitative polymerase chain reaction (qPCR) to measure CAdVEC viral genome copies at tumor sites. We then evaluated potential mechanisms of CAdVEC efficacy in vitro using live-cell imaging. Based on those results, we developed a new CAdVEC additionally expressing a T-cell engager molecule targeting CD44v6 to redirect tumor-infiltrating irrelevant T cells against cancer stem cell populations (CAdTetra) for further improvement of local CAdVEC treatment. We tested its efficacy against different cancer types both in vitro and in vivo including Ad pre-immunized humanized mice.Results We found that HDAd-infected cells escape Ad-specific T-cell recognition with enhanced tumor-specific T-cell activity through immunomodulatory transgenes. Since CAdVEC treatment initially amplified Ad-specific T cells in patients, we re-direct these virus-specific T cells to target tumor cells by additionally expressing CD44v6.BiTE from CAdTetra. CAdTetra significantly controlled tumor growth, repolarizing local and systemic responses against cancer cells in both immunologically “hot” and “cold” tumor models and also induced immunologic memory against rechallenged tumors.Conclusions Our results indicate that CAdTetra effectively induces adaptive T-cell responses against cancer cells by using tumor-infiltrating irrelevant T cells. |
| format | Article |
| id | doaj-art-2a3df0b8c8644bb4adc656bda3d66c80 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-2a3df0b8c8644bb4adc656bda3d66c802024-12-17T11:30:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-12-01121210.1136/jitc-2024-009741Additional expression of T-cell engager in clinically tested oncolytic adeno-immunotherapy redirects tumor-infiltrated, irrelevant T cells against cancer cells to enhance antitumor immunityBora Lim0Caroline Porter1Mae Woods2Masataka Suzuki3Daisuke Morita4Amanda Rosewell Shaw5Greyson Biegert6Spyridoula Vasileiou78 Breast Medical Oncology, The UT MD Anderson Cancer Center, Houston, TX, USA1 Department of Medicine, Baylor College of Medicine, Houston, TX, USA2 Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children`s Hospital, Houston Methodist Hospital, Houston, TX, USA1 Department of Medicine, Baylor College of Medicine, Houston, TX, USA2 Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children`s Hospital, Houston Methodist Hospital, Houston, TX, USA1 Department of Medicine, Baylor College of Medicine, Houston, TX, USA1 Department of Medicine, Baylor College of Medicine, Houston, TX, USA2 Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children`s Hospital, Houston Methodist Hospital, Houston, TX, USABackground Oncolytic adenoviruses (OAds) are the most clinically tested viral vectors for solid tumors. However, most clinically tested “Armed” OAds show limited antitumor effects in patients with various solid tumors even with increased dosages and multiple injections. We developed a binary oncolytic/helper-dependent adenovirus system (CAdVEC), in which tumors are coinfected with an OAd and a non-replicating helper-dependent Ad (HDAd). We recently demonstrated that a single low-dose CAdVEC expressing interleukin-12, programmed death-ligand 1 blocker, and HSV thymidine kinase safety switch (CAdTrio) induces significant antitumor effects in patients, including complete response. Similar to previous OAd studies, all patients primarily amplified Ad-specific T cells after treatment however, CAdVEC was still able to induce clinical responses even given at a 100-fold lower dose.Methods To address the mechanisms of CAdTrio-mediated antitumor effect in patients, we analyzed patients’ samples using Enzyme-linked immunosorbent spot (ELISpot) to measure T-cell specificity and quantitative polymerase chain reaction (qPCR) to measure CAdVEC viral genome copies at tumor sites. We then evaluated potential mechanisms of CAdVEC efficacy in vitro using live-cell imaging. Based on those results, we developed a new CAdVEC additionally expressing a T-cell engager molecule targeting CD44v6 to redirect tumor-infiltrating irrelevant T cells against cancer stem cell populations (CAdTetra) for further improvement of local CAdVEC treatment. We tested its efficacy against different cancer types both in vitro and in vivo including Ad pre-immunized humanized mice.Results We found that HDAd-infected cells escape Ad-specific T-cell recognition with enhanced tumor-specific T-cell activity through immunomodulatory transgenes. Since CAdVEC treatment initially amplified Ad-specific T cells in patients, we re-direct these virus-specific T cells to target tumor cells by additionally expressing CD44v6.BiTE from CAdTetra. CAdTetra significantly controlled tumor growth, repolarizing local and systemic responses against cancer cells in both immunologically “hot” and “cold” tumor models and also induced immunologic memory against rechallenged tumors.Conclusions Our results indicate that CAdTetra effectively induces adaptive T-cell responses against cancer cells by using tumor-infiltrating irrelevant T cells.https://jitc.bmj.com/content/12/12/e009741.full |
| spellingShingle | Bora Lim Caroline Porter Mae Woods Masataka Suzuki Daisuke Morita Amanda Rosewell Shaw Greyson Biegert Spyridoula Vasileiou Additional expression of T-cell engager in clinically tested oncolytic adeno-immunotherapy redirects tumor-infiltrated, irrelevant T cells against cancer cells to enhance antitumor immunity Journal for ImmunoTherapy of Cancer |
| title | Additional expression of T-cell engager in clinically tested oncolytic adeno-immunotherapy redirects tumor-infiltrated, irrelevant T cells against cancer cells to enhance antitumor immunity |
| title_full | Additional expression of T-cell engager in clinically tested oncolytic adeno-immunotherapy redirects tumor-infiltrated, irrelevant T cells against cancer cells to enhance antitumor immunity |
| title_fullStr | Additional expression of T-cell engager in clinically tested oncolytic adeno-immunotherapy redirects tumor-infiltrated, irrelevant T cells against cancer cells to enhance antitumor immunity |
| title_full_unstemmed | Additional expression of T-cell engager in clinically tested oncolytic adeno-immunotherapy redirects tumor-infiltrated, irrelevant T cells against cancer cells to enhance antitumor immunity |
| title_short | Additional expression of T-cell engager in clinically tested oncolytic adeno-immunotherapy redirects tumor-infiltrated, irrelevant T cells against cancer cells to enhance antitumor immunity |
| title_sort | additional expression of t cell engager in clinically tested oncolytic adeno immunotherapy redirects tumor infiltrated irrelevant t cells against cancer cells to enhance antitumor immunity |
| url | https://jitc.bmj.com/content/12/12/e009741.full |
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