Impact of tumor localization on antitumor immunity with conditionally activated CTLA-4 blockade
Background Immune checkpoint blockade (ICB) can induce antitumor efficacy but also induces immune-related adverse events. Systemically administered ICB can activate immune cells throughout the host. Conditionally active ICB with proteolytically cleaved masking domains can potentially reduce the adve...
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| Language: | English |
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BMJ Publishing Group
2025-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/4/e010566.full |
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| author | Lawrence Fong Miho Tanaka Jacob V Gorman Marcel Arias-Badia Chien-Chun Steven Pai Yee May Lwin PeiXi Chen Aahir Srinath Emily Musser Andrew Goodearl Wendy Ritacco |
| author_facet | Lawrence Fong Miho Tanaka Jacob V Gorman Marcel Arias-Badia Chien-Chun Steven Pai Yee May Lwin PeiXi Chen Aahir Srinath Emily Musser Andrew Goodearl Wendy Ritacco |
| author_sort | Lawrence Fong |
| collection | DOAJ |
| description | Background Immune checkpoint blockade (ICB) can induce antitumor efficacy but also induces immune-related adverse events. Systemically administered ICB can activate immune cells throughout the host. Conditionally active ICB with proteolytically cleaved masking domains can potentially reduce the adverse events seen with anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibody.Methods We examined how different formats of a conditionally activated dual variable domain IgG (DVD) that binds CTLA-4 and the tumor-associated antigen prostate stem cell antigen (PSCA) can lead to efficacy in syngeneic subcutaneous and metastatic murine tumor models. We also defined the capacity of these DVDs to modulate immune responses by multiparameter flow cytometry.Results Conditionally active DVDs can uncouple antitumor efficacy from toxicity. A fully cleavable construct (symmetric DVD, sDVD), which can be released from the target tumor cells, showed superior antitumor efficacy compared with asymmetric DVD, which retains its tumor antigen binding. The sDVD elicited the highest tumor-antigen-specific T-cell responses detected in tumors and tumor-draining lymph nodes, as well as presenting the highest rate of intratumoral and splenic “non-exhausted” antigen-specific CD8 T cells. SDVD also induced the highest degrees of T-cell memory and self-renewal potential. These effects were dependent on PSCA expression by the tumors.Conclusions These findings support the notion that ICB modulation of antitumor immunity away from the tumor cells is critically important for optimal antitumor immunity. The bispecific sDVD antibody design may enable improved systemic antitumor responses than traditional ICB in both primary tumors and metastases. |
| format | Article |
| id | doaj-art-dad64e4f67424112abe3304ffa932f51 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-dad64e4f67424112abe3304ffa932f512025-08-20T01:51:53ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-04-0113410.1136/jitc-2024-010566Impact of tumor localization on antitumor immunity with conditionally activated CTLA-4 blockadeLawrence Fong0Miho Tanaka1Jacob V Gorman2Marcel Arias-Badia3Chien-Chun Steven Pai4Yee May Lwin5PeiXi Chen6Aahir Srinath7Emily Musser8Andrew Goodearl9Wendy Ritacco10Department of Medicine, University of California San Francisco, San Francisco, California, USADepartment of Medicine, University of California San Francisco, San Francisco, California, USAAbbVie Inc, North Chicago, Illinois, USADepartment of Medicine, University of California San Francisco, San Francisco, California, USADepartment of Medicine, University of California San Francisco, San Francisco, California, USADepartment of Medicine, University of California San Francisco, San Francisco, California, USADepartment of Medicine, University of California San Francisco, San Francisco, California, USADepartment of Medicine, University of California San Francisco, San Francisco, California, USAAbbVie Bioresearch Center, Worcester, Massachusetts, USAAbbVie Bioresearch Center, Worcester, Massachusetts, USAAbbVie Bioresearch Center, Worcester, Massachusetts, USABackground Immune checkpoint blockade (ICB) can induce antitumor efficacy but also induces immune-related adverse events. Systemically administered ICB can activate immune cells throughout the host. Conditionally active ICB with proteolytically cleaved masking domains can potentially reduce the adverse events seen with anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibody.Methods We examined how different formats of a conditionally activated dual variable domain IgG (DVD) that binds CTLA-4 and the tumor-associated antigen prostate stem cell antigen (PSCA) can lead to efficacy in syngeneic subcutaneous and metastatic murine tumor models. We also defined the capacity of these DVDs to modulate immune responses by multiparameter flow cytometry.Results Conditionally active DVDs can uncouple antitumor efficacy from toxicity. A fully cleavable construct (symmetric DVD, sDVD), which can be released from the target tumor cells, showed superior antitumor efficacy compared with asymmetric DVD, which retains its tumor antigen binding. The sDVD elicited the highest tumor-antigen-specific T-cell responses detected in tumors and tumor-draining lymph nodes, as well as presenting the highest rate of intratumoral and splenic “non-exhausted” antigen-specific CD8 T cells. SDVD also induced the highest degrees of T-cell memory and self-renewal potential. These effects were dependent on PSCA expression by the tumors.Conclusions These findings support the notion that ICB modulation of antitumor immunity away from the tumor cells is critically important for optimal antitumor immunity. The bispecific sDVD antibody design may enable improved systemic antitumor responses than traditional ICB in both primary tumors and metastases.https://jitc.bmj.com/content/13/4/e010566.full |
| spellingShingle | Lawrence Fong Miho Tanaka Jacob V Gorman Marcel Arias-Badia Chien-Chun Steven Pai Yee May Lwin PeiXi Chen Aahir Srinath Emily Musser Andrew Goodearl Wendy Ritacco Impact of tumor localization on antitumor immunity with conditionally activated CTLA-4 blockade Journal for ImmunoTherapy of Cancer |
| title | Impact of tumor localization on antitumor immunity with conditionally activated CTLA-4 blockade |
| title_full | Impact of tumor localization on antitumor immunity with conditionally activated CTLA-4 blockade |
| title_fullStr | Impact of tumor localization on antitumor immunity with conditionally activated CTLA-4 blockade |
| title_full_unstemmed | Impact of tumor localization on antitumor immunity with conditionally activated CTLA-4 blockade |
| title_short | Impact of tumor localization on antitumor immunity with conditionally activated CTLA-4 blockade |
| title_sort | impact of tumor localization on antitumor immunity with conditionally activated ctla 4 blockade |
| url | https://jitc.bmj.com/content/13/4/e010566.full |
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