ArticleJournal for immunotherapy of cancer2025
Impact of tumor localization on antitumor immunity with conditionally activated CTLA-4 blockade.
Article in Journal for immunotherapy of cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- Leveraging multimodal cancer immunotherapy to amplify the efficacy of oncolytic viruses.Experimental hematology & oncology · 2026Review
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11 authors.
Funding
Abstract
backgroundImmune 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.
methodsWe 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.
resultsConditionally 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.
conclusionsThese 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.
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