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• W4308406732 abstract "<h3>Background</h3> Early clinical trials have provided evidence for RT-induced systemic effects in conjunction with aPD-1 or IL-2 in metastatic patients, but strong abscopal responses are clinically rare. Dual combinations of aPD-1 with more effective and less toxic IL-2 derivatives, e.g., CD122-directed pegylated IL-2, are also currently under investigation. Whether a combination of RT, aPD-1, and CD122-directed IL-2/anti-IL-2 complexes (IL-2c) can increase abscopal effects against established non-irradiated tumors is unknown. Also, in-depth analyses of the differentiation of tumor-specific CD8⁺ T cells have not yet been reported for aPD-1/IL-2c. We investigated how adding IL-2c to hRT/aPD1 affects tumor-specific CD8⁺ T cell differentiation and the potential of this triple combination to enhance the abscopal effect compared to the respective dual treatments. <h3>Methods</h3> Mice bearing bilateral tumors were treated with two fractions of 8 Gy (C51 colon carcinoma model) or 12 Gy (B16 melanoma model); aPD1 was given weekly; IL-2c was given for five consecutive days. CD8 T cell-depleting and CXCR3-blocking antibodies were used to determine if the therapeutic effects depend on CD8⁺ and CXCR3⁺ T cells. Differentiation stages of tumor-specific CD8⁺ T cells in tumor-draining lymph nodes, spleen, blood, and tumors were determined flow cytometrically using MHC-I tetramers and various antibodies. <h3>Results</h3> The abscopal effect was significantly stronger in triple-treated mice compared to mice treated with RT/aPD1 (C51 model: p < 0.01; B16 model: p < 0.05), RT/IL-2c (C51 model: p < 0.01; B16 model: p < 0.001) or aPD1/IL-2c (C51 model: p < 0.0001, B16 model: p < 0.01). Moreover, triple therapy improved survival and resulted in complete cures of 3/12 mice in the C51 model and 2/12 mice in the B16 model. These anti-tumor effects were associated with dramatic expansion of tumor-specific CD8⁺ T cells. Undifferentiated stem-like and effector-like but not terminally differentiated exhausted cells particularly strongly increased. Moreover, IL-2c induced CXCR3 mainly on non-terminally differentiated CD8⁺ T cells. Both CD8⁺ (C51 model: p < 0.0001; B16 model: p < 0.01) and CXCR3⁺ (C51 model: p < 0.0001) T cells were crucial for the RT-induced abscopal effect upon RT/aPD-1/IL-2c treatment. <h3>Conclusions</h3> RT/aPD-1/IL-2c triple treatment resulted in superior local and systemic expansion of tumor-specific CD8⁺ T cells with stem- and effector-like phenotypes. Also, IL-2c strongly increased CXCR3⁺ CD8+ T cells that were associated with pronounced abscopal responses in models with an established metastasis resistant to aPD-1/IL-2c and only transiently responding to RT/aPD-1 or RT/IL-2c. Therefore, such triple combinations appear promising for clinical evaluation in metastatic patients. <h3>Ethics Approval</h3> All animal experiments were approved by the Regierungspräsidium Freiburg, Germany (registration numbers: G18/066, G20-016)." @default.
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• W4308406732 date "2022-11-01" @default.
• W4308406732 modified "2023-10-16" @default.
• W4308406732 title "868 CD122-directed IL-2/anti-IL-2 complexes massively expand stem-like tumor-specific T cells and enhance abscopal responses to radiation and anti-PD-1" @default.
• W4308406732 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0868" @default.
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