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Treatment of B-cell lymphoma with irradiation and anti-CD40 induces a potent CD8 T-cell response and provides long-term tumour immunity



Treatment of B-cell lymphoma with irradiation and anti-CD40 induces a potent CD8 T-cell response and provides long-term tumour immunity



Blood 98(11 Part 1): 611a, November 16



The efficacy of combination monoclonal antibody (mAb) and radiation therapy has been assessed in vivo using murine models of lymphoma. Mice inoculated with the syngeneic B-cell lymphoma, A31 (106 iv), were treated with external beam, total body irradiation (TBI), in combination with anti-CD40 mAb. Used as single therapeutic modalities, neither TBI (1-5 Gy), or mAb (1mg iv), were able to extend survival over control cohorts by more than a few days (median survival time 26 days and 21 days respectively). In contrast, when used in combination, a clear radiation dose-response was seen with 80% of animals receiving 5 Gy TBI plus anti-CD40 becoming long-term disease free survivors (>100 days), and median survival times at lower doses of 42, 37 and 25 days for 4 Gy, 3 Gy and 1-2 Gy TBI plus anti-CD40 respectively (p<0.01). Moreover, long-term protected animals were immune to subsequent tumour re-challenge. To investigate the nature of this immunity, tracking experiments were performed to monitor the kinetics of tumour expansion in vivo and analyse any cellular response. Flow cytometric analysis revealed a dramatic expansion of CD8 T-cells (between 3 and 10-fold) in the 5Gy+anti-CD40 treated group compared with those animals which received TBI alone. Simultaneous with this was an observable decrease in the number of tumour cells. When the relative ratio of T-cells to tumour cells was compared, we observed a 10 to 15-fold increase in the number of CD8 T-cells per tumour cell in the long-term protected group, as compared to all other groups. To confirm the importance of CD8 T-cells to protection, therapy was conducted in mice depleted of this subset. Here, therapy provided by the combination treatment was almost completely abrogated. This response appears specific to TBI in combination with anti-CD40, as mAb to other targets (MHC class II, CD22) do not generate an immunological response, or provide protection. This data demonstrates for the first time that irradiation and anti-CD40 mAb can have an additive therapeutic effect in vivo, and that this effect is dependent upon CD8 T-cells. This has important implications for the application of RIT in the clinic.

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Accession: 035980337

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