Intratumoral injections of small doses of agonist anti-CD137 mAb to directly act on CD137+ TILs render systemic immunotherapeutic effects that are synergistic.

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Intratumoral injections of small doses of agonist anti-CD137 mAb to directly act on CD137+ TILs render systemic immunotherapeutic effects that are synergistic with PD-L1 (B7-H1) systemic blockade. Intratumoral injections of small doses of agonist anti-CD137 mAb to directly act on CD137+ TILs render systemic immunotherapeutic effects that are synergistic with PD-L1 (B7-H1) systemic blockade. A, mice bearing subcutaneous CT26 palpable tumors for 7 days were treated intratumorally with three 5-μg doses of control rat IgG or anti-CD137 mAb on days 7, 9, and 11 or/and with 3 i.p. doses of 100 μg anti-B7-H1 blocking mAb. Individual follow-up of tumor sizes is presented for each experimental group, the fraction of tumor-free mice at the end of the experiment is given in each graph, and the survival curves are presented. i.t., intratumorally. B, top, FACS histograms show that CT26 cells do not express B7-H1 in culture but are inducible by culture for 48 hours in the presence of IFN-γ or when cells are freshly recovered from grafted tumors in syngenic mice. Bottom FACS histograms show bright expression of PD-1 on CD3+CD4+ and CD3+CD8+ TILs harvested from CT26 tumors. C, dot plots showing CD137 and PD-1 double immunostaining on gated CD8+ and CD4+ T cells as indicated. Background immunostainings with isotype-matched control mAb tagged with the same fluorochromes are presented. D, BALB/c mice were subcutaneously inoculated with CT26 cells on days 0 and 4 in opposite flanks (black and red as indicated in schematic representation of the experiments). On days 7, 9, and 11, the primary tumor received intratumoral injections of 5 μg of 1D8 mAb or control IgG. Graphs represent individual tumor sizes for the primary (black) and secondary (red) tumors. The fraction of mice completely rejecting tumors is provided with the corresponding black and red graphs. Asís Palazón et al. Cancer Discovery 2012;2:608-623 ©2012 by American Association for Cancer Research