Pairing anti-PD-L1/PD-1 with avadomide effectively reactivates anti-CLL T cell killing function. (A) Illustration of the autologous cytotoxicity assay using treated patient T cells mixed with treated CLL cells and flow-based quantification of T-cell killing function against superantigen (sAg)-pulsed CLL cells as target cells (mean % CLL cell death ± SEM for n = 10 patients) following the treatments indicated. Aged-matched healthy donor T cell effector activity against autologous B cells loaded with sAg (as target cells) was included as a control. (B) Representative confocal images showing CD8⁺ tumor-infiltrated lymphocytes (TILs) forming granzyme B⁺ (Gzmb, green), F-actin (red) lytic synapses with primary autologous DLBCL tumor cells (blue) with avadomide treatment (nontumoricidal dose) (colocalization signal: yellow) (original magnification ×63, scale bars: 5 μm). (C) Relative recruitment index, RRI image analysis of Granzyme B (green) polarization in autologous CD8⁺ TIL:DLBCL conjugates following vehicle or avadomide treatment (n = 5). (D) Autologous T-cell killing function against patient CLL cells (n = 10) following treatment of patient T cells alone (before mixing with untreated CLL cells) or treating both T cells and CLL cells. (E) T-cell-mediated cytotoxicity against baseline autologous CLL cells using 12 CLL patient samples who had received ibrutinib-based therapy for 12 months. T cells and tumor cells were treated as indicated. *P < .05; **P < .01; ns, not significant using a repeated measures 1-way ANOVA with Tukey's multiple comparisons test (A and E) (or an unpaired t test for comparing CLL T-cell activity with healthy donor T cells), Wilcoxon signed-rank test (C) and 2-way ANOVA (D). Data presented as mean ± SEM.