Table 1.

Available evidence of effects of different therapeutic agents alone or in combination on the immune system in chronic lymphoid leukemia (CLL).

	CIT	BTKi	Pi3Ki	BCL2i	ImmTher
CIT	• FCR: T-cells decrease, mostly CD4+, γδ and T-reg • BR: T-cells decrease (CD4+) • C: T-cells decrease • Anti-CD20: complement pathway exhaustion, reduction of humoral response, reduction of CD4+ and transient reduction of CD8+ T-cells, NK cells decrease	• BTK inhibitors can inhibit anti-CD20-induced NK cell cytokine secretion, cell degranulation and FcR-stimulated NK ADCC in vitro • Ibr + anti-CD20: Enhancement of ADCP	• Ide may marginally reduce anti-CD20 effects	• V + Obi: reduction in healthy B-cells, T-cells (Tfh, T-reg and PD-1+ CD8+ T subtypes) and NK cells. Decrease in IFN-γ and TNF-α produced by CD8+ T-cells. Improved NK cell function
BTKi		• Ibr, Aca, Zanu: Decrease of IL-10, CD200 or BTLA in CLL B-cells. Reduce macrophage function, neutrophil to macrophage differentiation. Reduction of PD-1 and CTLA-4 expression in T-cells • Ibr: Transient increase of effector T-cells. Increase in TCR diversity and Th1 cells, activation of CD8+ T-cells. Reduction of exhausted and chronically activated T-cells. Preservation of naïve T-cells and naïve NK cells. Decrease of Th2 and T-reg cells. Improved immune and cytolytic synapses between T and CLL B-cells.		• Ibr+V: reduction in healthy B-cells, T-cells (Tfh, T-reg and PD-1+ CD8+ T subtypes) and NK cells. Decrease in IL-4 by CD4+ cells and TNF-α produced by CD8+ T-cells. Trend of improvement in the antibody production	• Ibr + CAR-T cells: Improved efficacy of CAR-T cells in ibr-treated patients • Ibr + bi-specific antibodies: enhanced activity in Ibr-treated patients • Ibr + ICI: Improved response to anti-PD-L1 treatment, especially patients with RT • br may improve autologous Vγ9Vδ2 T-cell therapy
Pi3Ki			• Ide: Decrease of T-reg cells, impairs their differentiation and suppressive functions. Decreases TNF-α, CD40L and IL-6 by T-cells; IFN-γ by NK cells and IL-10 by T-reg cells		• Ide-treated patients showed improved autologous CAR-T cells generation, expansion and cytotoxic effects. • Idelalisib caused a decrease in expression of PD-1
BCL2i				• V: reduction of CD4+ and CD8+ cells, increase proportion of effector memory T-cells vs naïve T cells, reduction of Tfh, T-reg and PD1+ CD8+ T-cells. Decreased NK cells but function restored
ImmTher					• CAR-T cells can restore functional capacity of T-cells by in vitro modification • Bi/Tri-specific antibodies may improve interactions between cytotoxic T-cells and CLL B-cells

Aca, acalabrutinib; ADCC: antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cell-mediated phagocytosis; BCL-2i, B-cell lymphoma 2 inhibitor; BR: bendamustine plus rituximab; BTKi, Bruton’s Tyrosine kinase inhibitor; BTLA, B- and T-lymphocyte attenuator; C, cyclophosphamide; CAR, chimeric antigen receptor; CIT: chemoimmunotherapy; CLL, chronic lymphocytic leukemia; FcR, receptor of antibody fragment crystallizable region; FCR: fludarabine, cyclophosphamide, rituximab; Ibr: ibrutinib; ICI, immune checkpoint inhibitor; Ide: idelalisib; IL, interleukin; ImmTher, immunotherapies; NK, natural killer; Obi: obinutuzumab; PD-1, programmed cell death protein 1; PD-L1, programmed cell death protein ligand 1; Pi3Ki, phosphoinositide 3-kinase inhibitor; T-reg, regulatory T-cell; TCR, T-cell receptor; Tfh, follicular T helper; TNF, tumor necrosis factor; RT, Richter transformation; V, venetoclax; Zanu, zanubrutinib.