Table 1 Available evidence of effects of different therapeutic agents alone or in combination on the immune system in chronic lymphoid leukemia (CLL).

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