Venetoclax May Restore Function in CD4 T Cells in CLL

Chronic lymphocytic leukemia (CLL) results in diminished functionality of CD4 T cells, revealed study findings, which also showed that treatment with venetoclax reverses this effect.

These findings were recently published in Blood Advances.

Analyzing CD4 T cells from patients with CLL, the researchers observed that the cells had impaired T-cell activation, demonstrated by reduced levels of GLUT-1—even within activated T cells—as well as lower oxidative phosphorylation and impaired mitochondrial fitness. According to the researchers, the cells could not initiate glycolysis form T-cell stimulation, which is a crucial component of CD4 T-cell effector function and for the ability to proliferate.

However, the authors of the study also found that treatment with venetoclax may be able to restore activation and proliferation of these cells, suggesting that plasticity of CD4 T cells can be leveraged for autologous T-cell–based treatments.

“Our results incentivize investigating whether efficacy of alternative autologous-based therapies such as CAR T-cell therapy can be similarly improved in vivo after venetoclax treatment or by adapting the CAR T cells to restore redox balance,” wrote the researchers. “This has yet to be described in CLL, but could possibly be achieved by designing a CAR which allows expression of the CAR itself and expression of a gene essential for achieving redox balance in tandem.”

The researchers studied the in vivoeffects of treatments based on indications from in vitro findings that eliminating CLL cells restored T-cell function. They collected data from the phase 2 HOVON 139 trial, providing samples from before and after treatment with venetoclax and obinutuzumab. Within the intent-to-treat group of patients, undetectable minimal residual disease in the peripheral blood was achieved in 88% of patients and in the bone marrow in 79% of patients following 12 cycles of induction treatment.

These results coincided with upregulated GLUT-1 and increased glucose intake among 6 patients enrolled in the study. Notably, treatment led to improved proliferation of T cells compared with untreated samples from baseline.

“Presence of regulatory T cells (Tregs) has often been described as a marker of clinical significance in CLL due to their immunosuppressive effect, increasing with disease progression,” described the researchers. “The proportion of Tregs was reduced after venetoclax/obinutuzumab treatment. In addition, dynamic analysis of CD4 T-cell activation of both CD4 T cells isolated prior to therapy and after 12 cycles demonstrated enhanced expression of CD25 in venetoclax/Obinutuzumab–treated patients over time, similar to levels in healthy donors.”

Reference

van Bruggen JAC, van der Windt GJW, Hoogendoorn M, Dubois J, Kater AP, Peters FS. Depletion of CLL cells by venetoclax treatment reverses oxidative stress and impaired glycolysis in CD4 T cells. Blood Adv. Published online May 17, 2022. doi:10.1182/bloodadvances.2022007034