Jump-starting the T cells in CLL

Immune dysfunction is typically observed in CLL and leads to the increased number of infections and second malignancies seen in this disease.²  In addition, decreased T-cell immune surveillance in CLL permits the survival of leukemia cells and likely explains the incurability of this disease with chemoimmunotherapy alone.³  This decreased immune surveillance has been shown in laboratory studies to be related to inhibition of both CD8⁺ and CD4⁺ T-cell function by adhering CLL cells, and this inhibition can be prevented by lenalidomide.^4,5  In the study by Shanafelt and colleagues, the authors make the novel observation that T-cell immune synapse function, and presumably immune surveillance, can be improved in patients with CLL by reducing tumor burden with chemoimmunotherapy and by lenalidomide.¹ 

Although CLL cells express tumor antigens, it has long been appreciated that there is no autologous immune response to these cells, allowing them to survive and for the disease to progress.³  This observation led to the question as to how CLL cells manage to evade T-cell surveillance. This puzzle has recently been answered, at least in part, in elegant studies by Ramsay et al,^4,5  who demonstrated that both CD4⁺ and CD8⁺ T cells in CLL have abnormal immune synapse formation on exposure to autologous CLL cells. Immune synapse formation occurs when the T-cell receptor comes in contact with antigen, and in the normal way, marked structural changes occur in the T cells as a result of polarization of the actin cytoskeleton with the accumulation of filamentous actin (F-actin) at the site of antigen binding. Many abnormalities are seen in the immune synapse formation when CD4⁺ and CD8+ T cells are exposed to CLL cells; these abnormalities include less binding of T cells to leukemia cells, less F-actin accumulation at the immune synapse, and less recruitment and activation of synapse signaling proteins, such as Lck.⁴ 

The abnormal T-cell immune synapse formation in CLL is also observed when leukemia cells are exposed to allogeneic T cells and is related to increased expression of 4 ligands on the CLL cell surface (CD200, CD270, CD274, and CD276).⁵  Although lenalidomide does not have any direct cytotoxic affect on CLL cells, it was found to downregulate the expression of the 4 ligands and improve immune synapse formation between CLL and autologous CD8⁺ and CD4⁺ cells.⁵  For patients receiving lenalidomide, ex vivo studies showed increased T-cell immune synapse formation between CLL cells and autologous T cells, leading the authors to suggest that this may be the underlying cause for the tumor flare observed with this agent in CLL.^4,5 

The present study by Shanafelt et al¹  has extended the above observations by examining immune synapse formation in patients treated initially with chemoimmunotherapy followed by lenalidomide. Patients were treated with 6 cycles of pentostatin, cyclophosphamide, and rituximab (PCR), which the authors have previously demonstrated is an effective and well-tolerated regimen in CLL.⁶  PCR therapy was followed by a median of 6 months of lenalidomide consolidation.

Compared with historical controls using PCR alone, the depth and duration of clinical response was improved in a quarter of patients by the addition of lenalidomide. To determine the effect of therapy on immune function, T-cell immune synapse formation was assessed at various times after treatment, when CLL cells obtained before treatment were incubated with autologous T cells obtained during and after therapy. Increased immune synapse formation was seen in 82% of patients after PCR, which appeared to be directly related to the reduction in tumor cell burden. Immune synapse activity increased further with lenalidomide and was paralleled by an increase in T-cell number and IgG levels.

This study is important in that it extends previous observations showing that T-cell immune synapse function can be improved in CLL with lenalidomide, suggesting that part of the activity of this drug is related to improved immune surveillance. Moreover, the study confirmed previous work showing that lenalidomide can improve overall immune function in CLL, producing an increase in immunoglobulin levels.⁷  Unfortunately, the study also confirmed that lenalidomide is toxic in CLL, with neutropenia and infections being the most common adverse effects.^1,7,8  Thus, a search for new analogs with improved tolerability and enhanced immunomodulation over lenalidomide is required. At this time, the only treatment to produce long-term remissions, and possibly cures, in CLL is allogeneic stem cell transplantation.⁹  The present study indicates that T-cell immune synapse formation is enhanced after PCR therapy and suggests that minimizing tumor burden before transplantation would optimize the graft vs leukemia effect. Finally, it is tantalizing to speculate that increasing immune surveillance in CLL with lenalidomide or chemoimmunotherapy may reduce the high incidence of second malignancies seen in this disease.²