Research Bcell

Emerging therapeutic options

A wealth of new information on the biology of CLL has led to a greater understanding of this disease.³⁸ New treatment strategies continue to uncover opportunities to change a patient's clinical course
Patient enrollment into clinical trials to help improve the clinical outcome in the treatment of CLL is encouraged⁴⁸
Currently, many molecules are under investigation as potential therapies in CLL^46,47 (Table 7). A number of cell signaling pathways have been implicated in the pathogenesis of CLL and may be potential therapeutic targets²⁹ (Figure 7)

Key CLL signaling pathways

Emerging agents under investigation in CLL

mAbs target antigens that are preferentially or exclusively expressed on the surface of B cells, the origin site of CLL^29,49
Antigen targets under investigation for CLL include CD19, CD20, and CD22, among others²⁹

In preclinical studies, mAbs have been shown to induce cytotoxicity through one or more of the following mechanisms: antibody-dependent cellular cytotoxicity (ADCC), induction of cell death, and complement-dependent cytotoxicity (CDC)⁴⁹
- ADCC occurs when mAbs attract immune-effector cells, such as natural killer cells, which recognize and kill antibody–labeled target cells⁴⁹
- Some mAbs have been shown to trigger an intracellular signal when bound to their target antigens on the cell surface, resulting in apoptosis or cell death^50,51
- CDC requires recruitment of the complement cascade. The result of this cascade is that complement proteins ultimately penetrate the cell membrane, and this leads to lysis of the target cell⁴⁹

CD20 is expressed specifically on B cells during most stages of B-cell development, but is absent in stem cells, plasma cells, and cells of other hematopoietic lineages⁵²
Typically, CD20 is not downregulated or shed upon antibody binding⁵²
Emerging mAbs that target CD20 with novel proposed mechanisms of action are now under investigation in B-cell malignancies^51,53
- Preclinical studies show that type II antibodies appear to cause higher direct cell death induction and are less reliant on CDC as a mechanism of killing malignant B cells than type I antibodies^51,53 (Table 8)
- Glycoengineering of the antibody results in stronger FcϒRIIIa binding, which enhances ADCC in vitro⁵¹

Differences between type I and type II anti-CD20 mAbs as demonstrated in vitro

CD22 is widely expressed on B cells⁵⁴
This receptor is involved in regulation of cell adhesion, B-cell survival, CD19 and BCR signal transduction, and BCR-induced cell death^47,54
The CD22 target is under investigation for both antibodies and antibody-drug conjugates (ADCs)^49,55

CLL is characterized by overexpression of antiapoptotic Bcl-2 family members (eg, Bcl-2, Bcl-X_L)⁵⁶
There also is evidence suggesting that resistance to apoptosis plays an important role in the pathogenesis of CLL⁵⁶
A number of strategies targeting Bcl-2 family proteins are under investigation in CLL, including small molecules that target the intrinsic apoptosis pathway by inhibiting Bcl-2 and its family members, such as Bcl-X_L, and Mcl-1^29,57
For more information about the role Bcl-2 plays in apoptosis, visit www.ResearchApoptosis.com

HSP90 is a ubiquitous chaperone protein that assists general protein folding and it is upregulated by cells in response to stress^58,59
HSP90 may be important for cancer cell growth and/or survival, and inhibition of HSP90 may result in protein destabilization and degradation⁵⁹
Preclinical studies in CLL have shown that HSP90 inhibition causes the degradation of ZAP-70 and other proteins associated with poor survival and that this may ultimately lead to apoptosis^58,60

Researchers are exploring the role of targeting the microenvironment in the treatment of CLL²⁹
While the mechanism of action is unknown, immunomodulators (IMiDs), or global regulators, may work by inhibiting tumor necrosis factor alpha (TNF-alpha), targeting angiogenesis, and activating the immune system, primarily T cells and natural killer cells^29,58

Phosphatidylinositol-3-kinase (PI3K) intracellular signaling pathway is crucial to cell growth and survival.²⁹ This pathway is activated as a downstream event from the activation of cell surface tyrosine kinase receptors⁶¹
Genetic changes in the PI3K pathway such as mutations, amplifications, and rearrangements occur more frequently in human cancer than in any other pathways with the exception of p53 and Rb^62,63
For this reason, the PI3K pathway is an attractive target in the design of anticancer therapies

The etiology of CLL may involve aberrant regulations of BCR-mediated protein tyrosine kinase activity and constitutive activation of the protein kinases Syk, Lyn, and PI3K^29,64
- These kinases transduce survival and anti-apoptotic signals, and are potential therapeutic targets^29,64
Recent studies have suggested a role for dysregulation of the tyrosine kinase Syk in B-cell malignancies⁶⁵
Syk is predominantly expressed in the B-cell lineage, and has been implicated in the signal transduction pathway of the BCR⁶⁵
- BCR activation results in tyrosine phosphorylation of Syk, which activates the PI3K/AKT pathway and promotes the survival of B cells⁶⁵
The suggested role of Syk tyrosine kinase activity for B-cell survival provides a strong rationale for targeting it therapeutically
Preclinical studies have shown that inhibitors targeting Syk may induce apoptosis in CLL and may inhibit BCR signaling as well⁶⁶