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Emerging therapeutic options

Novel approaches to target a variety of pathways are being investigated in fNHL in an attempt to improve outcomes^35-37 (Table 10)

Optimizing combinations of old and new agents and the sequencing of specific therapies are current areas of research⁵
- Ongoing studies are exploring the potential for combining new agents with mAbs and chemotherapy³⁸

Table 10. Emerging therapeutic approaches in fNHL

Monoclonal antibodies target antigens that are preferentially or exclusively expressed on the surface of B cells³⁹
Antigen targets under investigation for fNHL include CD19, CD20, and CD22, among others^36,39
In preclinical studies, monoclonal antibodies have been shown to induce cytotoxicity through 1 or more of the following proposed mechanisms: antibody-dependent cellular cytotoxicity (ADCC), induction of apoptosis or direct cell death, and complement-dependent cytotoxicity (CDC)⁴⁰
- ADCC occurs when mAbs attract immune-effector cells, such as natural killer cells, which recognize and kill antibody-labeled target cells⁴⁰
- Some monoclonal antibodies have been shown to trigger an intracellular signal when bound to their target antigen on the cell surface, which results in apoptosis or direct cell death^41,42
- 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 the osmotic lysis of the target cell⁴⁰

CD19 is a cell surface molecule that positively regulates antigen receptor signal transduction in mature B cells⁴³
CD19 and CD21 form a receptor on B cells and various B-cell lymphomas including NHL⁴⁴
Anti-CD19 immunotoxin conjugated with ricin A chain has been described in clinical literature, as well as a nonfucosylated anti-CD19, bispecific antibodies, and an Fc-engineered anti-CD19 mAb^36,44-46

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 lineages^47,48
Typically, CD20 is not downregulated or shed upon binding to a monoclonal antibody^47,48
Emerging mAbs that target CD20 with novel proposed mechanisms of action are now under investigation in B-cell malignancies^42,49
- 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^42,49 (Table 11)
- Glycoengineering of the antibody results in stronger FcγRIIIa binding, which enhances ADCC in vitro⁴²

Table 11. Characteristics of type I and type II anti-CD20 mAbs as demonstrated in vitro

CD22 is widely expressed on B cells and may be important in B-cell activation modulation of antigen-receptor signaling and cell-surface–receptor circulation³⁹
CD22 is a B-cell–specific adhesion molecule that is commonly expressed in NHL and may regulate B-cell receptor (BCR)–mediated signal transduction³⁶
The CD22 target is under investigation both with unarmed antibodies and antibody-drug conjugates^50,51

The chromosomal translocation t(14;18)(q32;21), a hallmark of fNHL, juxtaposes the Bcl-2 gene with the immunoglobulin heavy chain locus. This results in the overexpression of Bcl-2. Because Bcl-2 exerts an anti-apoptotic effect, overexpression decreases the cells' propensity to undergo apoptosis^37,52,53
Currently, small molecules that inhibit Bcl-2 activity are in clinical development^37,54
For more information about the role Bcl-2 plays in apoptosis, visit www.ResearchApoptosis.com

Genes that regulate cellular growth may be regulated by the way they are entwined around the histone proteins in the nucleosome. The positions of the histone proteins are partially determined by HDAC activity⁵⁵
Because HDAC inhibitors prevent histone deacetylation, they maintain the chromatin in an open structure and promote transcription of tumor suppressor genes and other genes⁵⁵

There is increasing evidence that supports targeting of the microenvironment in the treatment of B-cell malignancies³⁷
While the mechanism of action is unknown, immunomodulators (IMiDs) may work by inhibiting proinflammatory cytokines, targeting angiogenesis, and activating the immune system, primarily T cells and natural killer cells³⁷

The PI3K/AKT/mTOR pathway may play an important role in the development of lymphoma⁵⁶
mTOR is a serine/threonine kinase that controls cell cycle progression and protein translation⁵⁷
This pathway regulates the expression of cyclin D1 and c-Myc, important factors in cellular proliferation and growth^56,57
Inhibition of this pathway may be an important strategy in the treatment of lymphoma^37,58

Proteasomes are complexes within the cell that break up protein. Inhibition of proteasomes may inhibit pathways such as NFκB, which controls genes implicated in cell activation, proliferation, and apoptosis³⁷
Proteasome inhibition plays a major role in multiple myeloma. This therapeutic approach is now being investigated for NHLs as well³⁷

Recent studies have suggested a role for dysregulation of the tyrosine kinase Syk in B-cell malignancies^58-60
Syk is predominantly expressed in B-cell lines and has been implicated in the signal transduction pathway of the BCR⁶⁰
- BCR activation results in tyrosine phosphorylation of Syk, which activates the PI3K/AKT pathway and promotes the survival of B cells⁵⁸
The suggested role of Syk activity for B-cell survival provides a strong rationale for targeting it therapeutically⁵⁸
Preclinical studies have shown that inhibitors that target Syk may induce apoptosis in fNHL and may inhibit BCR signaling as well^60,61