Identifying CLL antigens for future combinational therapy.

In this issue of Blood, Dubovsky et al use novel methodology to identify lymphocyte cytosolic protein-1 (LCP1) as a putative tumor-associated antigen, Ag (TAA) that may play a critical role in regulating CLL cell homing to the leukemia niche. Their translational research approach further shows that kinase inhibitors (KIs) have the potential to block LCP1 activation, which raises the possibility that these drugs might be effectively combined with LCP1-targeted biological therapies. Novel approaches to CLL treatment are needed to prevent disease relapse. KIs targeting Bruton’s tyrosine kinase (BTK) and the phosphoinositide 39-kinase d (PI3Kd) are showing very impressive early clinical responses in CLL by inhibiting kinases that are essential for B-cell receptor (BCR) signaling and tumor microenvironment (TME) protective signaling. However, there is emerging evidence that the use of such targeted drugs in some CLL patients may lead to the emergence of resistant tumor cell variants that harbor mutations in kinase genes. It is also possible that leukemic cells could circumvent BCR-targeted therapies by co-opting alternative oncogenic signaling patterns, but these heterogenic signaling pathways in the TME remain to be fully delineated. CLL tumor cells are known to engage in incompletely defined cellular interactions with different stromal cells that reside in the complex TME that include activated CLL Ag-specific CD4 helper T-cells (contrasting with functionally suppressed CD8 cytotoxic T-cells in CLL patients). Clearly, identifying new membrane-associated receptors and their ligands in CLL will be essential to design new therapeutic targets that could complement KIs to combat therapy resistance. Clinical scientists are particularly interested in using agents with a mechanism-of-action distinct from the KIs. Immunotherapy aimed at harnessing endogenous anti-tumor immunity could help effectuate long-term tumor control or clearance. The combination of targeted therapy with immunotherapy has the potential to represent a next generation treatment strategy for CLL and other hematologic cancers. A major goal is the identification of TAA to harness the full potential of immunotherapy. This article by Dubovsky and colleagues describes a novel strategy that exploits the specificity of the cancer patient’s anti-tumor humoral immunity to identify LCP1 (also Summary schematic of the serological-based CLL membrane antigen (Ag) screening approach, migration functional assays, and translational implications. ID, identification; IgG, immunoglobulin G; IHC, immunohistochemistry; KIs, kinase inhibitors (eg, ibrutibib and idelalisib).