Obstacles to effective Toll-like receptor agonist therapy for hematologic malignancies

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

“…However, i.v. administration of the specific TLR7 agonist 852A did not result in strong antitumoral activity against CLL cells [131], although leukemic skin infiltrates in a patient with CLL disappeared after treatment with imiquimod [106]. In conclusion, alteration of the structure of synthetic TLR7/8 agonists might result in molecules with pharmacological features that make them a suitable treatment method for tumors other than skin tumors.…”

A phase I/II trial of TLR-7 agonist immunotherapy in chronic lymphocytic leukemia

“…One possibility is that microenvironmental factors, such as hypoxia, prevent strong TLR-7-mediated stimulation of CLL cells in vivo. 3 We have recently found that CLL cells treated with TLR-7 agonists in hypoxic conditions in vitro do not become sensitized to cytotoxic agents (not shown). Strategies to increase microenvironmental oxygen tension (such as hyperbaric oxygen) might then significantly improve the clinical efficacy of TLR-7 agonists.…”

“…Depending on the breakpoint in BCR, several BCR-ABL variants can be generated (Figure 1a), such as p190 BCR-ABL and p210 BCR-ABL , which are detected in the majority of cases of Ph-positive ALL and CML, respectively. 1 The p190 BCR-ABL isoform was previously reported to show elevated tyrosine kinase activity, 2,3 although the structural basis for increased kinase activity has not…”

“…1 One approach is suggested by the existence of immunogenic death, a differentiation process that is mediated by sustained activation of stress signaling pathways and culminates in either cell death or a state of heightened sensitivity to cytotoxic T cells and drugs. 2,3 Agents that force CLL cells into an immunogenic death pathway might improve clinical outcomes by eliminating the cells directly, enhancing the efficacy of conventional chemotherapy, or facilitating killing of cytotoxic T cells through increased tumor immunogenicity. Toll-like receptor (TLR)-7 agonists are potentially targeted immunogenic death agents for CLL.…”

Relação entre o oncogene BCR-ABL e os receptores de tipo TOLL (TLR).

“…Ensaios in vitro demonstraram que células leucêmicas só se tornaram sensíveis à ação das CTL (linfócitos T citotóxicos) depois de vários dias de ativação com agonistas de TLRs (Spaner et al, 2008).…”