Rupture of amyloid laden vessels is associated with CAA related intracerebral h

The results of our trial are in contrast to another trial that tested the combination of IL 21 with sunitinib, also a VEGFR TKI . That trial was discontinued after the observation of severe hematologic DLTs at the IL 21 dose of 10 mcg kg in combination with standard dose of sunitinib. However, sunitinib has proven to be a challen ging drug to combine with cytokines or other therapies INNO-406 臨床試験 due to its toxicity profile . Other VEGFR TKIs may be better suited for combination with cytokines. Two studies investigated the combination of sorafenib with standard dose IFN in previously untreated patients with good performance status, although efficacy results were encouraging, the majority of patients required IFN dose reductions with a high treatment discontinuation rate due to toxicities .

An other study compared sorafenib plus low dose IFN combination with sorafenib monotherapy and found no difference in efficacy between the two arms, although there was less toxicity in the combination arm than that ob served in the above mentioned trials Lapatinib 構造 using standard dose IFN . In our study, the MTD of IL 21 in combination with sorafenib is the same as the monotherapy dose of IL 21, further, IL 21 dose reductions were uncommon, allowing for full immunotherapeutic effects of the agent. Lymphocyte activation by IL 21, as determined by sCD25 levels, appears to be retained in the presence of sorafenib. Hence, IL 21 may represent a suitable immunotherapy for further exploration of combination strategies in mRCC, especially with the emerging more selective VEGFR TKIs and with other approaches designed to stimulate the immune system.

Trials LY2109761 investigating the combination of IL 21 with other immunotherapy agents, such as ipilimumab and anti PD 1 antibody, in patients with solid tumors including mRCC are also ongoing . Some preclinical studies have associated sorafenib, but not sunitinib, with relative impairment of the NK cell effector function and of the dendritic cells and adaptive immune responses . However, the clinical significance of these preclinical findings has been unclear. Sorafenib therapy has not been associated with increased risk of infections, which would have supported a drugs immunosuppressive potential, in the major clinical trials .

In the preclinical study of IL 21 plus sorafenib in the murine RenCa model, sorafenib did not inhibit the effects of IL 21 on CD4 or CD8 T cell proliferation, NK cell activation, or antibody dependent cellular cytotoxicity, and led to improved tumor shrinkage and survival time as compared to either therapy alone . Similarly, the com bination of sorafenib with Interleukin 2 in murine studies did not show any significant inhibitory effects of sorafenib on IL 2 induced NK cell expansion . While the paucity of well defined RCC antigens biomarkers limits our ability to rigorously assess the effects of sorafenib on IL 21 in duced tumor specific immune responses in this study, the data on sCD25 levels and the lymphocyte counts suggest that sorafenib did not interfere with the pharmacological effects of IL 21. Conclusions Combination therapy with IL 21 and sorafenib has anti tumor activity with acceptable safety in previously treated mRCC patients.