Consequence of Dose Scheduling of Sunitinib on Host Immune Response Elements and Vaccine Combination Therapy
Posted: Mon Jul 08, 2019 9:22 am
I was scouting the article on "Immune consequences of tyrosine kinase inhibitors that synergize with cancer immunotherapy" ( viewtopic.php?f=3&t=1319&p=10604&hilit= ... ces#p10604 ) and found this footnote article written in 2012 to be of interest , as we all embark on combination therapies involving TKIs and immunotherapy(ies)
It appears in my uneducated opinion, that continuous usage is of better results? Less immune suppressive?
Abstract
This study investigated the immunomodulatory effects of sunitinib in order to rationally design combinational platforms with immunotherapies for the treatment of solid tumors. Using a mouse model, we studied the effects of sunitinib given for 4 weeks at concentrations comparable to 37.5–50 mg/day in humans, followed by 2 weeks off the drug (sunitinib 4/2). We assessed the effect of differently timed combinations of sunitinib and a poxvirus-based vaccine encoding carcinoembryonic antigen (CEA) plus 3 costimulatory molecules on immune responses in CEA-transgenic (CEA-Tg) mice. Antitumor studies were performed in CEA-Tg mice bearing CEA-transfected MC38 murine colon carcinomas (MC38-CEA), treated either concurrently or sequentially with sunitinib and vaccine. In vitro, sunitinib inhibited PDGFR phosphorylation on MC38-CEA cells at concentrations similar to those biologically available during human treatment. In vivo, one cycle of sunitinib 4/2 caused bimodal immune effects: (a) decreased regulatory cells during the 4 weeks of treatment and (b) an immune-suppression rebound during the 2 weeks of treatment interruption. In a model using CEA-Tg mice bearing CEA+ tumors, continuous sunitinib followed by vaccine increased intratumoral infiltration of antigen-specific T lymphocytes, decreased immunosuppressant T regulatory cells and myeloid-derived suppressor cells, reduced tumor volumes, and increased survival. The immunomodulatory activity of continuous sunitinib administration can create a more immune-permissive environment. In combination with immunotherapies, sunitinib treatment should precede vaccine, in order to precondition the immune system, to maximize the response to vaccine-mediated immune enhancement.
Keywords: sunitinib, vaccine, immunotherapy, TKI, cancer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232304/
It appears in my uneducated opinion, that continuous usage is of better results? Less immune suppressive?
Abstract
This study investigated the immunomodulatory effects of sunitinib in order to rationally design combinational platforms with immunotherapies for the treatment of solid tumors. Using a mouse model, we studied the effects of sunitinib given for 4 weeks at concentrations comparable to 37.5–50 mg/day in humans, followed by 2 weeks off the drug (sunitinib 4/2). We assessed the effect of differently timed combinations of sunitinib and a poxvirus-based vaccine encoding carcinoembryonic antigen (CEA) plus 3 costimulatory molecules on immune responses in CEA-transgenic (CEA-Tg) mice. Antitumor studies were performed in CEA-Tg mice bearing CEA-transfected MC38 murine colon carcinomas (MC38-CEA), treated either concurrently or sequentially with sunitinib and vaccine. In vitro, sunitinib inhibited PDGFR phosphorylation on MC38-CEA cells at concentrations similar to those biologically available during human treatment. In vivo, one cycle of sunitinib 4/2 caused bimodal immune effects: (a) decreased regulatory cells during the 4 weeks of treatment and (b) an immune-suppression rebound during the 2 weeks of treatment interruption. In a model using CEA-Tg mice bearing CEA+ tumors, continuous sunitinib followed by vaccine increased intratumoral infiltration of antigen-specific T lymphocytes, decreased immunosuppressant T regulatory cells and myeloid-derived suppressor cells, reduced tumor volumes, and increased survival. The immunomodulatory activity of continuous sunitinib administration can create a more immune-permissive environment. In combination with immunotherapies, sunitinib treatment should precede vaccine, in order to precondition the immune system, to maximize the response to vaccine-mediated immune enhancement.
Keywords: sunitinib, vaccine, immunotherapy, TKI, cancer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232304/