Consequence of Dose Scheduling of Sunitinib on Host Immune Response Elements and Vaccine Combination Therapy

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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/

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Introduction

Sunitinib is an orally available inhibitor of multiple tyrosine kinase receptors (TKI). It was approved by the FDA in 2006 for the treatment of advanced renal cell carcinoma 1 and imatinib-resistant gastrointestinal stromal tumors (GIST) 2. Sunitinib is currently being investigated as a treatment for other solid and hematologic malignancies in numerous clinical trials, including nearly 150 sponsored by the National Cancer Institute3.

Tyrosine kinase receptors (TKRs) targeted by sunitinib, such as VEGF and PDGF receptors, are widely expressed in many tumor cell types 4, tumor vasculature 5, and as growth factor receptors and protectors of apoptosis, allowing sunitinib to act directly against tumor cells 6 and tumor stroma 4. Sunitinib also targets TKRs expressed on myeloid-derived suppressor cells (MDSCs), such as c-KIT and VEGFR-1, making it a promising immunomodulator 7–8. Sunitinib has been shown to exert powerful immunomodulatory effects in cancer patients, as evidenced by a shift from a Th2 to a Th1 immune response and inhibition of immune suppressor cells 9–10, making this TKI an attractive candidate for combination with immunotherapies 11. In this study, we show that a sunitinib treatment regimen of 4 weeks on/2 weeks off (sunitinib 4/2) has a bimodal effect on the immune system: a decrease in regulatory cells during the 4-week treatment period, followed by an immune-suppressant rebound during the 2-week interruption. We therefore investigated whether continuous daily administration of sunitinib would maintain an environment permissive to the induction of immune response. In a combination regimen, sunitinib given before vaccine increased intratumoral infiltration of antigen-specific T lymphocytes, decreased Tregs and MDSCs, reduced tumor volume, and increased survival.

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“From a therapeutic point of view, immunomodulation refers to any process in which an immune response is altered to a desired level. Microorganisms are also capable of modulating the response of the immune system to their presence, in order to establish or consolidate an infection. Thus, immunomodulation can be beneficial or detrimental to a host.”


https://www.encyclopedia.com/science/en ... modulation

[D.ap]

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/

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viewtopic.php?p=10087#p10087