THE IMMUNOLOGICAL EFFECTS OF CHECKPOINT BLOCKADE IN COMBINATION WITH A TYROSINE KINASE INHIBITOR IN A MURINE MODEL OF RENAL CELL CARCINOMA
| dc.contributor.advisor | Drake, Charles G. | |
| dc.creator | Alme, Angela Kay Brizendine | |
| dc.date.accessioned | 2018-05-22T04:03:12Z | |
| dc.date.available | 2018-05-22T04:03:12Z | |
| dc.date.created | 2015-12 | |
| dc.date.issued | 2015-08-24 | |
| dc.date.submitted | December 2015 | |
| dc.date.updated | 2018-05-22T04:03:12Z | |
| dc.description.abstract | Renal Cell Carcinoma (RCC) is responsible for approximately 13,500 deaths in the US each year and 65,000 new cases are diagnosed here annually. Despite the approval of multiple new drugs targeting mTOR and angiogenic pathways, there is still no curative treatment. Only 20-30% of patients respond to these targeted therapies; all eventually become resistant and progress. One of the most widely used targeted therapies is sunitinib, a tyrosine kinase inhibitor (TKI) primarily targeting the vascular endothelial growth factor receptors (VEGFRs). There is some evidence that sunitinib has off-target effects on the immune system, including reducing the number of myeloid derived suppressor cells (MDSCs) but also causing lymphopeania in patients. Recently completed and ongoing clinical trials of monotherapy with antibody blockade of Programmed Death 1 (PD-1) have demonstrated efficacy in RCC patients. We explored the therapeutic potential, as well as the immunomodulating effects, of combined sunitinib and anti-PD-1 antibody therapy using the orthotopic murine Renca model of RCC. Though short-term experiments did not reveal a significant increase in therapeutic potential over sunitinib alone, we did observe significantly more IFNγ+ CD8 T cells in the tumor-infiltrating lymphocytes (TIL) of combination-treated mice compared to those who received sunitinib alone. We also examined the effect of sunitinib therapy on the in vivo expression of B7-H1/PD-L1, a known ligand for PD-1, on tumor cells harvested from treated, tumor-bearing mice. In wild-type Balb/c mice, sunitinib therapy significantly reduced B7-H1 expression. This decrease in B7-H1 expression, as well as the dramatic therapeutic effect of sunitinib, were not seen in Balb/c RAG knockout mice, however. While the combination of sunitinib and anti-PD-1 antibody was not effective in our orthotopic Renca model, the rationale behind combining anti-angiogenic therapy, particularly TKIs, with immune checkpoint blockade is supported by an extensive body of literature and worthy of continued investigation. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | http://jhir.library.jhu.edu/handle/1774.2/58761 | |
| dc.language | en | |
| dc.publisher | Johns Hopkins University | |
| dc.publisher.country | USA | |
| dc.subject | PD-1 | |
| dc.subject | B7-H1 | |
| dc.subject | sunitinib | |
| dc.subject | renal cell carcinoma | |
| dc.subject | immunotherapy | |
| dc.subject | kidney cancer | |
| dc.subject | checkpoint blockade | |
| dc.subject | Renca | |
| dc.title | THE IMMUNOLOGICAL EFFECTS OF CHECKPOINT BLOCKADE IN COMBINATION WITH A TYROSINE KINASE INHIBITOR IN A MURINE MODEL OF RENAL CELL CARCINOMA | |
| dc.type | Thesis | |
| dc.type.material | text | |
| thesis.degree.department | Molecular Biology and Genetics | |
| thesis.degree.discipline | Immunology | |
| thesis.degree.grantor | Johns Hopkins University | |
| thesis.degree.grantor | School of Medicine | |
| thesis.degree.level | Masters | |
| thesis.degree.name | M.S. |