Download 2016 department of medicine research day

2016 DEPARTMENT OF MEDICINE RESEARCH DAY
Title of Poster: In situ tumor vaccination combined with checkpoint inhibition in a
murine model of lung cancer
Presenter: Ramin Salehi-Rad
Division: Pulmonary and Critical Care
☐ Faculty ☒ Fellow ☐ Resident ☐ Post-doc Research Fellow ☐ Graduate Student ☐ Medical Student ☐Other
Principal Investigator/Mentor: Dr. Steven M. Dubinett Co-Investigators: Tonya C. Walser, Stephanie Ong, Stacy
Park, Manash Paul, Linh Tran, Natalie Yakobian, Mi-Heon Lee, Sherven Sharma, Jay M. Lee
Thematic Poster Category: Development, Morphogenesis, Cell Growth and Differentiation, Apoptosis, Stem Cell
Biology, Carcinogenesis and Cancer Biology
Abstract
Adaptive immune resistance is a mechanism by which tumor cells limit host immune response via
upregulation of the programmed death-ligand 1 (PD-L1) and ligation to the programmed death-1 (PD1) receptor on antigen-specific CD8 T cells. Recent studies of the PD-1 checkpoint inhibitor in nonsmall cell lung cancer (NSCLC) patients reveal an approximately 20% observed response rate. This
includes robust and durable responses in previously treated patients with progressive locally advanced
or metastatic NSCLC. Other studies in melanoma and NSCLC patients treated with PD-1/PD-L1
checkpoint inhibitors have illustrated that durable response appears to be most often associated with
baseline high level PD-L1 expression as well as pre-existing T cell infiltration into the tumor. One
potential approach to extend the effectiveness of checkpoint inhibitors is to enhance T cell responses
by in situ vaccination that takes advantage of the full repertoire of available tumor antigens. In
preclinical studies as well as a clinical trial, we have discovered that CCL21 has antitumor properties
and CCL21-DC have the capacity to induce both local T cell recruitment and systemic immune
responses. We hypothesized that in situ vaccination with CCL21-DC could induce DC and T cell effector
infiltration of the tumor microenvironment (TME) and restore tumor antigen presentation, thereby
enhancing the efficacy of anti-PD-1 therapy in patients with minimal tumor T cell infiltration and low
baseline PD-L1 expression who often do not respond to anti-PD-1 monotherapy. To test this
hypothesis, we evaluated the efficacy of CCL21 and PD-1 inhibitor as monotherapy and in combination
in the syngeneic KRASG12D murine model of lung cancer. We observed decreased subcutaneous tumor
growth as well as systemic immunity evidenced by increased IFN-secreting CD8+ cells from the
spleen measured by flow cytometry (FACS). This anti-tumor response was more pronounced in the
anti-PD-1/CCL21 combination and anti-PD-1 monotherapy group compared to the CCL21 monotherapy
group. Furthermore, 20% of the mice treated with combination therapy or PD-1 inhibitor monotherapy
showed complete tumor eradication. To investigate the determinants of response, we are utilizing
immunohistochemistry (IHC) and FACS to evaluate immune cell number and function as well as other
markers, such as PD-1 and PDL-1, within the TME. Further work will concentrate on optimizing the
timing and concentration of anti-PD-1/CCL21 combination therapy. We anticipate the capacity of in
situ vaccination by CCL21 to induce DC and T cell effector infiltration into the tumors will augment the
efficacy of anti-PD-1 therapy in murine models of lung cancer, establishing the foundation for further
clinical trials in NSCLC patients.