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Investigating and Characterizing the Immune Response in Prostate Cancer Treatment

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Investigating and Characterizing the Immune Response in Prostate Cancer Treatment INVESTIGATING AND CHARACTERIZING THE IMMUNE RESPONSE IN PROSTATE CANCER TREATMENT Grossfeld, David J.; Reiss, Allison B.; Kasselman, Lora J.; Renna, Heather A.; Le Sueur, Amanda; Katz, Aaron E. Katz Winthrop Research Institute, Winthrop University Hospital, Mineola, New York Purpose Of Study •Prostate cancer is second leading cause of cancer deaths in men in the US •Activating the immune system and altering the tumor microenvironment as a treatment •4 Treatment Groups: total prostate cryotherapy (TC, Group 1), radical prostatectomy (RP, Group 2), focal prostate (hemiablation) cryotherapy (FC, Group 3) or stereotactic body radiation therapy via CyberKnife (SBRT, Group 4). Xu H, Hu MB, Bai PD, et al. Proinflammatory cytokines in prostate cancer development and progression promoted by high-fat diet. Biomed Res Int. 2015;2015:249741. doi:10.1155/2015/249741 How CryoablationWorks Controlled freezing of the prostate gland Leads to denaturation, disruption of blood supply, and coagulative necrosis Target temperature of -40 °C Rapid freezing, slow thawing, 2 cycles Minimally-invasive Total ablation or hemi-ablation (freezing only half of the prostate) Methods 40 patients treated as described in Groups 1-4 for histologically proven prostate adenocarcinoma. Urine and Plasma samples were analyzed at 3 time points: ◦ before PCa treatment ◦ immediately following treatment (2 ± 1 week) ◦ 3 months post-treatment. Cytokines evaluated via ELISA ◦ IL1a, IL1b, IL2, IL4, IL6, Il8, IL10, IL12, IL17A, IFN-y, TNF-a, GM-CSF Blood draw (20cc) and urine sample at each visit (screening, 1st immune assessment at 2-3 weeks, and 2nd immune assessment approximately 3 months after treatment) Results IL10 IL6 4000 1500 Total cryotherapy Total cryotherapy (7,12,21, 27, 36, 3000 (7,12,21, 27, 36, 38, 41, 43, 45) 1000 38, 41, 43, 45) 2000 Radical Prostatectomy Radical Prostatectomy (17,18,22,23,24,25,26,3 500 (17,18,22,23,24,25,26,3 1000 0,31,32) 0,31,32) Focal 0 Focal 0 Cryoablation Cryoablation (2,4,5,8,11,1 (2,4,5,8,11,1 -1000 3,14,16,37) -500 3,14,16,37) 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 it it it it it it it it it it it it Cyberknife (33,35,47,48) it it it it it it it it it it it it Cyberknife (33,35,47,48) is is is is is is is is is is is is is is is is is is is is is is is is v v v v v v v v v v v v v v v v v v v v v v v v Interleukin 10 (IL10) and IL6 levels increased during visit 2 (2 weeks post-op) in the radical prostatectomy cohort, then decreased close to baseline during visit 3. IL10 Roles of IL10 and IL6 • is anti inflammatory • Limits production of pro –inflammatory cytokines (IL1a, IL6, IL12, TNFa) by acting on CD4+ T cells • Directly effect Th1 and Th2 response in lymph nodes Kevin N. Couper, Daniel G. Blount, Eleanor M. Riley. The Journal of Immunology May 1, 2008, 180 (9) 5771-5777; IL6 • aids in activation of T cells, differentiation of B cells • Levels can rise substantially in the blood in a disease state • Shown to be involved in autoimmunity in cancer and homeostatic basal regulation • link with IL-6 and tumor growth and tumor-linked inflammation • , C., Jones, S. Correction: Corrigendum: IL-6 as a keystone cytokine in health and disease. Nat Immunol18, 1271 (2017). https://doi.org/10.1038/ni1117-1271b IL1a 600 Total cryotherapy (7,12,21, 27, 36, 400 38, 41, 43, 45) Radical Prostatectomy 200 (17,18,22,23,24,25,26,3 0,31,32) 0 Focal Cryoablation (2,4,5,8,11,1 -200 3,14,16,37) 1 2 3 1 2 3 1 2 3 1 2 3 it it it it it it it it it it it it Cyberknife (33,35,47,48) is is is is is is is is is is is is v v v v v v v v v v v v IL1a changed significantly over time (P= 0.0175). In the Total cryotherapy and focal cryotherapy cohorts, IL1a levels increased post-treatment at visits 2 and 3 relative to baseline. In the Cyberknife group, IL1a levels only increased at visit 3 (3 months post- treatment), with a large positive percent change relative to baseline IFN-y 800 Total cryotherapy 600 (7,12,21, 27, 36, 38, 41, 43, 45) 400 Radical Prostatectomy 200 (17,18,22,23,24,25,26,3 0,31,32) 0 Focal -200 Cryoablation (2,4,5,8,11,1 -400 3,14,16,37) e 1 2 e 1 2 e 1 2 e 1 2 n t t n t t n t t n t t Cyberknife (33,35,47,48) li n n li n n li n n li n n e e e e e e e e e e e e s m m s m m s m m s m m a s s a s s a s s a s s b s s b s s b s s b s s e e e e e e e e s s s s s s s s s s s s s s s s a a a a a a a a e e e e e e e e n n n n n n n n u u u u u u u u m m m m m m m m im im im im im im im im Similar to IL1a, IFN-y levels rose slightly during visits 2 and 3 in Total Cryotherapy and Focal cryoablation cohorts. Additionally, the Cyberknife group demonstrated a post-treatment rise in cytokine levels in IFN-y and IL1a. To Consider: IL6 and IL1a role in Prostate Cancer IL6 • IL6 and the Jak/STAT pathway • IL6 levels in serum are raised in patients with metastatic prostate cancer • Experimental therapy using Siltuximab • Phase II clinical study showed biological, but not clinical, activity in patients that have already undergone chemotherapy IL1a • Anti-IL-1a antibody is being tested in clinical trials • Pro-inflammatory cytokine, can work in conjunction with TNF-a • IL1a and B expression has been found in multiple tumor lines Culig Z, PuhrM. Interleukin-6: a multifunctional targetable cytokine in human prostate cancer. Mol Cell Endocrinol. 2012;360(1-2):52–58. doi:10.1016/j.mce.2011.05.033 Conclusions • Inflammatory cytokine profile may therefore be a useful indicator of therapeutic response and prognosis. • Pre- vs. post-treatment cytokine levels differ in patients receiving SBRT, RP, TC, or FC. • IL6 and IL10 • IL1a and IFN-y • IFN-y as key player in tumor microenvironment when administering radiation treatment • We will be continuing plasma analysis with patients in the cryotherapy cohort https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3668027/ Where do we Go From here? • Potential in exploring High fat Diet? TRAMP mice • Worth studying MIC-1 (Macrophage inhibitory cytokine 1), which has been found to be upregulated in Pca with poorer prognosis • Link between androgen deprivation therapy and dementia in prostate cancer patients • Continue plasma inflammatory analysis in cryotherapy cohort Xu H, Hu MB, Bai PD, et al. Proinflammatory cytokines in prostate cancer development and progression promoted by high-fat diet. Biomed Res Int. 2015;2015:249741. doi:10.1155/2015/249741 and Sfanos KS, De Marzo AM. Prostate cancer and inflammation: the evidence. Histopathology. 2012;60(1):199–215. doi:10.1111/j.1365-2559.2011.04033.x.
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