Bioplastics

Biography

Biography: Blanka Rihova

Abstract

DOX^HYD-HPMA is doxorubicin bound through hydrazone bond to synthetic polymeric carrier based on N-(2-hydroxypropyl)methacrylamide. It is effective anticancer polymeric prodrug with decreased side-toxicity and the ability to induce immunogenic cancer cell death releasing site-specific tumor antigen and thus acting as endogenous vaccine. We have compared chemo-immunotherapy combination treatment of EL4 T cell lymphoma and 4T1 breast carcinoma with DOX^HYD-HPMA and with immune checkpoint blocking anti-CTLA-4 and anti-PD-1 MAbs either alone or in a mixture. To document the role of intestinal microbiota we use germ-free (GF) mice and GF mice monocolonized with Bifidobacterium thetaiotamicron. Acute model of disease when mice are transplanted once with a lethal dose of tumor cells was compared with chronic model where mice are injected six times every other day with a low number of tumor cells. Healthy mice treated with anti-CTLA-4 and anti-PD-1 mAbs did not show any signs of toxicity while significant co-toxicity was seen in cancer-bearing mice. Treatment with checkpoint inhibitors only exerted a very limited cancer response as no long term survivors (LTS) were recorded. On the other hand more than 60% of mice injected also with therapeutically suboptimal dose of DOX^HYD-HPMA survived disease-free for more than 100 days. Those suffering from chronic model of cancer showed considerably higher proportion of PD-1⁺ cells in tumor microenvironment and reacted substantially better to anti-CTLA-4 or anti-PD-1 treatment than mice with the acute model