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Blanka Rihova

Director Institute of Microbiology AS CR, Czech Republic

Title: HPMA Copolymer-Bound Doxorubicin as Endogenous Vaccine Substantially Increases Therapeutic Effect of Check-Point Blockade Monoclonals: Acute versus Chronic Model

Biography

Biography: Blanka Rihova

Abstract

DOXHYD-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 vaccines. We have compared chemo-immunotherapy combination treatment of EL4 T cell lymphoma and 4T1 breast carcinoma with DOXHYD-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 DOXHYD-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

Recent Publications

  1. Říhová B, Etrych T, Šírová M, Tomala J, Ulbrich K, KováÅ™ M (2011) Synergistic effect of EMF-BEMER-type pulsed weak electromagnetic field and HPMA-bound doxorubicin on mouse EL4 T-cell lymphoma. J Drug Target 19, 890-899.
  2. Votavova P, Tomala J, Subr V, Strohalm J, Ulbrich K, Rihova B, Kovar M (2015) Novel IL-2-Poly(HPMA)nanoconjugate based  immunotherapy J Biomed Nanotechnol 11, 1662-1673.  
  3. Tomalova B, Sirova M,  Rossmann P,  Poola R,  Strohalm J,  Chytil P,  Cerny V, Tomala J, Kabesova M, Rihova B, Ulbrich K, Etrych T, Kovar M (2016) The Structure-dependent toxicity pharmacokinetics and anti-tumour activity of HPMA copolymer conjugates in the treatment of solid tumours and leukemia J Control Rel 223, 1-10.   
  4. Sivák L, Šubr V, Tomala J, Říhová B, Strohalm J, Etrych T, KováÅ™ M (2017) Overcoming multidrug resistance via simultaneous delivery of cytostatic drug and P-glycoprotein inhibitor to cancer cells by HPMA copolymer conjugate Biomaterials 115, 65 – 80.               
  5. Šírová M, Strohalm J, Chytil P, Lidický O, Tomala J,  Å˜íhová B, Etrych T (2017) The structure of polymer carriers controls   the efficacy of the experimental combination treatment of tumors with HPMA copolymer conjugates carrying doxorubicin and docetaxel. J Control Rel 246, 1 – 11.