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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02693

Polyoxidinium® activates cytotoxic lymphocyte responses through Dendritic Cell maturation: clinical effects in breast cancer

 catherine alexia1,  Maïlys CREN1,  Pascale L. Plence1,  Dang-Nghiem Vo1, yasamine el-ahmadi1, emilie dufourcq2, zhao-yang lu1,  JAVIER HERNANDEZ1,  Farkhad Shamilov3, Olga Chernysheva3,  m vasilieva4, I vorotnikov3, Yana Vishnevskay3, nikolay tupitsyn3, jean-françois rossi5, 6 and  Martin Villalba1, 2*
  • 1INSERM U1203 Développement Embryonnaire Précoce Humain et Pluripotence, France
  • 2Centre Hospitalier Universitaire de Montpellier, France
  • 3Federal State Budget Institution National Medical Research Radiology Center of the Ministry of Healthcare of the Russian Federation (FSBI NMRRC), Russia
  • 4Voronezh Regional Clinical Oncologic Dispensary, Russia
  • 5Institut Sainte Catherine Avignon, France
  • 6Université de Montpellier, France

Immunotherapy, which is seen as mayor tool for cancer treatment, requires in some cases the presence of several agents to maximize its effects. Adjuvants can enhance the effect of other agents. But despite their long-time use, only a few adjuvants are licensed today and their use in cancer treatment is scarce. Azoximer bromide, marketed under the trade name Polyoxidonium® (PO), is the copolymer of N-oxide of 1,4-ethylenepiperazine and (N-carboxyethyl)-1,4-ethylene piperazinium bromide. It was described as an immune adjuvant and immunomodulator used that is clinically used with excellent tolerance. PO is used in treatment and prophylaxis of diseases connected with damage of immune system and there is an interest to test it in antitumor therapy. We show here that PO treatment for one week induces positive pathological changes in 6 out of 20 patients with breast cancer, including complete response in a triple negative patient. This correlated with increased percentage of tumor CD4+ T-lymphocytes infiltrating rate. PO immune effects are associated with myeloid cell activation and little is known about PO action on the lymphocyte lineages such as natural killer (NK) and T cells. We reveal that PO increases T cell proliferation in vitro without negative effects on any activation marker. PO does not affect dendritic cell (DC) viability and increases expansion of immature DC (iDC) and mature DC (mDC) at 100 µg/ml and stimulates expression of several DC co-stimulatory molecules inducing proliferation of allogeneic T cells. In contrast, PO decreases DC viability when added at day 5 post-expansion. PO is not toxic for NK cells at doses up to 100 µM and does not affect their activation, maturation and cytotoxicity, but tends to increase degranulation. This could be beneficial against target cells that show low sensitivity to NK cells, e.g. solid tumor cells. Finally, we have found great variability of PO responses between donors. In summary, our in vitro results show that PO increases the number of costimulatory molecules on DC that prime T cells favoring the production of effector T cells. This may support future clinical development of PO in cancer treatment.

Keywords: polyoxidinidum, Dendritic Cells, cytotoxic lymphocyte, breast cancer, Aliphatic polyamines, Natural Killar Cells, T cell

Received: 09 Jul 2019; Accepted: 01 Nov 2019.

Copyright: © 2019 alexia, CREN, Plence, Vo, el-ahmadi, dufourcq, lu, HERNANDEZ, Shamilov, Chernysheva, vasilieva, vorotnikov, Vishnevskay, tupitsyn, rossi and Villalba. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Martin Villalba, INSERM U1203 Développement Embryonnaire Précoce Humain et Pluripotence, Montpellier, France, martin.villalba@inserm.fr