Nano Immuno Chemotherapy to treat cancers

Transcription

1 Nano Immuno Chemotherapy to treat cancers Dr. Giovanna Lollo, MiNT, France Dr. Ilaria Marigo, IOV, Italy University of Angers MiNt: Micro et Nanomedicines Biomimetiques France Instituto Oncologico Veneto Italy

2 Lymphonanocarriers for the treatment of Metastatic Cancer LYMPHOTARG The LYMPHOTARG project proposes to develop specifically targeted anticancer treatments, by associating anticancer drug to specific nanostructures composed of lipids and polymers, which have a specific affinity for the lymph nodes. In this way, we expect to prevent the process of metastatic spreading through lymphatic vessels.

3 Design and development of Gemcitabine loaded LNC Water Oil Triglyceride (labrafac) Heating PEG-HS (Solutol) PIZ Surfactant (Span 80) O/W W/O Cooling Heating C Gem-C 12 Temperature Dilution (Water 20 C) 50 nm Gem-C 12 : Modified Gemcitabine

4 Biodistribution Studies n=5 Biodistribution studies on healthy mice following i.v. and s.c. administration of fluorescent labelled LNC

5 Biodistribution Studies LNC reach the lymph nodes and remain there for a while (4 days for i.v. and 2 weeks for s.c.). Accumulation in liver and spleen following i.v. and s.c. administration was also evidenced.

6 Cumulative proportion surviving mice Antitumor efficacy SCID-CB17 mice grafted at day 0 with Ma44-3 cells and treated at day 5, 7 and 9 for IV treatment and at day 5 and 9 for SC treatment (N = 10). A total maximal tolerated dose of 40mg/kg (equivalent molar of gemcitabine) was used to treat groups with Gemzar, GemC12 micelles (GemC12) or LNC GemC P < 0.05 salin iv gemzar iv gemc12 LNC blank iv LNC gemc12 iv LNC blank sc LNC gemc12 sc C u m u la tiv e P r o p o S u r v iv in g Day post tumor-graft

7 Evaluation of systemic side effects Hematologic toxicity Complete blood count (CBC) complete granulocyte count (WBC) platelet count (PLT) WBC (G/L) RBC (T/L) HGB (g/dl) HCT (%) PLT (G/L) Saline IV 0,2 ± 0,1 9,8 ± 0,3 15,1 ± 0,3 47 ± ± 50 Gemzar IV 0,2 ± 0,1 9,2 ± 0,3 14,0 ± 0,4 45 ± ± 63 GemC12 IV 0,3 ± 0,2 9,1 ± 0,6 14 ± 1 45 ± ± 63 Lnc Blank IV 0,6 ± 0,3 9,8 ± 0,2 15,1 ± 0,3 47,7 ± 0,9 465 ± 44 Lnc GemC12 IV 0,14 ± 0,03 8,9 ± 0,2 13,7 ± 0,3 43,1 ± 0,9 284 ± 24 Lnc Blank SC 0,4 ± 0,1 9,4 ± 0,7 14 ± 1 46 ± ± 20 Lnc GemC12 SC 0,26 ± 0,06 9,4 ± 0,5 14,5 ± 0,8 45 ± ± 83 * * P < 0,05 (Kruskall- Wallis test) Severe combined immunodefiency mice very low WBC level Deficient lymphocytes B and T Normal natural killer cells, macrophages, granulocytes Abnormal thymus and lymph nodes Gemzar induce significant myelosuppression on SCID-CB17 mice as revealed by platelet count in comparaison to saline group. Neither blank LNC or LNC loaded by GemC12 delivered by i.v. or s.c. induced significant myelosuppresion

8 Next step... NICHE: Nano Immuno CHEmotherapy The global objective of the project is to develop a novel, synergistic strategy between nanomedicine and immunotherapy to treat cancer. A double approach combining the relief of tumor-induced immunosuppression and the stimulation of a specific immune response against the tumor is proposed.

9 Nano Immuno Carriers Good nanocarrier (LNC) prototype from an immunological point of view was developed. Gem-loaded LNC suppress BM-MDSC differentiation in vitro and in vivo Cross talk between neoplastic and remote sites, such as the bone marrow and spleen, determine the release of soluble factors that drive the accumulation of myeloid cells (MDSC); these myeloid cells subsequently promote neovascularization and metastasis. LNC accumulate into spleen and could probably interact with the MDSC Bronte and Gabrilovich, Nat. Rev. Immunol., 2010

10 Immunesuppressive cells impair cancer immunotherapy Endogenous suppressive cells Adoptive Cell Transfer therapy (ACT) T T Adoptivel y transferr ed T cells Adapted from Restifo, Dudley and Rosenberg. Nature reviews in Immunology 2012

11 NICHE Project Target Mechanism of action Nanomedicine Monocyte Revert immunosuppression TAM Spleen MDSC Tumor microenvironment Primary tumor ICD Antigens DC Stimulate immune response Lymph node Tumor cell CRT HMGB-1 ATP CD8 + CD4 + Cross Presentation Activation of CD8 + and CD4 +

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