Hi-TIDe : Immune landscape, drug screening and TILs expansion platform

The team mission is to deeply characterize the Tumor MicroEnvironment (TME) and to develop new Tumor Infiltrating Lymphocytes (TILs) Rapid Expansion Protocols targeting the optimal immune-modulatory pathways capable of expanding tumor reactive TILs for Adoptive T cell therapy. 

Adoptive T Cell Therapy (ACT) involves ex-vivo isolation and expansion of antigen-specific T cells from autologous tumors for adoptive transfer back to patients. Although clinical benefit has been observed in melanoma, the efficacy of ACT for the treatment of most solid tumors is limited. The necessity for extensive culturing (3 to 5 weeks) of the tumor-specific T cells to obtain sufficient numbers for infusion, influences the quality of the T cells and their persistence in-vivo.  Thus, we will attempt to shorten the TILs culture time by providing the crucial costimulatory signal in combination with cytokine(s), to reactivate tumor specific T cells and to promote their proliferation and survival. In addition, targeting the Antigen Presenting Cells by blocking immunosuppressive pathways (anti-IL-10, anti-TGFβ) or by their activation with a Toll Like Receptor agonist, may further promote TILs' expansion and activation. Molecules targeting metabolic pathways will also be assessed to reprogram TILs' fitness.

The functionality and specificity of these TILs will be assessed in-vitro against autologous organotypic TME cultures or derived cell lines, as well as in-vivo in humanized autologous patient-derived xenograft models.

In order to unveil new biomarkers predictive of the immuno-modulation combination and capable of generating high numbers of activated tumor specific T cells, a comprehensive immune phenotype analysis of the initial TILs sample using immunohistochemistry assessment will be conducted. This allows for an appraisal of the topography of cellular interactions, flow cytometry analysis of dissociated samples and transcriptomic analysis.

These dynamic analyses will allow a better understanding of the cellular mechanisms of response OR resistance to immune-modulation therapy and thereby help to improve immunotherapy. 

• Rusakiewicz S, et al., NKp30 isoforms and NKp30 ligands are predictive biomarkers of response to imatinib mesylate in metastatic GIST patients. Oncoimmunology. 2016; 6(1):e1137418. 

• Semeraro M*, Rusakiewicz S* et al.,Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients. Sci Transl Med, 2015 (283):283ra55

• Rusakiewicz S et al., Immune infiltrates are prognostic factors in localized gastrointestinal stromal tumors. Cancer Res. 2013,73(12):3499-510. 

• Delahaye NF*, Rusakiewicz S*, Martins I* et al, Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat Med. 2011, 17(6):700-7.

• Jacquelot N, Roberti MP, Enot DP, Rusakiewicz S, et al., Immunophenotyping of Stage III Melanoma Reveals Parameters Associated with Patient Prognosis. J Invest Dermatol. 2016, 136(5):994

   

• SystemsX for the MelanomX and PrionX projects
• SNF Agora