Microther

Title: Improving immunotherapy of solid tumors by targeting the immunosuppressive tumor microenvironment: from pre-clinical proof-of-concept to the development of phase Ib study

Project Coordinator:
Massimo DI NICOLA (Italy) Fondazione IRCCS, Istituto Nazionale Tumori, Medical Oncology, Milano

Project Partners:
François GHIRINGHELLI (France) Department of Medical Oncology, Center Georges François Leclerc, Dijon
Pedro BERRAONDO (Spain) Immunology and Immunotherapy Programme, Center for Applied Medical Research. University of Navarra, Pamplona
Pei-Jen Alex LOU (Taiwan) Department of Otolaryngology National Taiwan University Hospital  and  National Taiwan University College of Medicine, Taipei
Wojciech GOLUSINSKI (Poland) Department of Head and Neck Surgery Poznan University of Medical Sciences, The  Greater  Poland  Cancer Centre, Poznan

Project Abstract:
Background – Immunotherapy with immune checkpoint blockers (ICB) is effective against several malignancies, but only a fraction of patients achieve clinical benefit. Identification of innate resistance mechanisms is crucial to improve the rate of response.
Hypothesis – Assessment and pre-clinical targeting of main immunosuppressive mechanisms in the tumor microenvironment (TM) may lead to more effective immunotherapeutic combinations.
Aims – 1. A retrospective bio-molecular characterization of immunosuppressive cells and matricellular proteins in TM of 4 tumors (triple negative breast cancer, TNBC; head and neck, HNSCC; melanoma and colorectal cancer, CRC). The immunosuppressive TM will be evaluated even in pre e post-chemotherapy (CT) lesions from patients receiving neoadjuvant therapy; 2. exploit mouse models for testing synergistic anti-tumor activity of ICB combined with drugs targeting the immunosuppressive TM. Combinations will be based on results from Aim 1 as well as on available off-the-shelf drugs known to target the TM; 3. To design phase Ib clinical study in TNBC, HNSCC, melanoma and CRC assessing activity of ICB associated with microenvironment modulators chosen according to results of Aim 1 and 2.
Methods - TM will be analyzed by IHC, multi-parametric fluorescence-based digital pathology analysis, flow cytometry in freshly isolated surgical specimens, qPCR on FFPE tissues and interrogation of gene expression data. Models based on transplantable and spontaneous tumors will be used to test the activity of radiotherapy and drugs known to target immunosuppressive cells and matricellular proteins. According to the preclinical data, phase Ib study will be designed in order to verify the safety of combo approaches.
Expected results – Pre-clinical and early clinical results supporting the development of advanced immunotherapy approaches based on concurrent targeting of immune checkpoints and of relevant immunosuppressive mechanisms.

Final Publishable Summary:
Background- Immunotherapy with immune checkpoint blockers (ICB) is effective against several  malignancies, but only a fraction of patients achieves clinical benefit. Identification of innate resistance mechanisms is crucial to improve the rate of response.
Hypothesis – Assessment and pre-clinical targeting of main immunosuppressive mechanisms in the tumor microenvironment (TM) may lead to more effective immunotherapeutic combinations.
Aims –

1. A retrospective bio-molecular characterization of immunosuppressive cells and matricellular proteins in TM of four tumors, triple negative breast cancer (TNBC), head and neck (HNSCC), melanoma and colorectal cancer (CRC). The immunosuppressive TM will be evaluated even in pre- and post-chemotherapy (CT) lesions from patients receiving neoadjuvant therapy; 2. exploit mouse models for testing synergistic anti-tumor activity of ICB combined with drugs targeting the immunosuppressive TM. Combinations will be based on results from Aim 1 as well as on available off-the-shelf drugs known to target the TM; 3. To design phase Ib clinical study in TNBC, HNSCC, melanoma and CRC assessing activity of ICB associated with microenvironment modulators chosen according to results of Aim 1 and

Methods - TM will be analyzed by IHC, multi-parametric fluorescence-based digital pathology analysis, flow cytometry in freshly isolated surgical specimens, qPCR on FFPE tissues and interrogation of gene expression data. Models based on transplantable and spontaneous tumors will be used to test the activity of radiotherapy and drugs known to target immunosuppressive cells and matricellular proteins.
Expected results – Pre-clinical results supported the analyses of gene expression data to discriminate patients that could be directly treated with ICIs from those for which the chemotherapy is required to convert the immunosuppressive microenvironment. In particular, the discovery of novel targets whose expression is deregulated following standard chemotherapy, offered the possibility to target in a more specific way the immunosuppressive environment responsible for treatment failure.

(Project selected for funding under JTC 2015)