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.