Program in Immunology and Bio-immunotherapy of Cancer (PIBIC)

Heads: Giorgio Parmiani and Paolo Dellabona

Vision

The Program in Immunology and Bio-Immunotherapy of Cancer (PIBIC) brings together experts in immunology, cancer biology and medical onco-hematology to investigate fundamental aspects of tumor immunology and translate them into innovative immunotherapy strategies for phase I/II clinical trials.

Goals

Major objectives of the PIBIC are:

  • a deeper understanding of the mechanisms underlying the tumor/immune system interactions;
  • a provision of new immunotherapy strategies that are rationally designed to increase significantly the therapeutic efficacy of the current ones.

Main achievements (updated 2012)

The research of the program is advancing towards the definition of several new concepts in tumor immunology and cancer immunotherapy, through the investigation in both preclinical models and patients. A highthroughput platform to identify unique tumor antigens in colorectal cancer has been implemented by combining next generation sequencing of the cancer transcriptome with reverse immunology. We have also defined a new class of methylated lyso-phospholipid antigens expressed by acute leukemia that are recognized by CD1 autoreactive T cells. Further insight into new mechanisms of immunosuppression in the tumor microenvironment have been obtained, providing the definition of new potential targets for therapies aimed at restoring the balance towards immunesurveillance. Most notable advancements concern:

  • the action of oxysterols, another product of the altered cancer cell metabolism, as immunosuppressive agents;
  • the identification of the suppressive action of PMN subsets in pancreatic cancer at resulting from a cross-talk between cancer cells, fibroblasts and dendritic cells;
  • the identification of IL-4 produced by colon cancer stem cells as a powerful immunosuppressive mechanisms for anti-tumor T cell responses.

Both angiogenesis and tumor-microenvironment remain a focus of new studies that revealed the remarkable pro-angiogenic activity of chromogranin fragments, generated by proteolysis associated with tumor progression. The implementation of innovative therapeutic strategies has also proceeded forward by showing that targeting TNF-α selectively to tumor-associated vascular endothelium resulted in enhanced T lymphocyte infiltration in tumors and increased therapeutic potential of immunotherapy. In parallel, significant advancement in T cell adoptive immunotherapy strategies was achieved by showing the possibility to safely redirect allogeneic T lymphocytes against leukemia, by engineering them with exogenous TCR genes specific for tumor associated antigens and concomitant editing the endogenous TCR genes with zinc-finger targeted nucleases. Finally, new clinical trials that incorporate the conceptual advancements conceived within PIBIC are being activated: 1) A pilot phase I and II study of NGR-hTNF in combination with a peptide-based vaccine for metastatic melanoma, NGRVax; 2) A pilot phase I study combining vaccination, NGR-hTNF anti-vascular therapy, and adoptive immunotherapy in metastatic melanoma. The studies combine tumor vascular targeting with NGR-TNF-α with tumor antigen-specific active and/or adoptive immunotherapy in metastatic melanoma patients, with the objective to enhance tumor-specific T cell homing and functions by the inflammation and cell death evoked by the targeted cytokine. The translational area of PIBIC has given fundamental contribution also to the completion of the first collaborative bio-immunotherapy clinical trial entirely performed by the Italian Network for Tumor Biotherapy (NIBIT): Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trial.