Immunology, Transplantation and Infectious diseases
Lymphocyte activation
T lymphocytes act as living drugs. Tumor-specific T cells can be purified from tumors or genetically engineered to express tumor-specific receptors. Efficacy against solid tumors remains limited. What limits therapeutic efficacy? Could antigen expressed by the tumor and by component of tumor stroma prove superior against heterogeneous tumors? Could conventional and more innovative strategies be used in combination? Our goal is to answer these questions by dissecting the intracellular events controlling primary T cell activation and differentiation and exploiting T cell engineering and combined therapies to instruct superior anti-tumor efficacy for unmet clinical need.
Research activity
This unit is taking advantage of preclinical mouse models of solid tumors, well recapitulating human diseases and studying T cell phenotypes in patients. We have acquired extensive expertise TRAMP mice (TRansgenic Adenocarcinoma of the Mouse Prostate) with genetically imprinted and autochthonous cancer development and set up a model of pancreas adenocarcinoma liver metastases. In the next future we will extend activities to glioblastoma.
1) Prostate cancer bearing TRAMP mice well recapitulate human conditions, as both central and peripheral T cell tolerance hinders T cell protective immunity. We found that engineered T cells can replenish the immune repertoire with functional T cells, and yet per se are not sufficient to elicit tumor eradication. However, when delivered in combination with deposition of pro-inflammatory cytokines or immune checkpoint blockers they can instruct therapeutic tumor debulking and long-term mice survival (Manzo and Sturmheit, Cancer Res. 2017; Elia et al. Cancer Res 2018; Gasparri A. Small, 2019; Basso, in preparation). We are now studying the combination of clinically relevant prostate-confined fractionated radiotherapy and engineered T cells (Catucci et al, submitted), and dissecting the immunomodulatory potential of radiotherapy in patients, to set the ground for a phase I study with the combination of radiotherapy and T cell therapy.
2) In a novel model of pancreas adenocarcinoma (PDAC) liver metastasis we found that efficacy of CAR T to be inversely proportional to the metastatic burden, due to immune suppression and immune-escape (Pocaterra, unpublished). For more potent efficacy, we have developed a novel peptide-based CAR molecule (pCAR) able of αvβ6- and αvβ8-integrin recognition, suitable to target PDAC in vitro and in vivo. We are now: i) investigating the mechanism subtending efficacy, ii) exploiting peptide-mediated engineering of additional CAR and iii) peptide-mediated engineering of costimulatory chimeric receptor (pCCR) and iii) developing antigen-unrestricted cytokine-initiated killing (TRUCKs) for local delivery of inflammatory cytokines. We will be testing combinatorial administration for more efficient tumor rejection (Pocaterra, Catucci 2022).
