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ITOC2 – 038. Role of exosomes in immune suppression
Abstracts / 51 (2015) S1–S13
Using methods adapted from the field of deep learning, we have developed an approach to multivariate test development for benefit from therapy able to work with the most clinically meaningful endpoints, by simultaneously refining the definition of relative benefit groups, the subset of most relevant genetic or proteomic information, and the diagnostic test itself. During the iterative process of test creation, the system learns what subset of the available molecular data is useful for the particular problem being addressed. We will demonstrate how this method has been used to develop a test predictive of benefit from an immunotherapy in adjuvant pancreatic cancer.
S13
and differentiated T cells (having effector memory phenotype) that are ready to kill (express high levels of Granzyme B). Taken together, these preclinical data show that CEA TCB is a novel tumour-targeted T cell bispecific antibody with promising antitumour activity and the novel ability to modify the tumour microenvironment. Phase 1 clinical trials with CEA TCB are currently ongoing. Future studies will focus on identification of combination partners that inhibit T cell suppression and unleash the full potential of T cell activity. Presented in Plenary Session 4 : Immunomodulatory agents.
http://dx.doi.org/10.1016/j.ejca.2015.01.051 http://dx.doi.org/10.1016/j.ejca.2015.01.050
INVITED FACULTY ABSTRACTS
ITOC2–037. CEA TCB, A NOVEL T-CELL BISPECIFIC ANTIBODY WITH POTENT IN VITRO AND IN VIVO ANTITUMOUR ACTIVITY AGAINST SOLID TUMOURS Marina Bacac, Tanja Fauti, Sara Colombetti, Johannes Sam, Valeria Nicolini, Nathalie Steinhoff, Oliver Ast, Peter Bruenker, Ralf Hosse, Thomas Hofer, Ekkehard Moessner, Christiane Jaeger, Jose Saro, Vaios Karanikas, Christian Klein, Pablo Uman˜a . Roche Pharmaceutical Research & Early Development, Roche Innovation Center Zurich, Switzerland T cell bispecific antibodies (TCBs) are potent molecules that upon simultaneous binding to tumour cells and T cells trigger strong T cell activation resulting in the killing of tumour cells. CEA TCB (RG7813) is a novel bispecific antibody targeting carcinoembryonic antigen (CEA), often overexpressed on solid tumours (e.g. colorectal, gastric, pancreatic, lung carcinoma etc.), and the CD3 epsilon chain present on T cells. CEA TCB bears several innovative technological features that distinguish it from other bispecific antibodies currently in (pre-)clinical development: (a) bivalency for tumour antigen translating into higher avidity, superior potency and better differentiation between high and low antigen-expressing cells; (b) head-to-tail fusion geometry for anti-tumour and CD3-binding domains, resulting in higher potency compared to conventional IgG-based TCBs; (c) extended half-life compared to non-Fc-based TCBs; (d) fully silent Fc ensuring lower risk of FcgR-mediated infusion reactions; and (e) robust production using standard manufacturing processes (enabled by “CrossMAb” and knob-into-hole bispecific antibody technologies). In vitro, CEA TCB mediates potent target-dependent T cell cytotoxicity, T cell activation, proliferation, and cytokine release in killing assays, exclusively in the presence of CEA-expressing target-cells. CEA TCB activity correlates with CEA expression level, showing higher potency against tumour cells with high expression of CEA. In vivo, CEA TCB induces dose- and time-dependent regression of CEAexpressing tumours with variable amounts of immune cell infiltrate. In fully humanised NOG mice, CEA TCB is efficacious in poorly-infiltrated tumours and converts non-inflamed into highly-inflamed tumours. Histological and FACS analyses revealed that CEA TCB recruits new T cells into tumours and/or expands pre-existing ones and is able to induce T cell re-localisation from the tumour periphery into the tumour bed. Surprisingly, CEA TCB treatment also qualitatively alters the composition of intratumoural T cells resulting in an increased frequency of activated (CD69, CD25), proliferating (Ki67)
ITOC2–038. ROLE OF EXOSOMES IN IMMUNE SUPPRESSION Veronica Huber, Viviana Vallacchi, Lorenza Di Guardo, Agata Cova, Silvana Canevari, Mario Santinami, Valentina Bollati, Monica Rodolfo, Licia Rivoltini. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Exosomes are endosome-derived nanovesicles involved in intercellular cross-talk through the transfer of proteins and genetic material. In cancer, exosomes can contribute to mould host micro- and macroenvironment, conditioning tumour immunity both at local and systemic level. We have been collecting evidence that these nanovesicles exert a broad array of detrimental effects on the immune system, ranging from apoptosis in activated antitumour T cells to impairment of monocyte differentiation into dendritic cells and induction of suppressive effectors. More recently, we observed that cells with phenotypic and functional properties overlapping with those displayed by myeloid-derived suppressor cells (MDSC) can be generated in vitro by culturing normal monocytes with exosomes released by melanoma cells (Exo-MDSC). Compared to untreated monocytes, Exo-MDSC show increased mRNA level and release of protumourigenic and immunosuppressive cyto/chemokines, down-modulate the expression of HLA-DR and TLRs, and acquire the ability to inhibit T cell proliferation. A defined gene-expression and miRNA signature, involving HIF1alfa, IL6 and several immune-related genes, has been identified in Exo-MDSC as triggered by exosomal TGFb, CCL2 and selected miRNA. Given their ability to efficiently recirculate in body fluids, tumour exosomes could spread systemically and directly condition myelopoiesis. This hypothesis is supported by the evidence that peripheral MDSC from melanoma patients share defined traits of Exo-MDSC gene-expression and miRNA signature, in addition with phenotypic and functional features of these cells. MDSC accumulate in peripheral blood of melanoma patients as an early event and in association with disease progression. High MDSC frequency is an acknowledged negative prognostic factor in several tumour histologies and predicts poor response to immunotherapy, including checkpoint blockade. The identification of exosomes as a potential pathway responsible for MDSC mobilisation and accrual paves the way to the development of novel immune-based therapeutic strategies and prognostic biomarkers in cancer patients. Supported by Italian Association For Cancer Research – AIRC Grant code 12162.
http://dx.doi.org/10.1016/j.ejca.2015.01.052
Using methods adapted from the field of deep learning, we have developed an approach to multivariate test development for benefit from therapy able to work with the most clinically meaningful endpoints, by simultaneously refining the definition of relative benefit groups, the subset of most relevant genetic or proteomic information, and the diagnostic test itself. During the iterative process of test creation, the system learns what subset of the available molecular data is useful for the particular problem being addressed. We will demonstrate how this method has been used to develop a test predictive of benefit from an immunotherapy in adjuvant pancreatic cancer.
S13
and differentiated T cells (having effector memory phenotype) that are ready to kill (express high levels of Granzyme B). Taken together, these preclinical data show that CEA TCB is a novel tumour-targeted T cell bispecific antibody with promising antitumour activity and the novel ability to modify the tumour microenvironment. Phase 1 clinical trials with CEA TCB are currently ongoing. Future studies will focus on identification of combination partners that inhibit T cell suppression and unleash the full potential of T cell activity. Presented in Plenary Session 4 : Immunomodulatory agents.
http://dx.doi.org/10.1016/j.ejca.2015.01.051 http://dx.doi.org/10.1016/j.ejca.2015.01.050
INVITED FACULTY ABSTRACTS
ITOC2–037. CEA TCB, A NOVEL T-CELL BISPECIFIC ANTIBODY WITH POTENT IN VITRO AND IN VIVO ANTITUMOUR ACTIVITY AGAINST SOLID TUMOURS Marina Bacac, Tanja Fauti, Sara Colombetti, Johannes Sam, Valeria Nicolini, Nathalie Steinhoff, Oliver Ast, Peter Bruenker, Ralf Hosse, Thomas Hofer, Ekkehard Moessner, Christiane Jaeger, Jose Saro, Vaios Karanikas, Christian Klein, Pablo Uman˜a . Roche Pharmaceutical Research & Early Development, Roche Innovation Center Zurich, Switzerland T cell bispecific antibodies (TCBs) are potent molecules that upon simultaneous binding to tumour cells and T cells trigger strong T cell activation resulting in the killing of tumour cells. CEA TCB (RG7813) is a novel bispecific antibody targeting carcinoembryonic antigen (CEA), often overexpressed on solid tumours (e.g. colorectal, gastric, pancreatic, lung carcinoma etc.), and the CD3 epsilon chain present on T cells. CEA TCB bears several innovative technological features that distinguish it from other bispecific antibodies currently in (pre-)clinical development: (a) bivalency for tumour antigen translating into higher avidity, superior potency and better differentiation between high and low antigen-expressing cells; (b) head-to-tail fusion geometry for anti-tumour and CD3-binding domains, resulting in higher potency compared to conventional IgG-based TCBs; (c) extended half-life compared to non-Fc-based TCBs; (d) fully silent Fc ensuring lower risk of FcgR-mediated infusion reactions; and (e) robust production using standard manufacturing processes (enabled by “CrossMAb” and knob-into-hole bispecific antibody technologies). In vitro, CEA TCB mediates potent target-dependent T cell cytotoxicity, T cell activation, proliferation, and cytokine release in killing assays, exclusively in the presence of CEA-expressing target-cells. CEA TCB activity correlates with CEA expression level, showing higher potency against tumour cells with high expression of CEA. In vivo, CEA TCB induces dose- and time-dependent regression of CEAexpressing tumours with variable amounts of immune cell infiltrate. In fully humanised NOG mice, CEA TCB is efficacious in poorly-infiltrated tumours and converts non-inflamed into highly-inflamed tumours. Histological and FACS analyses revealed that CEA TCB recruits new T cells into tumours and/or expands pre-existing ones and is able to induce T cell re-localisation from the tumour periphery into the tumour bed. Surprisingly, CEA TCB treatment also qualitatively alters the composition of intratumoural T cells resulting in an increased frequency of activated (CD69, CD25), proliferating (Ki67)
ITOC2–038. ROLE OF EXOSOMES IN IMMUNE SUPPRESSION Veronica Huber, Viviana Vallacchi, Lorenza Di Guardo, Agata Cova, Silvana Canevari, Mario Santinami, Valentina Bollati, Monica Rodolfo, Licia Rivoltini. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Exosomes are endosome-derived nanovesicles involved in intercellular cross-talk through the transfer of proteins and genetic material. In cancer, exosomes can contribute to mould host micro- and macroenvironment, conditioning tumour immunity both at local and systemic level. We have been collecting evidence that these nanovesicles exert a broad array of detrimental effects on the immune system, ranging from apoptosis in activated antitumour T cells to impairment of monocyte differentiation into dendritic cells and induction of suppressive effectors. More recently, we observed that cells with phenotypic and functional properties overlapping with those displayed by myeloid-derived suppressor cells (MDSC) can be generated in vitro by culturing normal monocytes with exosomes released by melanoma cells (Exo-MDSC). Compared to untreated monocytes, Exo-MDSC show increased mRNA level and release of protumourigenic and immunosuppressive cyto/chemokines, down-modulate the expression of HLA-DR and TLRs, and acquire the ability to inhibit T cell proliferation. A defined gene-expression and miRNA signature, involving HIF1alfa, IL6 and several immune-related genes, has been identified in Exo-MDSC as triggered by exosomal TGFb, CCL2 and selected miRNA. Given their ability to efficiently recirculate in body fluids, tumour exosomes could spread systemically and directly condition myelopoiesis. This hypothesis is supported by the evidence that peripheral MDSC from melanoma patients share defined traits of Exo-MDSC gene-expression and miRNA signature, in addition with phenotypic and functional features of these cells. MDSC accumulate in peripheral blood of melanoma patients as an early event and in association with disease progression. High MDSC frequency is an acknowledged negative prognostic factor in several tumour histologies and predicts poor response to immunotherapy, including checkpoint blockade. The identification of exosomes as a potential pathway responsible for MDSC mobilisation and accrual paves the way to the development of novel immune-based therapeutic strategies and prognostic biomarkers in cancer patients. Supported by Italian Association For Cancer Research – AIRC Grant code 12162.
http://dx.doi.org/10.1016/j.ejca.2015.01.052