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Immunotherapy of gastric cancer: Enhancing T cell recruitment into tumors

English title Immunotherapy of gastric cancer: Enhancing T cell recruitment into tumors
Applicant Bourquin Carole
Number 138284
Funding scheme Project funding (Div. I-III)
Research institution Département de Médecine Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Experimental Cancer Research
Start/End 01.01.2012 - 31.05.2015
Approved amount 296'000.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Immunology, Immunopathology

Keywords (3)

Cancer; Immunotherapy; T cells

Lay Summary (English)

Lead
Lay summary

Despite advances in the diagnosis and therapy of stomach cancer, mortality remains high for this affection. New therapeutic strategies are required, in particular for unresectable tumors and metastases. Immunotherapeutic approaches aim to restore effective antitumor immune responses and represent an emerging field in the treatment of cancer. For these approaches to be effective, it is crucial that cells of the immune system such as T cells are recruited to the site of the tumor where they can exert their anti-tumoral functions. In this project, we aim to develop strategies that enhance T cell infiltration in tumors in order to improve the efficacy of cancer immunotherapy. Pharmacological treatment strategies to facilitate infiltration of T cells into tumors will be explored, as will engineering of T cells to induce a gastric “tumor-homing” behavior. Results from this project will lead to a better understanding of how tumor-specific T cells infiltrate gastric tumors and how recruitment of these cells can be controlled by pharmacological intervention. This knowledge basis will be of high relevance for defining new strategies to improve the immunotherapy of gastric cancer and other gastrointestinal tumors.    

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Selective Bispecific T Cell Recruiting Antibody and Antitumor Activity of Adoptive T Cell Transfer
Kobold Sebastian, Steffen Julius, Chaloupka Michael, Grassmann Simon, Henkel Jonas, Castoldi Raffaella, Zeng Yi, Chmielewski Markus, Schmollinger Jan C., Schnurr Max, Rothenfusser Simon, Schendel Dolores J., Abken Hinrich, Sustmann Claudio, Niederfellner Gerhard, Klein Christian, Bourquin Carole, Endres Stefan (2015), Selective Bispecific T Cell Recruiting Antibody and Antitumor Activity of Adoptive T Cell Transfer, in JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 107(1), 364.
A new bispecific T cell recruiting antibody enhances anti-tumor activity of adoptive T cell transfer
Kobold S., Steffen J., Lampert C., Castoldi R., Schmollinger J. C., Sustmann C., Niederfellner G., Klein C., Bourquin C., Endres S. (2014), A new bispecific T cell recruiting antibody enhances anti-tumor activity of adoptive T cell transfer, in ONCOLOGY RESEARCH AND TREATMENT, 50, 50.
Phage idiotype vaccination: first phase I/II clinical trial in patients with multiple myeloma
Roehnisch Tim, Then Cornelia, Nagel Wolfgang, Blumenthal Christina, Braciak Todd, Donzeau Mariel, Boehm Thomas, Flaig Michael, Bourquin Carole, Oduncu Fuat S. (2014), Phage idiotype vaccination: first phase I/II clinical trial in patients with multiple myeloma, in JOURNAL OF TRANSLATIONAL MEDICINE, 12, 267.
The dipeptidylpeptidase-IV inhibitors sitagliptin, vildagliptin and saxagliptin do not impair innate and adaptive immune responses.
Anz D, Kruger S, Haubner S, Rapp M, Bourquin C, Endres S (2014), The dipeptidylpeptidase-IV inhibitors sitagliptin, vildagliptin and saxagliptin do not impair innate and adaptive immune responses., in Diabetes, obesity & metabolism, 16(6), 569-72.
A new EGFR - EpCAM bispecific antibody enhances the efficacy of adoptive T-cell therapy in a murine gastric tumor model
Kobold S., Steffen J., Grassmann S., Henkel J., Castoldi R., Schmollinger J. C., Sustmann C., Niederfellner G., Klein C., Bourquin C., Endres S. (2013), A new EGFR - EpCAM bispecific antibody enhances the efficacy of adoptive T-cell therapy in a murine gastric tumor model, in ONKOLOGIE, 36, 36.
Chemically linked phage idiotype vaccination in the murine B cell lymphoma 1 model
Roehnisch Tim, Then Cornelia, Nagel Wolfgang, Blumenthal Christina, Braciak Todd, Donzeau Mariel, Bohm Thomas, Bourquin Carole, Oduncu Fuat (2013), Chemically linked phage idiotype vaccination in the murine B cell lymphoma 1 model, in JOURNAL OF TRANSLATIONAL MEDICINE, 11, 267.
TLR activation excludes circulating naive CD8+ T cells from gut-associated lymphoid organs in mice.
Heidegger Simon, Kirchner Sophie-Kathrin, Stephan Nicolas, Bohn Bernadette, Suhartha Nina, Hotz Christian, Anz David, Sandholzer Nadja, Stecher Bärbel, Rüssmann Holger, Endres Stefan, Bourquin Carole (2013), TLR activation excludes circulating naive CD8+ T cells from gut-associated lymphoid organs in mice., in Journal of immunology (Baltimore, Md. : 1950), 190(10), 5313-20.
Virus-associated activation of innate immunity induces rapid disruption of Peyer's patches in mice.
Heidegger Simon, Anz David, Stephan Nicolas, Bohn Bernadette, Herbst Tina, Fendler Wolfgang Peter, Suhartha Nina, Sandholzer Nadja, Kobold Sebastian, Hotz Christian, Eisenächer Katharina, Radtke-Schuller Susanne, Endres Stefan, Bourquin Carole (2013), Virus-associated activation of innate immunity induces rapid disruption of Peyer's patches in mice., in Blood, 122(15), 2591-9.
Chronic progressive HIV-1 infection is associated with elevated levels of myeloid-derived suppressor cells
Vollbrecht Thomas, Stirner Renate, Tufman Amanda, Roider Julia, Huber Rudolf M., Bogner Johannes R., Lechner Andreas, Bourquin Carole, Draenert Rika (2012), Chronic progressive HIV-1 infection is associated with elevated levels of myeloid-derived suppressor cells, in AIDS, 26(12), 31-37.
Pre-clinical assessment of EpCAM as a target for antibody based therapies of gastric cancer
Kobold S., Henkel J., Steffen J., Grassmann J., Zimmermann W., Bourquin C., Endres S. (2012), Pre-clinical assessment of EpCAM as a target for antibody based therapies of gastric cancer, in IMMUNOLOGY, 137, 137.

Collaboration

Group / person Country
Types of collaboration
Prof. Curzio Rüegg, Université de Fribourg Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. Eric Alléman, Université de Genève Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
BayImmuNet Immunotherapy Network Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
DFG Research Training Group 1202 Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Wolfgang Uckert, Max-Delbrück Center Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Immunofest 2014 Talk given at a conference Cancer immunotherapy: Timing is everything! 25.09.2014 Munich, Germany Bourquin Carole;
Cancer: Antibodies Vaccines/Adjuvants & Delivery 2014 Talk given at a conference Adjuvants for cancer vaccines: timing is everything 19.09.2014 Lausanne, Switzerland Bourquin Carole;
Cancer Immunotherapy: Taking lessons from nature Individual talk Cancer Immunotherapy: Taking lessons from nature 27.06.2014 Geneva, Switzerland Bourquin Carole;
St Gallen Conference Individual talk Cancer immunotherapy: Breakthrough of the year 2013 23.01.2014 St Gallen, Switzerland Bourquin Carole;
World Immune Regulatory Meeting Talk given at a conference TLR activation excludes naïve CD8+ T cells from gut-associated lymphoid organs 18.03.2013 Davos, Switzerland Bourquin Carole;
Timing is everything: Improving the outcome of cancer immunotherapy Individual talk Timing is everything: Improving the outcome of cancer immunotherapy 27.02.2013 Bern, Switzerland Bourquin Carole;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions 125e Jubilé de l’Université de Fribourg Western Switzerland 2014
Other activities Children's Workshops: Cancer research Western Switzerland 2014
Talks/events/exhibitions Pouvons-nous activer nos défenses immunitaires contre le cancer? Western Switzerland 2014

Awards

Title Year
Poster prize Research Day HFR-UNIFR 2013

Associated projects

Number Title Start Funding scheme
157752 Microchip-based flow cell sorting in biomedicine and material sciences 01.05.2015 R'EQUIP
156871 Understanding the interaction of nanoparticles with B lymphocytes in vitro and in vivo 01.02.2015 Project funding (Div. I-III)
156372 RLR/TLR combination therapy: Mechanisms of T-cell recruitment into gastric tumors 01.06.2015 Project funding (Div. I-III)
137079 Cell migration in tumorigenesis and metastasis 01.01.2012 ProDoc

Abstract

BackgroundDespite advances in the diagnosis and therapy of stomach cancer, mortality remains high for this affection. New therapeutic strategies are required, in particular for unresectable tumors and micrometastases. Immunotherapeutic approaches, such as cancer vaccines or the adoptive transfer of tumor-specific T lymphocytes, aim to restore effective antitumor immune responses and represent an emerging field in the treatment of cancer. For the generation of effective immune responses, it is crucial that T cells are recruited to the site of the tumor where they can exert their effector functions. Strategies that enhance T cell infiltration in tumors may therefore improve the efficacy of T cell-based immunotherapy.Working hypothesisIn a transgenic SV40 T Ag model of gastric cancer, we have recently shown that upon adoptive transfer of tumor-specific T cells, lymphocyte infiltration is mainly limited to peritumoral areas of the submucosa and T cells do not infiltrate the central area of the autochthonous tumor. In contrast, in the same mice, transferred T cells strongly infiltrate SV40 T Ag-expressing subcutaneous tumors and cause tumor regression. Thus, even a strong antitumor T cell response will not efficiently penetrate the tumor in the absence of additional therapeutic strategies targeting the tumor microenvironment. Our system provides a model for identifying approaches to improve intratumoral effector T cell infiltration and for assessing their impact on survival. Specific aimsUsing the dual tumor model established in our laboratory, we aim to:•Determine the factors that control effector T cell recruitment to gastric tumors•Target the microenvironment to enhance homing of tumor-specific T cells into gastric tumors•Engineer tumor-specific T cells to enhance their homing into gastric tumorsThe direct comparison of subcutaneous and autochthonous tumors with contrasting T cell infiltration in the same mice will allow investigation of the factors that control lymphocyte recruitment. Immunopharmacological treatment strategies to facilitate homing of T cells into tumors will be explored, based on existing expertise in the group. Engineering of T lymphocytes to induce a gastrointestinal homing phenotype will be performed. To visualize lymphocyte recruitment into tumors, cellular and histological techniques as well direct in vivo imaging will be performed. Validation experiments to confirm findings in human gastric cancer will be performed. Expected valueResults from this project will lead to a better understanding of how effector T cells infiltrate gastric tumors and how recruitment and activation of lymphocytes can be controlled by pharmacological intervention. This knowledge basis will be of high relevance for defining new strategies to improve the immunotherapy of gastric cancer and other gastrointestinal tumors. The insights gained within this project may directly influence the design of new translational studies.
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