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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.