E-resources
Peer reviewed
Open access
-
Genssler, Sabrina; Schaetzlein, Daniel; Leo, Eugen; Haake, Markus; Schuberth-Wagner, Christine
Journal for immunotherapy of cancer, 11/2023, Volume: 11, Issue: Suppl 1Journal Article
BackgroundGDF-15, a member of the TGF-beta superfamily, is a critical factor of feto-maternal tolerance, but also of local immune suppression at sites of cellular stress. Various solid tumor types secrete high levels of this immunosuppressive cytokine. In cancer patients, elevated GDF-15 serum levels correlate with poor prognosis and reduced overall survival.1 Mechanistically GDF-15 interferes with LFA-1/ICAM-1 dependent immune cell extravasation and thus limits immune infiltration into GDF-15 expressing tumors. In line with immune infiltration as a prerequisite of checkpoint-inhibitor responses GDF-15 serum levels negatively correlate with the response to anti-PD-(L)1 CPI therapy.2 3 Neutralization by clinical stage GDF-15 neutralizing antibody visugromab (CTL-002; GDFather-1/2 trial NCT04725474) restores responsiveness to anti-P(L)1 by increasing extravasation of immune cells into the tumor microenvironment.2 To be active, bispecific T-cell engagers are dependent on infiltration of T-cells into the tumor tissue. Once bound to both T-cell and tumor cell, bispecifics retain T-cells at cancer cell sites. In this study we tested the synergy of visugromab with tebentafusp, a CD3-cell redirecting bispecific fusion protein for gp100+ tumors, to enhance effector T-cell retention in the tumor.MethodsSpecific binding and cytotoxic activity of tebentafusp was qualified by flow-cytometry and cytotoxicity assays with HLA-A2+ gp100+ human SK-MEL-5-melanoma cells, respectively. In vivo T-cell retention was tested in PBMC-humanized NOG mice, treated with tebentafusp4 and isotype or a combination of tebentafusp and visugromab. After five days body weight, serum GDF-15, tumor size/weight and mouse and human immune cell infiltration were measured as a final read-out.ResultsTebentafusp bound gp100 on GDF-15 secreting HLA-A2+ SK-MEL-5 melanoma cells and mediated tumor specific killing by T cells in vitro. In vivo, treatment with tebentafusp in combination with isotype resulted in a 4.3-fold increase in T-cell numbers in s.c. SK-MEL-5 tumors in PBMC-humanized NOG mice, while in combination with visugromab, a 15.3-fold increase was observed.ConclusionsGDF-15 is an inhibitor of immune infiltration, and its neutralization enhances effector cell presence in tumors. Bispecific T-cell engagers are dependent on proper effector cell infiltration into tumors to induce significant tumor cell killing. In a PD study combining tebentafusp with anti-GDF-15 antibody visugromab significantly increased the number of intratumoral T cells in mice. Increasing the number of effector cells in the tumor microenvironment is expected to have a direct positive impact on the anti-tumor activity of different bispecific T-cell engaging treatments.ReferencesWischhusen J, et al. Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint. Front Immunol. 2020 May 19;11:951. PubMed PMID: 32508832Haake M, et al. Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment. Nat Commun. 2023, in press Hong G, et al. Plasma GDF15 levels associated with circulating immune cells predict the efficacy of PD-1/PD-L1 inhibitor treatment and prognosis in patients with advanced non-small cell lung cancer. J Cancer Res Clin Oncol. 2023 Jan;149(1):159–171. PubMed PMID: 36472770Chen LN, Carvajal RD. Tebentafusp for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. Expert Rev Anticancer Ther. 2022 Oct;22(10):1017–1027. PubMed PMID: 36102132Ethics ApprovalThis study was approved by EPO Berlin’s Ethics Board; approval number E0023–23.
Shelf entry
Permalink
- URL:
Impact factor
Access to the JCR database is permitted only to users from Slovenia. Your current IP address is not on the list of IP addresses with access permission, and authentication with the relevant AAI accout is required.
Year | Impact factor | Edition | Category | Classification | ||||
---|---|---|---|---|---|---|---|---|
JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
Select the library membership card:
If the library membership card is not in the list,
add a new one.
DRS, in which the journal is indexed
Database name | Field | Year |
---|
Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
---|
Source: Personal bibliographies
and: SICRIS
The material is available in full text. If you wish to order the material anyway, click the Continue button.