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.
BackgroundGDF-15 (Growth and differentiation factor 15) is a distant member of the TGF-beta protein family and has a critical function during pregnancy as a component of the feto-maternal tolerance. ...It was shown that tumors overexpress GDF-15 to inhibit LFA-1 dependent immune cell infiltration and make use of its immunosuppressive function within the tumor microenvironment.1 2 Chemokine sensing on the surface of endothelia activates LFA-1 via an inside-out signaling cascade promoting transendothelial migration.3 While GDF-15 signaling via GFRAL in the brain-stem is well defined, the signaling pathways in T-cells downstream of GDF-15 impairing T-cell adhesion remain elusive. Recent work indicated an involvement of protein tyrosine phosphatase SHP-1 (SH-2 containing phosphatase-1) in GDF-15 mediated inhibition of myeloid cells.4 5 In this study we investigated the signaling events downstream of GDF-15 inhibiting LFA-1 activation and the involvement of SHP-1 in T-cells.MethodsIn flow-adhesion assays, primary T-cells or Jurkat cells pre-treated +/- GDF-15 were perfused over an activated layer of endothelial cells or recombinant adhesion molecules. Adhesion and transmigration were monitored by live imaging microscopy. Intracellular signaling was investigated in high-density-culture restore assays with human PBMCs. Inhibiting bioactive compounds or genetic disruption were used to interfere with pathways of interest. Effects were investigated and validated by intracellular flow cytometry, immunoblot and reporter assays.ResultsTreatment with GDF-15 resulted in reduced adhesion of CXCL12 or CXCL9/10 stimulated primary and immortalized T-cells on activated endothelial cells. GDF-15 also reduced the amount of high affinity LFA-1 conformation induced by chemokine CXCL12 and CD3/CD28 co-stimulation. Intracellularly, GDF-15 prevented TALIN phosphorylation in a bead-binding assay and led to a reduction of phosphorylated ZAP-70 in a high-density culture. In flow-adhesion assays, inhibition or deletion of SHP-1 abrogated the GDF-15 mediated adhesion inhibition in T-cells.ConclusionsGDF-15 is an important immune modulator and regulator of immune cell infiltration. In this study we identified SHP-1 as a central mediator of GDF-15-related inhibition of T-cell adhesion. In addition, we confirmed that GDF-15 via SHP-1 inhibits phosphorylation of ZAP-70 that is involved in LFA-1 inside-out activation and T cell receptor signaling. These data connect immunosuppressive GDF-15 to SHP-1, a negative regulator of antigen-dependent activation and proliferation of T-cells.4 This supports neutralization of GDF-15 as a promising new approach to enhance intratumoral T-cell infiltration and to increase antitumoral immune responses.1 A clinical Ph1/2a study with our GDF-15 neutralizing antibody visugromab in combination with nivolumab is currently ongoing GDFather-1/2 trial; NCT04725474, abstract 2122.ReferencesWischhusen J, et al. Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint. Front Immunol 2020;11:951Haake 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 pressCinamon G, et al. Shera forces promote lymphocyte migration across vascular endothelium bearing apical chemokines. Nat Immunol. 2001;2(6):515–522.Weng JH, et al. Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation. Nat Metab. 2021;3(4):513–22Hebeisen M, et al. SHP-1 phosphatase activity counteracts increased T cell receptor affinity. J Clin Invest. 2013;123(3):1044–56.
BackgroundGrowth and differentiation factor 15 (GDF-15) is a TGF-β superfamily member physiologically expressed mainly in placenta and linked to feto-maternal tolerance. Under pathophysiologic ...conditions, prevention of excessive immune cell infiltration during tissue damage and cachexia induction have been ascribed to GDF-15. Recent research has though indicated a prominant role in modulation of the tumor microenvironment and the immune synapse, too1 2 indicating that GDF-15 may be a major tumor-derived immunosuppressant. Importantly, several cancer entities secrete high levels of GDF-15, correlating with poor prognosis and reduced overall survival Front Immunol 2020 May 19;11:951. To block this effect the GDF-15 neutralizing antibody CTL-002 was generated. In preclinical models CTL-002 demonstrated potent effector T cell shifting into tumor tissue by neutralizing GDF-15.MethodsThis is a phase 1, first-in-human (FIH), two-part, open-label clinical trial of intravenous (IV) administration of CTL-002 given as monotherapy and in combination with an anti-PD-1 antibody in subjects with advanced-stage, relapsed/refractory solid tumors who relapsed or were refractory to a prior anti-PD-1/PD-L1 therapy. Eligible subjects have exhausted all available approved standard treatments, including prior anti-PD1/-PD-L1 treatment, and present with a biopsy-accessible tumor for serial biopsy taking. The trial is termed GDFATHER, for ”GDF-15 Antibody-mediaTed Effector cell Relocation”.Main endpoints are safety of CTL-002 monotherapy and CTL-002 combination with an anti-PD-1 antibody, pharmacokinetics, pharmacodynamics (e.g. degree of GDF-15 neutralization achieved and change in immune-cell number and composition in the tumor tissue) as well as preliminary clinical efficacy (tumor mass reduction; anticachexia effect)In part A of the trial (dose escalation) up to 24 subjects will receive escalating doses of CTL-002 IV (0.3 – 20 mg/kg) in a ”mono-followed-by-combination”-design with CTL-002 given as monotherapy and followed by combination with an anti-PD-1 checkpoint inhibitor. In part B (expansion) up to 5 cohorts with up to 25 subjects per cohort with defined tumor entities expected to be GDF-15 dependent will be treated to determine the recommended phase 2 dose (RP2D) and further evaluate safety and preliminary efficacy of CTL-002 monotherapy and the combination.The study was initiated in December 2020 and enrolled the first patient on Dec 09, 2020. Cohort 4 is ongoing at time of submission (07/2021) and so far no DLT has occurred. Updated safety, biomarker and response assessments will be reported at the meeting. The ClinicalTrials.gov Identifier is NCT04725474. For more information please contact info@catalym.com.Trial RegistrationNCT04725474ReferencesWischhusen J, Wistuba-Hamprecht K, Harter PN, Cheng P, Martens A, Gogolla F, Nonomura Y, Romer P, Koch SD, Haake M, Schuberth-Wagner C, Rudiger M, Leo E, Mittelbronn M, Levesque MP, Hackl H, Dummer R, Weide B. Identifying GDF-15 as potential novel immunotherapeutic target linked to immune cell exclusion in tumors and resistance to anti-PD-1 treatment abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27–28 and Jun 22–24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl): Abstract nr 2161.Hurt E, Thomas S, Mulgrew K, Blackmore S, Moynihan J, Cusdin F, Dodd R, Cariuk P, Sigurdardottir A, Brannigan E, Dobson C, Kumar R, Cobbold M. AZD8853: A novel antibody targeting GDF15 for immunotherapy refractory tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10–15 and May 17–21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl): Abstract nr 1828.Ethics ApprovalAll participants gave informed consent prior to participation. EC approval by Gobierno de Navarra, Departamento de Salud, EC_2020/30, Dated: Oct 13, 2020 in Pamplona, Spain. Respective additional national lead EC approvals for Germany (Ethikkommission der Universität Würzburg, 203–20ff of Oct 26, 2020) and Switzerland (Kantonale Ethikkommission Zürich, 2020–02308 of Nov 24, 2020).
Multi-antigen immunotherapy approaches against Staphylococcus aureus are expected to have the best chance of clinical success when used in combinatorial therapy, potentially incorporating opsonic ...killing of bacteria and toxin neutralization. We recently reported the development of a murine monoclonal antibody specific for the immunodominant staphylococcal antigen A (IsaA), which showed highly efficient staphylococcal killing in experimental infection models of S. aureus. If IsaA-specific antibodies are to be used as a component of combination therapy in humans, the binding specificity and biological activity of the humanized variant must be preserved. Here, we describe the functional characterization of a humanized monoclonal IgG1 variant designated, hUK-66. The humanized antibody showed comparable binding kinetics to those of its murine parent, and recognized the target antigen IsaA on the surface of clinically relevant S. aureus lineages. Furthermore, hUK-66 enhances the killing of S. aureus in whole blood (a physiological environment) samples from healthy subjects and patients prone to staphylococcal infections such as diabetes and dialysis patients, and patients with generalized artery occlusive disease indicating no interference with already present natural antibodies. Taken together, these data indicate that hUK-66 mediates bacterial killing even in high risk patients and thus, could play a role for immunotherapy strategies to combat severe S. aureus infections.
Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don't respond to immune therapy. Across different tumor types, pre-existing T cell ...infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.
Abstract
Background: Growth and differentiation factor 15 (GDF-15) is a remote member of the TGF-β protein family with low to absent expression in healthy tissue. During pregnancy GDF-15 is secreted ...in high amounts by placenta contributing to feto-maternal tolerance. Similarly, GDF-15 expression is upregulated following tissue injury serving as a key inhibitor of excessive and disruptive immune infiltration. Importantly, various major tumor types secrete high levels of GDF-15 correlating with poor prognosis and reduced overall survival.
Methods: In a flow-adhesion assay different immune cell subsets pre-treated +/- GDF-15 were perfused over an activated layer of endothelial cells or recombinant adhesion molecules. Adhesion and transmigration processes were monitored by live imaging microscopy. Impact of a proprietary GDF-15 neutralizing antibody (CTL-002) regarding T cell trafficking were analyzed. In a humanized (CD34+-HPSC engrafted) PDX mouse model inoculated with the PD-L1hi and GDF-15 secreting human melanoma tumor cell line HV18-MK T cell infiltration was analysed +/- CTL-002 by FACS.
Results: Adhesion of T cells to the endothelial cell layer was significantly impaired by addition of GDF-15. Among T-cell subsets CD8+ T-cells were most affected while adhesion of other immune cells was not reduced. Inhibitory effects of GDF-15 on CD8+ T-cell adhesion were comparable to potent blockade of LFA-1 by TS1/18 antibody and could be rescued by the anti-GDF-15 antibody CTL-002. In vivo, neutralization of GDF-15 in HV18-MK melanoma-bearing humanized mice by CTL-002 resulted in a strong increase of tumor infiltrating leukocyte numbers. Subset analysis revealed an overproportional enrichment of T-cells, especially CD8+-T cells.
Conclusion: Our in vitro and in vivo data show that elevated GDF-15 levels block T-cell infiltration into the tumor tissue. Neutralizing GDF-15 with a proprietary antibody (CTL-002) restored the ability of T cells (especially CD8+-T-cells) to extravasate blood vessels and enter tumor tissue both in vitro and in vivo. As it is known that presence of tumor-infiltrating lymphocytes correlates with better patient outcomes in a multitude of cancers and is a predictor of response to checkpoint inhibitors, high levels of GDF-15 in the tumor may contribute to failure of immunotherapies and poor overall survival. Neutralization of GDF-15 could be a new and promising approach to increase response rates of immunotherapies and increase overall survival of cancer patients.
Citation Format: Markus Haake, Neha Vashist, Sabrina Genssler, Kristin H. Eichler, Birgitt Fischer, Jessica Kammer, Paula S. Romer, Manfred Rudiger, Eugen Leo, Falk Nimmerjahn, Christine Schuberth-Wagner, Jorg Wischhusen. Tumor-derived GDF-15 suppresses T-lymphocyte recruitment to the tumor microenvironment abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5597.
Abstract
Introduction:
Growth and differentiation factor 15 (GDF-15) is a TGF-β superfamily member mainly expressed in placenta and prostate of healthy individuals. GDF-15 has been linked to ...feto-maternal tolerance, prevention of excessive immune cell infiltration during tissue damage and to anorexia. In cancer patients, GDF-15 serum levels are frequently elevated and associated with poor prognosis, via so far mostly unknown mechanism(s). A recent study elucidated a mechanism by which GDF-15 inhibits LFA-1 activation on CD8+ T cells, thus interfering with T cell recruitment to tissues Haake et al. AACR 2020; submitted. To further delineate the role of GDF-15 in cancer in this study GDF-15 serum and tissue levels were analyzed and correlated with tumoral immune-cell infiltration and clinical anti-PD1 response.
Methods:
In-silico, TCGA-derived mRNA levels of GDF-15 were compared in cancer vs. normal tissue. Two independent melanoma patient cohorts (88 and 34 patients) treated with nivolumab or pembrolizumab were analyzed regarding baseline GDF-15 serum levels, correlation with clinical response and overall survival. Melanoma brain metastases from 80 patients were collected to assess and compare intratumoral GDF-15 levels vs. CD3+, CD8+ and Foxp3+ cell numbers by immunohistochemistry (IHC).
Results:
TCGA-based analyses demonstrated significantly elevated GDF-15 mRNA levels in tumor vs. surrounding normal tissue in various major cancer types such as e.g. colorectal, prostate, head & neck and melanoma. In the two independent, anti-PD1 treated melanoma patient cohorts baseline serum GDF-15 levels were predictive for superior overall survival and clinical response to anti-PD1 treatment (p<0.0001 and p=0.0382, respectively). In melanoma biopsies an inverse correlation of GDF-15 levels (histoscore) with CD3+ (R=-0.26; p=0.016) and CD8+ T cells (R=-0.21; p=0.05), but no correlation with Foxp3+ T cells was shown.
Conclusion:
GDF-15 is elevated in serum and tumor tissue of various major cancer types. In melanoma, patients with higher GDF-15 levels have significantly shorter survival and are less likely to respond to anti-PD1 therapy. In addition, intratumoral GDF-15 levels in melanoma brain metastasis correlate inversely with CD3+ and CD8+ T cell infiltration. Consequently, GDF-15 may serve as a predictive biomarker for anti-PD1 response and potentially represent a novel target in the immunotherapy of cancer to improve tumor immune cell infiltration and anti-PD1 response.
Citation Format: Jorg Wischhusen, Kilian Wistuba-Hamprecht, Patrick N. Harter, Phil Cheng, Alexander Martens, Falk Gogolla, Yumi Nonomura, Paula Romer, Sven D. Koch, Markus Haake, Christine Schuberth-Wagner, Manfred Rudiger, Eugen Leo, Michael Mittelbronn, Mitchell P. Levesque, Hubert Hackl, Reinhard Dummer, Benjamin Weide. Identifying GDF-15 as potential novel immunotherapeutic target linked to immune cell exclusion in tumors and resistance to anti-PD-1 treatment abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2161.
Abstract
Background: Growth and differentiation factor 15 (GDF-15) is a TGF-β superfamily member physiologically expressed mainly in placenta and linked to feto-maternal tolerance. Under ...pathophysiologic conditions, prevention of excessive immune cell infiltration during tissue damage and cachexia induction have been ascribed to GDF-15. A recent study Haake et al. AACR2020; Abstract #5597 elucidated a mechanism by which GDF-15 inhibits LFA-1 activation on CD8+ T cells, thus interfering with effector T cell recruitment to tissues. Importantly, several cancer entities secrete high levels of GDF-15, correlating with poor prognosis and reduced overall survival reviewed in Front Immunol 2020 May 19;11:951. To block this effect the GDF-15 neutralizing antibody CTL-002 was generated. In preclinical models CTL-002 demonstrated potent effector T cell shifting into tumor tissue by neutralizing GDF-15 and enhancing response to checkpoint inhibitor therapy. Methods: This is a phase 1, first-in-human (FIH), two-part, open-label clinical trial of intravenous (IV) administration of CTL-002 given as monotherapy and in combination with an anti-PD-1 antibody in subjects with advanced-stage, relapsed/refractory solid tumors who relapsed on or were refractory to a prior anti-PD-1/PD-L1 therapy. Eligible subjects have exhausted all available approved standard treatments, including prior anti-PD1/-PD-L1 treatment, and present with a biopsy-accessible tumor for serial biopsy taking. The trial is termed GDFATHER, for “GDF-15 Antibody-mediaTed Effector cell Relocation”. Main endpoints are safety of CTL-002 monotherapy and CTL-002 combination with an anti-PD-1 antibody, pharmacokinetics, pharmacodynamics (e.g., degree of GDF-15 neutralization achieved and change in immune-cell number and composition in the tumor tissue) as well as preliminary clinical efficacy (tumor mass reduction; anticachexia effect). In part A of the trial (dose escalation) up to 24 subjects will receive escalating doses of CTL-002 IV (0.3 – 20 mg/kg) in a „mono-followed-by-combination“-design with CTL-002 given as monotherapy and followed by combination with an anti-PD-1 checkpoint inhibitor. In part B (expansion) up to 5 cohorts with up to 25 subjects per cohort with defined tumor entities expected to be GDF-15 dependent will be treated to determine the recommended phase 2 dose (RP2D) and further evaluate safety and preliminary efficacy of CTL-002 monotherapy and the combination. The study was initiated in December 2020 and enrolled the first patient on Dec 09, 2020. Cohort 4 is ongoing at time of submission (07/2021) and so far no DLT has occurred. Updated safety, biomarker and response assessments will be reported. The ClinicalTrials.gov Identifier is NCT04725474.
Citation Format: Ignacio Melero, Emiliano Calvo, Maria-Elisabeth Goebeler, Elena Garralda, Reinhard Dummer, María Rodríguez-Ruiz, María De Miguel, Cyrus Sayehli, Guzman Alonso Casal, Egle Ramelyte, Martin Schuler, Tanja Gromke, Miguel Sanmamed, Irene Moreno, Ralf Bargou, Maria Lostes, Julia-Tatjana Maul, Heike Richly, Petra Fettes, Kathrin Klar, Christine Schuberth-Wagner, Markus Haake, Joerg Wischhusen, Eugen Leo. A phase I, first-in-human clinical trial of the GDF-15 neutralizing antibody CTL-002 in subjects with advanced stage solid tumors (Acronym: GDFATHER) abstract. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P06-01.
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e14532
Background: Growth and differentiation factor 15 (GDF-15) is a divergent member of the TGF-β superfamily with low to absent expression in healthy tissue. GDF-15 has been linked ...to feto-maternal immune tolerance, to prevention of excessive immune cell infiltration during tissue damage, and to anorexia. Various major tumor types secrete high levels of GDF-15. In cancer patients, elevated GDF-15 serum levels correlate with poor prognosis and reduced overall survival (OS). Methods: Impact of a proprietary GDF-15 neutralizing antibody (CTL-002) regarding T cell trafficking was analyzed by whole blood adhesion assays, a HV18-MK melanoma-bearing humanized mouse model and a GDF-15-transgenic MC38 model. Additionally, patient GDF-15 serum levels were correlated with clinical response and overall survival in oropharyngeal squamous cell carcinoma (OPSCC) and melanoma brain metastases. Results: In whole blood cell adhesion assays GDF-15 impairs adhesion of T and NK cells to activated endothelial cells. Neutralization of GDF-15 by CTL-002 rescued T cell adhesion. In HV18-MK-bearing humanized mice CTL-002 induced a strong increase in TIL numbers. Subset analysis revealed an overproportional enrichment of T cells, in particular CD8
+
T cells. As immune cell exclusion is detrimental for checkpoint inhibitor (CPI) therapy, a GDF-15-transgenic MC38 model was tested for anti-PD-1 therapy efficacy. In GDF-15 overexpressing MC38 tumors response to anti PD-1 therapy was reduced by 90% compared to wtMC38 tumors. Combining aPD-1 with CTL-002 resulted in 50% of the mice rejecting their GDF-15 overexpressing tumors. Clinically, inverse correlations of GDF-15 levels with CD8
+
T cell infiltration were shown for HPV
+
OPSCC and for melanoma brain metastases. GDF-15 serum levels were significantly higher in HPV- than in HPV+ OPSCC patient (p < 0.0001). Low GDF-15 levels corresponded to longer OS in both HPV- and HPV+ OPSCC. In two independent melanoma patient cohorts treated with nivolumab or pembrolizumab low baseline serum GDF-15 levels were predictive for clinical response to anti-PD1 treatment and superior OS. Bivariate analysis including LDH indicates that GDF-15 independently predicts poor survival in aPD-1 treated melanoma patients. Conclusions: Taken together our in vitro and in vivo data show that elevated GDF-15 levels block T-cell infiltration into tumor tissues. Neutralizing GDF-15 with CTL-002 restores the ability of T cells to extravasate blood vessels and enter tumor tissue both in vitro and in vivo. In melanoma, patients with higher GDF-15 levels have significantly shorter survival and are less likely to respond to anti-PD1 therapy. GDF-15 may thus serve as a new predictive biomarker for anti-PD1 response, but most importantly also represents a novel target for cancer immunotherapy to improve tumor immune cell infiltration and response to anti-PD1 therapy.
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TPS2658
Background: Growth and differentiation factor 15 (GDF-15) is a TGF-β superfamily member physiologically expressed mainly in placenta and linked to feto-maternal tolerance. Under ...pathophysiologic conditions, prevention of excessive immune cell infiltration during tissue damage and cachexia induction have been ascribed to GDF-15. A recent study Haake et al. AACR2020; Abstract #5597 elucidated a mechanism by which GDF-15 inhibits LFA-1 activation on CD8+ T cells, thus interfering with effector T cell recruitment to tissues. Importantly, several cancer entities secrete high levels of GDF-15, correlating with poor prognosis and reduced overall survival reviewed in Front Immunol 2020 May 19;11:951. To block this effect the GDF-15 neutralizing antibody CTL-002 was generated. In preclinical models CTL-002 demonstrated potent effector T cell shifting into tumor tissue by neutralizing GDF-15. Methods: This is a phase 1, first-in-human (FIH), two-part, open-label clinical trial of intravenous (IV) administration of CTL-002 given as monotherapy and in combination with an anti-PD-1 antibody in subjects with advanced-stage, relapsed/refractory solid tumors who relapsed post or were refractory to a prior anti-PD-1/PD-L1 therapy. Eligible subjects have exhausted all available approved standard treatments. Further key eligibility criteria include having received at least one prior anti-PD1/-PD-L1 treatment and having relapsed on or after it or having been refractory to it, and presenting with a biopsy-accessible tumor for serial biopsy taking. The trial is termed GDFATHER, for “GDF-15 Antibody-mediaTed Effector cell Relocation”. Main endpoints are safety of CTL-002 monotherapy and CTL-002 combination with an anti-PD-1 antibody, pharmacokinetics, pharmacodynamics (e.g. degree of GDF-15 neutralization achieved and change in immune-cell number and composition in the tumor tissue) as well as preliminary clinical efficacy (tumor mass reduction; anticachexia effect) In part A of the trial (dose escalation) up to 24 subjects will receive escalating doses of CTL-002 IV (0.3 – 20 mg/kg) in a „mono-followed-by-combination“-design with CTL-002 given as monotherapy and followed by combination with an anti-PD-1 checkpoint inhibitor. In part B (expansion) up to 5 cohorts with up to 25 subjects per cohort with defined tumor entities expected to be GDF-15 dependent will be treated to determine the recommended phase 2 dose (RP2D) and further evaluate safety and preliminary efficacy of CTL-002 monotherapy and the combination. The study was initiated in December 2020 and enrolled the first patient on Dec 09, 2020. Cohort 1 has been completed without DLT and enrollment for cohort 2 began in February 2021. Clinical trial information: NCT04725474.
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