Browsing Over 346 Presentations
118P - The role of asunercept as a selective CD95L inhibitor in cutaneous melanoma: Rationale and results from an enhanced TiRP model
- A. Krendyukov (Heidelberg, Germany)
- A. Krendyukov (Heidelberg, Germany)
- N. Kneisel (Heidelberg, Germany)
- J. Zhu (Brussels, Belgium)
- C. Merz (Heidelberg, Germany)
- D. Richards (Heidelberg, Germany)
- C. Gieffers (Heidelberg, Germany)
- B. Van den Eynde (Brussels, Belgium)
Abstract
Background
CD95/CD95L signalling plays an important role in cancer cells resistant to CD95-mediated apoptosis and CD95L inhibition can overcome this mechanism. Several mechanisms related to apoptosis induction or dysfunction of effector T-cells via CD95L in the tumour microenvironment (TME) have also been investigated, with supporting evidence from preclinical melanoma models.
Methods
An autochthonous mouse model of melanoma (TiRP), genetically engineered to express P1A (defined MAGE-type antigen) mimics the T-cell suppressive effects of the TME through CD95L, which normal transplantation models cannot replicate. An advanced version of this murine melanoma TiRP model has been recently developed. This model can generate synchronized tumours in multiple mice in which treatments can be compared simultaneously while maintaining the advantages of the previous model regarding the role of CD95L in the TME interaction. This enhanced TiRP model was used to verify the effect of CD95L inhibition on apoptosis of tumour specific TILs using asunercept.
Results
In this novel synchronized in vivo melanoma model, asunercept decreased intra-tumour apoptosis among tumour-specific T cells by 67% vs controls (9% vs 28%, p = 0.04). This validates the immune-suppressive interaction between the TME and infiltrating tumour-specific T cells in this model. Furthermore, cross-species specific asunercept prevents T cell apoptosis triggered by the tumour microenvironment, highlighting a rationale for potential application of CD95L inhibition in immuno-oncology for other solid tumours.
Conclusion
Selective CD95L inhibition by asunercept might have potential clinical implications in different tumours beyond recurrent glioblastoma, including cutaneous melanoma. To date, asunercept has demonstrated clinical efficacy and safety in patients with recurrent glioblastoma and myelodysplastic syndromesand may warrant further investigation in clinical trials.
Legal entity responsible for the study
The authors.
Funding
Apogenix AG.
Disclosure
A. Krendyukov: Full / Part-time employment: Apogenix AG. N. Kneisel: Full / Part-time employment: Apogenix AG. J. Zhu: Research grant / Funding (self), Full / Part-time employment: Ludwig Institute for Cancer Research. C. Merz: Full / Part-time employment: Apogenix AG. D. Richards: Full / Part-time employment: Apogenix AG. C. Gieffers: Full / Part-time employment: Apogenix AG. B. van den Eynde: Research grant / Funding (self), Full / Part-time employment: Ludwig Institute for Cancer Research; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Officer / Board of Directors: iTeos Therapeutics.
Immune therapy in non-metastatic bladder cancer
- M. Van der Heijden (Amsterdam, Netherlands)
- M. Van der Heijden (Amsterdam, Netherlands)
152P - Replicative potency of oncolytic VSV-GP differentially shapes the immune signature in three distinct syngeneic tumour models
- G. Wollmann (Innsbruck, Austria)
- G. Wollmann (Innsbruck, Austria)
- B. Spiesschaert (Innsbruck, Austria)
- K. Das (Innsbruck, Austria)
- L. Schreiber (Innsbruck, Austria)
- P. Erlmann (Innsbruck, Austria)
- B. Stierstorfer (Biberach, Germany)
- D. Von Laer (Innsbruck, Austria)
- P. Mueller (Biberach, Germany)
- C. Urbiola (Innsbruck, Austria)
Abstract
Background
Oncolytic viruses (OV) induce potent antitumor treatment effects not only via direct tumour infection and lysis but also via activation of innate and adaptive immune responses. As such, they show strong synergism in combination with various immunotherapy strategies. Here we address the question to what extend intratumoral viral replication of the vesicular stomatitis virus variant VSV-GP affects the tumour microenvironment of three different syngeneic mouse tumour models B16, TRAMP and LLC.
Methods
To model tumours with higher permissivity for OVs we generated interferon receptor deficient cells (TRAMP-IFNAR1-/- and LLC1-IFNAR1-/-). Bio-luminescent imaging was used to assess intratumoral virus propagation. Efficacy of VSV-GP was assessed in vivo in syngeneic C57BL/6 mice. The tumour micro environment was studied using flow cytometry, histology, multiplex cytokine ELISA and NanoString® transcriptome analysis.
Results
Intratumoral viral propagation was enhanced in the IFNAR1-/- tumours compared to B16. In LLC1-IFNAR1-/- tumours, VSV-GP treatment resulted in significant upregulation of over 300 immune-related genes, increase in tumour infiltrating lymphocytes and expression of pro-inflammatory cytokines. In contrast, immune activation markers in virus replication-restricted B16 tumours were only slightly increased. Yet, based on transcriptional analysis, we found a common VSV-GP treatment-associated immune gene signature. Furthermore, we have observed that VSV-GP induces an up-regulation of inflammatory cytokines in all tumour models, such as type-I IFN, IFN-γ and TNF-α, which correlates with an increase of the T-cell infiltration in the tumour. Other cytokines, such as IL-6 or IL-10, were found to be differently regulated depending on the model.
Conclusion
In conclusion, we present a number of immune-activating consequences of virotherapy treatment in syngeneic tumour models with varying degree of virus propagation. Higher virus activity in the tumour qualitatively and quantitatively shapes the tumour microenvironment differently compared to tumours with restricted virus activity.
Legal entity responsible for the study
The authors.
Funding
Christian Doppler Research Association.
Disclosure
G. Wollmann: Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim. B. Spiesschaert: Full / Part-time employment: Boehringer Ingelheim. P. Erlmann: Full / Part-time employment: Boehringer Ingelheim. B. Stierstorfer: Full / Part-time employment: Boehringer Ingelheim. D. von Laer: Advisory / Consultancy: Boehringer Ingelheim; Shareholder / Stockholder / Stock options, Licensing / Royalties: ViraTherapeutics. P. Mueller: Full / Part-time employment: Boehringer Ingelheim. All other authors have declared no conflicts of interest.
The role of tumour-conditioned myeloid cells in shaping anti-tumor immunity
- V. Bronte (Verona, Italy)
- V. Bronte (Verona, Italy)
General discussion / Q&A
DC-based immunology and antigen presentation
- T. De Gruijl (Amsterdam, Netherlands)
- T. De Gruijl (Amsterdam, Netherlands)
DOI session
9P - Overall assessment of tumour-infiltrating lymphocytes in early-stage nasopharyngeal carcinoma
- A. Almangush (Helsinki, Finland)
- A. Almangush (Helsinki, Finland)
Abstract
Background
Nasopharyngeal carcinoma (NPC) has distinct histopathology and associated with high mortality rate. Identification of NPC cases that have aggressive behavior at an early-stage can aid in improvement of the survival. Assessment of tumor-infiltrating lymphocytes (TILs) has shown a promising prognostic value in many epithelial cancers.
Methods
This study included a multicenter cohort of 44 cases treated for early-stage (I-II) NPC at the five Finnish university hospitals (Helsinki, Turku, Tampere, Kuopio and Oulu). Hematoxylin and eosin-stained cancer sections were used to evaluate TILs. We followed the guidelines that recently introduced by International Immuno-Oncology Biomarkers Working Group for assessment of TILs in different tumors including head and neck cancer.
Results
The score of intra-tumoral TILs showed a promising prognostic value for predicting survival in early NPC. A hazard ratio of 2.45 and 95% confidence interval of 1.07 to 5.62 (P = 0.03) was reported, indicates that tumors with low TILs have a higher risk of mortality.
Conclusion
In early-stage of NPC, assessment of TILs has a significant prognostic value that can be useful to identify cases with aggressive behavior. Further studies are necessary to validate the importance of TILs in larger cohorts of early NPC.
Legal entity responsible for the study
Alhadi Almangush.
Funding
Has not received any funding.
Disclosure
The author has declared no conflicts of interest.
43P - Enhancing the therapeutic effect of dendritic cell therapy by oncolytic adenovirus 3 encoding CD40-ligand
- S. Zafar (Helsinki, Finland)
- S. Zafar (Helsinki, Finland)
- D. Quixabeira (Helsinki, Finland)
- O. Hemminki (Helsinki, Finland)
- V. Cervera-Carrascon (Helsinki, Finland)
- J. Santos (Helsinki, Finland)
- A. Kanerva (Helsinki, Finland)
- A. Hemminki (Helsinki, Finland)
Abstract
Background
Dendritic Cell (DC) therapy is considered as a promising immunotherapeutic approach for treatment of advanced cancer. However, the tumor microenvironment is highly immunosuppressive that leads to DC dysfunction. Therefore, in clinical trials DC therapy has generally failed to fulfill its expectations. Oncolytic adenoviruses are well tolerated and have shown to preferentially target and kill cancer cells. Therefore, to improve the therapeutic efficacy of DC therapy, we armed oncolytic adenovirus with CD40 ligand (CD40L). CD40L is well known to regulate immune responses through its capacity to stimulate dendritic cells that lead to the activation of cytotoxic T-cells.
Methods
In this study, we generated a novel virus Ad3-hTERT-CMV-hCD40L (Ad3-hCD40L), which is fully serotype 3 adenovirus. It features a human telomerase reverse transcriptase promoter for tumor specificity and expresses human CD40L (hCD40L) under a cytomegalovirus promoter for induction of antitumor immune responses. Animal experiments were implanted in immunocompetent and in humanized mice model. To further deeply dissect if Ad3-hCD40L can modulate tumor microenvironment, tumor histocultures derived from prostate patients were used.
Results
In syngeneic studies in animal models, DC therapy with Ad3-hCD40L showed significant antitumor immune response. This enhanced therapeutic effect is associated with increased tumor specific T-cells and induction of T-helper type 1 immune response. Moreover, Ad3-hCD40L and human DCs showed 100 percent survival in conjunction with tumor control. Tumor histocultures treated with Ad3-hCD40L showed that virally expressed hCD40L in the tumor microenvironment leads to significant activation of dendritic cells and induction of Th1 immune response.
Conclusion
To conclude, CD40L armed oncolytic adenovirus 3 improves DC therapy by favorable alteration of tumor microenvironment. These findings support clinical trials where DC therapy is enhanced with oncolytic adenovirus.
Legal entity responsible for the study
Cancer Gene Therapy Group, University of Helsinki.
Funding
University of Helsinki.
Disclosure
V. Cervera-Carrascon: Full / Part-time employment: TILT Biotherapeutics Ltd. J.M. Santos: Full / Part-time employment: TILT Biotherapeutics Ltd. A. Hemminki: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: TILT Biotherapeutics Ltd. All other authors have declared no conflicts of interest.
79P - Nivolumab treatment beyond progression disease in advanced non-small cell lung cancer
- T. Enomoto (Sakai, Japan)
- T. Enomoto (Sakai, Japan)
- A. Tamiya (Sakai, Japan)
- K. Matsumoto (Sakai, Japan)
- Y. Adachi (Sakai, Japan)
- K. Azuma (Sakai, Japan)
- Y. Inagaki (Sakai, Japan)
- S. Kouno (Sakai, Japan)
- Y. Taniguchi (Sakai, Japan)
- N. Saijo (Sakai, Japan)
- K. Okishio (Sakai, Japan)
- S. Atagi (Sakai, Osaka, Japan)
Abstract
Background
Nivolumab is one of immune checkpoint inhibitors, which is reported to have efficacy in previously treated patients with advanced non-small cell lung cancer (NSCLC) in checkmate 017 / 057 / 078. It is suggested nivolumab treatment beyond progression disease (PD) may be associated with improved survival in patients with melanoma and renal cell carcinoma. However, the efficacy of beyond PD in patients with NSCLC is still unclear.
Methods
To evaluate the efficacy of beyond PD about nivolumab, we retrospectively reviewed the continuous patients with advanced NSCLC, who received nivolumab as 2nd line treatment in our institution between February 2016 and February 2019. The patients were eligible if they had been diagnosed PD using RECIST v1.1 by 28 February 2019. Baseline characteristics, overall response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), the period between RECIST v1.1 PD and clinical PD, post-PD OS, and safety were evaluated on 26 July 2019.
Results
Of the 144 advancer NSCLC patients treated with 2nd line nivolumab, 95 patients were eligible. Post-PD OS was 12.2 months (95% confidence interval [CI]: 5.8–26.6) in 28 patients continuing nivolumab beyond PD, 9.3 months (95% CI: 6.4–13.8) in 46 patients switching to other anti-cancer therapy, and 0.7 months (95% CI: 0.4–1.7) in 21 patients receiving no further therapy. The median period between RECIST v1.1 PD and clinical PD was 3.8 months (95% CI: 2.8–6.6) in 28 patients continuing nivolumab beyond PD. During nivolumab beyond PD, one patient died due to acute liver involvement and interstitial lung disease, one patient stopped to receive nivolumab due to grade 3 diarrhea, and one patient stopped to receive nivolumab due to grade 2 interstitial lung disease.
Conclusion
Post-PD OS trended to be longer in patients continuing nivolumab beyond PD than in patients switching to other anti-cancer therapy. Within the limitations of this retrospective analysis, this study suggests nivolumab treatment beyond PD may have efficacy and safety in patients with advanced NSCLC.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
108P - Phosphatidylserine suppresses T cells through GPR174, and co-inhibition of adenosine receptors and GPR174 synergistically enhances Th1 cytokine production
- M. Gavin (Seattle, United States of America)
- M. Gavin (Seattle, United States of America)
- A. Gragerov (Seattle, WA, United States of America)
- E. Espling (Seattle, WA, United States of America)
- A. Rohde (Seattle, WA, United States of America)
- T. Sexton (Seattle, WA, United States of America)
- C. Doulami (Seattle, WA, United States of America)
- G. Gaitanaris (Seattle, WA, United States of America)
Abstract
Background
Extracellular phosphatidylserine (PS) is a potent modulator of immune responses. In addition to exposure during apoptosis, PS is observed on activated platelets, leukocytes, endothelial cells, tumor cells, and exosomes. While PS exposed during apoptosis is known to suppresses inflammatory responses in phagocytic cells, whether either form of exposed PS acts directly on T lymphocytes has not been extensively studied.
Methods
HEK293 cells expressing GPR174 and GloSensor were used to detect GPR174 agonism. Immune cells were stimulated with anti-CD3/CD28 with GPCR inhibitors, NECA, or PS liposomes; and cytokines in media were measured. WT or GPR174-KO mice inoculated with syngeneic tumor cells and treated with anti-GITR (DTA-1) were evaluated for tumor growth.
Results
Here we show that PS suppresses T cells through GPR174, a Gαs-coupled GPCR. PS liposomes were more potent than lyso-PS in stimulating GPR174, and PS exposed on various cell types agonized GPR174. Several GPR174 inhibitors of different chemical classes were identified. PS liposomes attenuated Th1 cytokine production from human T cells and WT but not GPR174-KO mouse T cells, and GPR174 inhibitors reversed this suppression. Th1 cytokines were increased by GPR174 inhibition in the presence of tumor exosomes. GPR174 inhibition or genetic deletion also reduced CTLA-4 expression, an immune checkpoint known to be induced by cAMP. Compared to WT mice, GPR174-KO mice significantly controlled tumor growth when Treg were transiently depleted with anti-GITR. GPR174 is similar to A2A/B adenosine receptors in that both suppress Th1 immunity through cAMP in response to products of cell stress and death abundant in the tumor microenvironment. Inhibition of GPR174 and A2A/B synergistically increased cytokine production, GPR174 and A2A/B agonists suppressed T cells to the same extent as both combined, and A2A/B inhibition was more effective on GPR174-KO T cells vs. WT T cells.
Conclusion
Our findings suggest that for T cells to effectively overcome cAMP-mediated immunosuppression in the tumor microenvironment, both GPR174 and the adenosine pathway must be inhibited.
Legal entity responsible for the study
Omeros Corporation.
Funding
Omeros Corporation.
Disclosure
M.A. Gavin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Omeros Corporation. A. Gragerov: Shareholder / Stockholder / Stock options, Full / Part-time employment: Omeros Corporation. E. Espling: Shareholder / Stockholder / Stock options, Full / Part-time employment: Omeros Corporation. A. Rohde: Shareholder / Stockholder / Stock options, Full / Part-time employment: Omeros Corporation. T. Sexton: Shareholder / Stockholder / Stock options, Full / Part-time employment: Omeros Corporation. C. Doulami: Shareholder / Stockholder / Stock options, Full / Part-time employment: Omeros Corporation. G. Gaitanaris: Shareholder / Stockholder / Stock options, Full / Part-time employment: Omeros Corporation.