Browsing Over 173 Presentations
7IN - Targeting histone H3K36me3-deficient cancers
- Timothy Humphrey (Oxford, GB)
- Timothy Humphrey (Oxford, GB)
Abstract
Background
SETD2-dependent histone H3 lysine 36 trimethylation (H3K36me3) plays a central role in both maintaining genome stability and in suppressing tumorigenesis, and is frequently depleted in particular cancer types. We find this histone mark plays an important role in promoting homologous recombination (HR) repair of DNA double-strand breaks. Further, H3K36me3 also performs an essential role in facilitating DNA replication following WEE1 kinase inhibition, through promoting efficient deoxyribonucleotide synthesis. Accordingly, H3K36me3-deficient cancers can be specifically targeted using the WEE1 inhibitor, AZD1775, resulting in replicative catastrophe and cell death. The use of AZD1775 to target H3K36me3-deficient cancers is now in clinical trials. Mechanistic insights into the targeting of H3K36me3-deficient cancers with AZD1775 and its implications will be presented.
Legal entity responsible for the study
CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK
Funding
Medical Research Council; Cancer Research UK; Clarendon Scholarship; Swiss National Science Foundation
Disclosure
The author has declared no conflicts of interest.
8IN - BET domain inhibitors
- Irene Brana Garcia (Barcelona, ES)
- Irene Brana Garcia (Barcelona, ES)
9IN - HDAC inhibitors and check point inhibitors
- René Bartz (Planegg, DE)
- René Bartz (Planegg, DE)
Abstract
Background
Despite successes in the treatment of melanoma patients with checkpoint inhibitors (CI), most patients do not respond to CI alone and a high unmet medical need remains for these patients. One promising approach is to enhance the immunogenicity and alter the tumor microenvironment from a more immune-deserted to an immune-inflamed phenotype by means of combination therapy. Epigenetic modulation has been reported as one key determining factor in shaping the immune microenvironment and compounds altering these processes (e.g. histone deacetylases (HDAC) inhibitors) are particularly promising.
Methods
Tumor bearing animals (CT26 and C38 syngenic models) were treated with 4SC-202, an orally available clinical stage combined HDAC class I/LSD1 inhibitor, or CIs PD-(L)-1 alone as well as in combination. Tumor growth was assessed continuously and after approx. 2 weeks of treatment tumors were excised and analyzed by flow cytometry and gene expression profiling. Additionally, animals not intended for these analyses were further monitored and tumor growth/survival was monitored.
Results
4SC-202 treatment led to an increase of MHC molecules and enhanced expression of inflammatory markers like IFN-γ and various chemokines in tumors. Furthermore, detailed analysis of the tumor revealed that 4SC-202 strongly altered the immune cell composition and particularly the number of cytotoxic T cells (CTL) was markedly increased. Importantly, subsequent combination treatment of 4SC-202 with CIs in syngenic animal models showed a strong synergistic effect resulting in significant longer survival in both models leading to 55% of tumor free animals (C38 model).
Conclusions
NCT03278665
Clinical trial identification
ClinicalTrials.gov Identifier:
NCT03278665
Clinical trial identification
NCT03278665
Legal entity responsible for the study
4SC AG
Funding
Has not received any funding
Disclosure
R. Bartz: I do not conduct activities that would involve a conflict of interest with CME-accreditable training, but that in the past 2 (two) years I have been a paid employee of 4SC AG.
Q&A / Panel Discussion
Q&A / Panel Discussion
13IN - Personalized therapy in adult acute lymphocytic leukemia: Path to the cure
- Elias Jabbour (Houston, US)
- Elias Jabbour (Houston, US)
10IN - Introduction and Metabolism interference or epigenetics treatment with special focus on haematological diseases
- Tak Mak (Toronto, CA)
- Tak Mak (Toronto, CA)
11IN - Genomic-guided trials in lymphoma
- Anas Younes (New York, US)
- Anas Younes (New York, US)
12IN - Genomic-guided metabolism drug development in myeloid diseases
- David Schenkein (Cambridge, US)
- David Schenkein (Cambridge, US)
Abstract
Background
Mutations in isocitrate dehydrogenase (IDH)1 or IDH2 are seen in ~15–20% of patients with acute myeloid leukemia (AML). Mutant IDH (mIDH) reduces α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG), leading to histone hypermethylation and a block in myeloid differentiation. Ivosidenib (AG-120) and enasidenib (AG-221) are potent, selective, oral small molecule inhibitors of mIDH1 and mIDH2, respectively. Both have been shown preclinically to reduce aberrant 2-HG levels and promote myeloid differentiation, and as monotherapy are associated with robust overall response rates in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Enasidenib received full approval in the United States in Aug 2017 for the treatment of adult patients with R/R AML with an IDH2 mutation. A New Drug Application was recently submitted to the FDA for ivosidenib for the treatment of patients with R/R AML and an IDH1 mutation, based on evidence in patients showing clinical activity and observation of clinical benefit, including achievement of transfusion independence, and a decrease in the frequency of comorbidities such as febrile neutropenia and infections in responding patients. Additional data demonstrate that ivosidenib monotherapy results in deep IDH1 mutation clearance in a subset of patients with R/R AML and untreated AML who achieve clinical response. Tolerability and preliminary clinical activity data were also recently presented from two Phase 1 studies evaluating ivosidenib and enasidenib in combination with standard induction (7+3) chemotherapy or azacitadine in newly diagnosed AML patients. Independent clinical trials are currently underway for ivosidenib in mIDH1-positive malignancies in the solid tumor context. This presentation will focus on the discovery of these investigational medicines, as well as the promising clinical and translational results from the hematologic malignancy and solid tumor trials.
Legal entity responsible for the study
Agios Pharmaceuticals, Inc.
Disclosure
D. Schenkein: Agios: Full time employee, stock ownership, board of directors. Bluebird Bio: board of directors. Denali Therapeutics: board of directors.
Funding
Agios Pharmaceuticals, Inc.
51P - Active immunotherapy with a VEGF targeted vaccine HeberSaVax: The road so far and the future ahead
- Mónica Bequet-Romero (Havana, CU)
- Mónica Bequet-Romero (Havana, CU)
- Yanelys M. Díaz (Cubanacán, Playa, CU)
- Javier S. Ramírez (Cubanacán, Playa, CU)
- Katty-Hind Selman-Housein (Havana, CU)
- Francisco Hernández-Bernal (Cubanacán, Playa, CU)
- Ana De la Torre Santos (Santa Clara, CU)
- Jesús Piñero (Santa Clara, CU)
- Cimara Bermúdez (Cubanacán, Playa, CU)
- Jorge V. Gavilondo Cowley (Cubanacán, Playa, CU)
- Marta Ayala Avila (Cubanacán, Playa, CU)
Abstract
Background
The vascular endothelial growth factor (VEGF) plays a central role in angiogenesis and immunosuppressive cascades inherent to tumor development. Success of drugs targeting this growth factor and their receptors signaling cascade built upon these facts. Such passive targeting of VEGF/VEGFR pathway had two major caveats: non-manageable side effects and the induction of resistance phenomena. To overcome some of these problems we design an active immunization approach based on the use of a functionally deficient VEGF 121 isoform as antigen. Herein we present preclinical and clinical development data of HeberSaVax vaccine (formerly known as CIGB-247).
Methods
Safety, antitumoral and immunological effects of HeberSaVax administration were analyzed in mouse, rats, rabbits, non-human primates and in two Phase I clinical trials. Formulations containing the adjuvants VSSP (Very Small Size Particles from Neisseria Meningitides) or Alum phosphate were used. Vaccine was administered once a week (VSSP) or bi-weekly (Alum Phosphate) for 8 weeks. Immune response was evaluated using direct and indirect ELISA methods and IFN-gamma ELISPOT.
Results
HeberSaVax administration inhibits implantation and growth of tumors and metastases favoring a significant increase in animals’ survival. In mice, rats, rabbits and on non-human primates the vaccine administration result in non-toxic induction of sustained antibody titers that specifically neutralized VEGF binding to VEGF receptors. Immunizations also induce VEGF specific cell mediated cytotoxicity. A total of 80 patients were included in the phase I/Ib clinical trials. Results indicated: a good safety profile that allows combining the vaccine with the existing arsenal for cancer therapy; the induction of specific humoral and cellular responses despite the advance stage of patient’s tumors and; an unexpected long term immune responses after 4 years of continuous treatment. As part of the trials three complete responses, one partial response and four stable diseases have been documented.
Conclusions
Altogether these results encourage further development of HeberSaVax vaccine for cancer therapy. Henceforth, a total of four Phase II/III clinical trials are planned to start in 2018 in specific localizations.
Clinical trial identification
RPCEC00000102 and RPCEC00000155
Legal entity responsible for the study
Center for Genetic Engineering and Biotechnology (CIGB)
Funding
Heber Biotec, and Chemo
Disclosure
All authors have declared no conflicts of interest.
52P - A novel rMVA combination immunotherapy triggers potent innate and adaptive immune responses against established tumors
- Jose Medina (Martinsried, DE)
- Jose Medina (Martinsried, DE)
- Maria Hinterberger (München, DE)
- Marco Testori (Martinsried, DE)
- Marlene Geiger (Martinsried, DE)
- Raphael Giessel (Martinsried, DE)
- Paul Chaplin (Martinsried, DE)
- Hubertus Hochrein (Martinsried, DE)
- Henning Lauterbach (Martinsried, DE)
Abstract
Background
Virus-based vaccines and appropriate costimulation enhance potent antigen-specific T cell immunity against cancer. In the present study we exploit both innate and adaptive immune responses triggered by a novel recombinant modified vaccinia virus Ankara (rMVA) encoding costimulatory CD40L against solid tumors in combination regimes to overcome tumor-induced resistance to immunotherapy.
Methods
Mice bearing tumors > 50 mm3 in volume were immunized intravenously and treated with monoclonal antibodies when indicated. Immune infiltrates were analyzed by flow cytometry. When indicated, immune populations were isolated to perform functional assays.
Results
Therapeutic treatment with rMVA-CD40L resulted in strong antitumor effects in unrelated established tumor models. Tumor infiltration was composed of non-exhausted, antigen-specific CD8+ T cells with proliferative capacity after rMVA-CD40L immunization. Strikingly, this antitumor effect was not entirely dependent on cross-presenting CD8α+ DC -induced CD8+ T cell expansion. Indeed, rMVA-CD40L-induced tumor control did not depend on cytosolic DNA sensor STING. Interestingly, rMVA-CD40L induced strong NK cell activation and thereby potent Antibody Dependent Cell Cytotoxicity (ADCC) against Tumor-Associated Antigen (TAA) targeting antibodies. Hence, the combination of TAA targeting antibodies and rMVA-CD40L resulted in increased therapeutic antitumor efficacy.
Conclusions
We describe a novel and translationally relevant therapeutic synergy between viral vaccination and CD40L costimulation. We connect CD40 ligation to cross-presenting CD8α+ DC -mediated expansion of non-exhausted CD8+ T cells in the tumor microenvironment. Taking advantage from intrinsic MVA-induced NK cell activation and further improved NK cell function by CD40 ligation, we show strengthened antitumor immune responses when both rMVA-CD40L-induced innate and adaptive immune mechanisms are exploited by combining immunotherapeutic regimes. This finding has a direct potential impact in clinical trials where TAA targeting antibodies are currently under evaluation.
Legal entity responsible for the study
Bavarian Nordic GmbH
Funding
Bavarian Nordic GmbH
Disclosure
J. Medina, M. Hinterberger, M. Testori, M. Geiger, R. Giessel, H. Hochrein, H. Lauterbach: Employee of Bavarian Nordic GmbH. P. Chaplin: CEO of Bavarian Nordic GmbH
53P - Impact of chronic hepatitis virus infection on the feasibility and efficacy for Asian patients with hepatocellular carcinoma in phase I clinical trials
- Takafumi Koyama (Tokyo, JP)
- Takafumi Koyama (Tokyo, JP)
- Shunsuke Kondo (Tokyo, JP)
- Toshio Shimizu (Tokyo, JP)
- YUTAKA Fujiwara (Tokyo, JP)
- Shigehisa Kitano (Tokyo, JP)
- Takahiro Ebata (Chiba, JP)
- Akihiko Shimomura (Tokyo, JP)
- Chigusa Morizane (Tokyo, JP)
- Takuji Okusaka (Tokyo, JP)
- Noboru Yamamoto (Tokyo, JP)
Abstract
Background
In Asia, chronic hepatitis B and C virus infections (CHVI) are major risk factors for liver fibrosis and hepatocellular carcinoma (HCC). Patients with advanced HCC have limited effective therapeutic options and are potential candidates for early phase clinical trials for new anti-cancer agents. The impact of CHVI on the feasibility and efficacy for patients with HCC in Phase I trials (P-Is) has not been reported or elucidated in Western countries.
Methods
We retrospectively analyzed the characteristics and outcomes of HCC patients participating in P-Is, with emphasis on CHVI. Patients testing positive for anti-hepatitis C virus (HCV) antibody or hepatitis B virus surface antigen (HBsAg) were diagnosed with CHVI.
Results
Eighty-five patients were enrolled in P-Is at our center. There were no significant differences in the clinical and laboratory variables, including the liver function test results, between the 46 (54%) CHVI-positive and 39 (46%) CHVI-negative patients in this study. The median time to treatment failure (TTF) and overall survivals (OS) from enrollment of the P-I were 60 days (95% confidence interval [CI]: 51–85) and 412 days (95% CI: 267–478), respectively. There is no significant difference between positive and negative for hepatitis virus in the best response based on the RECIST. The frequency of abnormal liver function test (LFT) adverse events (grade ≥ 3) was significantly different among CHVI-positive and -negative patients. No patient discontinued P-I treatment secondary to abnormal LFT results or developed reactivation of hepatitis virus, and no treatment-related mortality was observed. Multivariate analysis revealed that the number of prior systemic treatments significantly contributed to poor TTF (≥2; HR: 2.1, 95% CI: 1.3–3.6,
Conclusions
CHVI did not independently predict TTF and OS. Abnormal LFT adverse events could be related to CHVI but did not lead to discontinuation of P-I treatment. Thus, patients advanced HCC with CHVI can be enrolled in the P-Is.
Legal entity responsible for the study
N/A
Funding
Has not received any funding
Disclosure
All authors have declared no conflicts of interest.