- Giuseppe Giaccone (Washington DC, US)
- Josep Tabernero (Barcelona, ES)
Introduction
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.