Abstract 2498: The MVA viral platform for the treatment of cancer and chronic infectious diseases: Clinical experience from four randomized controlled phase II studies
Authors: LIMACHER Jean-Marc , QUOIX Elisabeth , WEDEMEYER Heiner , GARCIA Francisco , NIEMINEN Pekka , LACOSTE Gisèle , AGATHON Delphine , HONNET Geraldine , CALLEJA Elizabeth , DIDILLON Isabelle , MARIE-BASTIEN Berangère 
Published: August 2015

Abstract
The modified vaccinia strain Ankara (MVA) is attenuated and non-propagative but retains infectivity and immunogenicity, its large DNA genome allows the insertion of several full-length coding sequences for disease associated antigens or other transgenes of interest. MVA based targeted immunotherapeutics are designed to induce a cytolytic cellular immune response.
TG4010 expresses the full-length sequences of MUC1 and IL2 and was tested in combination with first line platin-based chemotherapy in stage IV non-small cell lung cancer (NSCLC) versus chemotherapy alone (NCT00415818 and NCT01383148); 108 plaque forming units (pfu) was given S/C weekly for 6 weeks then every three weeks up to progression. TG4001 expressing E6 and E7 of HPV16, and IL2 was assessed versus placebo in women with cervical intra-epithelial neoplasia (CIN2/3) (NCT01022346) at the dose of 5.107 pfu, three S/C injections a week apart. TG4040 expresses the HCV antigens NS3, NS4 and NS5B and was evaluated in combination with peg-interferon-α and ribavirin versus the same treatment alone in treatment-naïve patients with chronic hepatitis C, (107 pfu). Two distinct schedules of administration were evaluated: with or without immunotherapy run-in phase (NCT01055821).
A total of 729 patients were included and randomized in these four studies: 443 in active arms (185 NSCLC, 136 CIN2/3, 122 HCV) and 286 in control arms. In all studies the repeated S/C administration of the MVA vectors alone or in combination therapies appeared feasible and well tolerated, neither dose reduction nor modification of the schedules of administration have been necessary. Injection site reactions have been the most frequent adverse events associated with treatment, mild to moderate in the majority of cases. Despite lower doses they seemed more prevalent for vectors expressing xenoantigens (TG4001 99% pts, TG4040 42% pts) than for TG4010 (31%). The phase II studies with TG4010 met their primary endpoints based respectively on 6 month progression free survival (PFS) and overall PFS. The primary endpoint of improvedcomplete early viral response (cEVR) was also achieved in the study with TG4040. These studies had in common 1/ to combine the MVA from the beginning of standard of care and 2/ to use a schedule of administration with a run-in phase of 6 or more weekly injections followed by at least monthly injections. The study with TG4001 did not meet its threshold-based primary endpoint of complete response but significantly more women in the experimental arm had a clearance of their cervical lesions at a conization performed 6 months later.
Three MVA-based immunotherapeutics have shown meaningful clinical activity in different settings. Their favorable safety profile allows the combination of these products with standard of care therapies and also with immune checkpoint inhibitors (ongoing).
Citation Format: Jean-Marc LIMACHER, Elisabeth QUOIX, Heiner WEDEMEYER, Francisco GARCIA, Pekka NIEMINEN, Gisèle LACOSTE, Delphine AGATHON, Geraldine HONNET, Elizabeth CALLEJA, Isabelle DIDILLON, Berangère MARIE-BASTIEN. The MVA viral platform for the treatment of cancer and chronic infectious diseases: Clinical experience from four randomized controlled phase II studies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2498. doi:10.1158/1538-7445.AM2015-2498