Transgene SA

2638 Background: Human papillomavirus (HPV) is a small DNA virus associated with cervical, anogenital (AG) cancers and squamous cell carcinoma of the head and neck. TG4001 is a therapeutic vaccine based on modified vaccinia virus Ankara with insertion of modified non-oncogenic HPV-16 E6 and E7 antigens and interleukin-2 as adjuvant. The phase I trial of TG4001 combined with ave showed a favorable safety profile (Borcoman E. et al, 2023). Methods: Pts with R/M cervical and anogenital cancer and who were checkpoint inhibitors naïve were randomized independent of PD-L1 expression between ave plus TG4001 or ave alone. Pts were required to have no more than one prior line of therapy for R/M disease and no liver involvement. Primary endpoint was PFS. Subgroup analysis (cervical, anal, other genital cancer) was preplanned in the protocol. Results: 90 pts were randomized between June 2021 and April 2024. 49 (54%), 27 (30%) and 14 (16%) pts had cervical, anal, and other genital cancers, respectively. Patients’ demographics were well balanced between the 2 arms. Median PFS (mPFS) was 3.0 and 2.8 months (mo) in the experimental and control arm, respectively (HR=0.87 [90%CI: 0.59-1.29], p=0.28). In the cervical cancer subgroup, mPFS was 4.3 and 2.1 mo in the experimental and control arm, respectively (HR=0.58 [90%CI: 0.33-1.01], p=0.053). Overall Response Rate (ORR) in the whole population was 15.2% (7/46pts) in the experimental arm and 13.6% (6/44pts) in the control arm. In the cervical cancer subgroup ORR was 20% (5/25pts) in the experimental arm and 8.3% (2/24pts) in the control arm. There were no new safety signals. Three pts (6.5%) in the experimental arm and 2 pts (4.5%) in the control arm presented grade 3 or 4 treatment-related AEs. Translational analysis including immunogenicity results will be presented. Conclusions: TG4001 combined with ave did not improve PFS over ave alone in the whole patient population. Preplanned subgroup analysis in cervical cancer showed a positive efficacy signal in the combined arm. Avelumab was provided by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945). Clinical trial information: NCT03260023 .

6016 Background: Approximately one third of pts with resected LA HNSCC recur. T-cells targeting tumor specific mutations drive anti-tumor immune responses. TG4050 is a viral-based personalized cancer vaccine, encoding up to 30 tumor-specific DNA sequences bearing in-silico predicted class I and class II epitopes. We hypothesized that TG4050 prime an adaptive immune response against tumor antigens and prevent relapse in pts with resected LA HNSCC after treatment with curative intent ( NCT04183166 ). Methods: The multicenter, open label, randomized, 2-arm Phase I trial evaluated TG4050 in LA HNSCC pts achieving complete remission following surgery and adjuvant radiotherapy +/- chemotherapy. Pts were randomized to receive (Arm A) weekly doses of TG4050 for 6 weeks followed by a maintenance period of one dose every 3 weeks for up to 20 doses or no vaccine (Arm B, vaccination at relapse in combination with SOC). Safety, efficacy and immunogenicity were evaluated. In selected pts, exploratory characterization of the T cell response was performed using tetramer staining, bulk and single-cell (sc)TCR sequencing. Results: 33 pts were randomized between January 2021 and April 2023, 17 pts to Arm A and 16 pts to Arm B. Median age was 61 years (26-79 years), tumor location was oral cavity in 24 pts (72.7%), hypopharynx and oropharynx in 4 pts (12.1%), respectively and larynx in one pt (3.0%). TG4050 was safe and well tolerated with only grade 1 or 2 treatment-related adverse events (AEs). The most frequently reported were injection site reactions. After a median follow-up of 28.5 months, all 16 pts receiving TG4050 in Arm A remained disease-free whereas 3 out of 16 pts in Arm B relapsed. Disease Free Survival (DFS) data at 24 months for all patients will be presented. Exploratory qualitative analyses of the neoantigen-specific T cell response by ELISpot were presented previously. In-depth characterization of the neoantigen-specific T cells including clonal expansion by TCR sequencing and longitudinal analysis by tetramer staining will be presented. Conclusions: TG4050 is safe and induces immune responses in pts with resected LA HNSCC. No relapse occurred in the vaccine arm as opposed to 19% in the control arm. With the evolution of the landscape, adjuvant anti-PD1 therapy may become standard in resected LA HNSCC. TG4050 warrants further evaluation in combination with anti-PD1 therapy in phase III trials. Clinical trial information: NCT04183166 .

The monkeypox virus (MPXV) outbreak of 2022 caused a human disease with unusual epidemiological and clinical features, notably an increase in human-to-human transmission through sexual contact, predominantly among men who have sex with men (MSM). This evolution underscores the need to reassess prevention and control strategies in the context of a sexually transmitted disease. Here, we show that rectal challenge of male cynomolgus macaques with a 2022 clade IIb MPXV isolate mimics sexual transmission, leading to rectal infection, with systemic and male genital tract dissemination and seminal fluid shedding. Vaccination with modified-vaccinia Ankara (MVA) protected the macaques from subsequent rectal MPXV challenge. However, MVA failed to prevent the disease when administered four days post-exposure to MPXV. These findings have a critical impact on outbreak management and highlight the importance of reevaluating MVA post-exposure prophylaxis protocols.