Brandely-Talbot, Maud

2630 Background: Human papillomavirus 16 (HPV-16) infection is associated with several cancer types with limited treatment options in the locally R/M settings. Furthermore, immune checkpoint inhibitors have limited activity against advanced HPV-cancers. TG4001 is a viral vector vaccine targeting HPV E6 and E7 antigens. We have previously shown in a single-arm, dose finding phase 1 study that TG4001 combined with PD-L1 blockade using avelumab was safe and associated with a response rate of 22%. Herein we report preliminary data on immunogenicity and clinical activity of TG4001 in a randomized phase 2 study comparing TG4001 plus avelumab versus avelumab alone. Methods: Eligibility criteria: R/M HPV16+ anogenital cancer including cervical, vulvar, vaginal, penile, and anal cancers; immunotherapy naïve and with no more than one prior line of chemotherapy. HPV-16 positivity was required and centrally determined using a PCR based assay. Patients were randomly assigned 1:1 to receive either TG4001 plus avelumab (Vaccine arm) or avelumab alone. Randomization was stratified by tumor type (cervical, anal, genital). TG4001 was administered s.c at 5·107 pfu, Q1w for 5 weeks, then Q2w until month 6 followed by Q12w until progressive disease and avelumab i.v at 800 mg Q2w until progressive disease. PBMCwere collected at baseline, day 43 and day 85 to assess T-cell responses against E6 and E7 antigens using ex-vivo IFNg ELISPOT and immunophenotyping of circulating T cells. Vaccine immune response (IR) was defined as onset of a new T-cell response against either antigen or amplification of a pre-existing response under treatment. Tumor response was assessed using RECIST 1.1. Results: 59 pts had been randomized by the time of data cut-off. IR was assessed in 24 pts in the vaccine arm and 16 pts in the avelumab arm. T cells against E6 or E7 antigens at baseline were rare with only 4 pts having a low intensity ELISPOT readout against either target prior to initiation of treatment. 11/24 pts in the vaccine arm had an IR, while none of the patients in the avelumab arm had an IR. Occurrence of IR was detected at day 43 and tended to gain in intensity at D85. In the vaccine arm, IR was associated with tumor response with 3 clinical responders among 11 pts with positive IR versus 1 response observed among the 13 patients without IR. Conversely, only 2 progressive disease pts among 11 positive IR compared favorably to the 6/13 vaccine arm pts with no IR. Remarkably, a complete clinical response was observed in a vaccine treated pt exhibiting the strongest E6 and E7 IR. Conclusions: TG4001 can induce a de novo immune response against HPV-16 antigens E6 and E7 in advanced HPV-16 cancers. The data suggest that these IRs are associated with anti-tumor response and that TG4001 vaccination in combination with ICI has the potential to drive clinical benefit in R/M anogenital cancers. Clinical trial information: NCT03260023 .

2637 Background: Mutation-associated neoantigens (MANAs) constitute attractive antigens for the design of cancer vaccines. However, clinical implementation remains challenging because of the patient specific nature of MANAs, hereby requiring that a bespoke vaccine is designed for each subject. We developed a pipeline for the genomic characterization and the design of tailored vaccine using a modified vaccinia Ankara viral vector. Methods: Immunogenicity, safety and early clinical activity of personalized cancer vaccines are being assessed in two phase I trials, respectively in high grade serous OC and HPV-negative HNSCC. Patients (Pts) at high risk of relapse are enrolled in the study being in remission following surgical primary treatment. High risk is defined as stage IIIC or IVA for OC and stage III or IVA for HNSCC. A vaccine is manufactured for each patient. OC pts are treated at asymptomatic relapse based on radiological finding or elevation of CA-125 with the vaccine alone; HNSCC pts in complete remission after surgery and adjuvant therapy are randomized to receive the vaccine either at the end of locoregional treatment or in combination with standard of care at relapse. The vaccine was administered weekly for 6 weeks and a booster dose every three weeks over a year or until progression, whichever occurred first. Results: At the time of the data cut-off, a total of 8 pts were treated: 4 relapsing OC pts, 3 HNSCC pts in complete remission and 1 relapsing HNSCC pt. AE attributable to the vaccine were mainly grade 1 injection site reactions and fatigue. One OC pt displayed an objective response 6 weeks after initiation of vaccine and for 9 months with a normalization of CA-125 until death from an unrelated cause; 1 other OC pt remains on treatment with a stable radiological disease for 11 months. The 2 other OC progressed at the first evaluation on day 43. HNSCC pts treated in complete remission received respectively 20, 15 and 4 doses, and remain on treatment and disease free. One HNSCC patient received 9 doses of vaccine after relapse in conjunction with chemotherapy and anti-PD-1 therapy and remains on treatment with stable disease after 5 months. Immune monitoring demonstrates priming of a polyepitopic T cell response against class I and II antigens. Responses were observed regardless of HLA and without cross-reactivity to the germline protein. Adaptive response was associated with a shift of CD4 and CD8 T cells toward an effector phenotype and innate cellular immunity was activated with a strong maturation and activation of NK cells. Immune changes were stronger in pts with controlled disease versus progressors. Conclusions: Data demonstrate that TG4050 is safe, well tolerated and able to induce T cell responses whatever the HLA haplotype. Early signs of clinical activity were observed in OC pt. These data pave the way for further development and synergistic immunotherapeutic combinations. Clinical trial information: NCT04183166.