Uveal melanoma (UM) is the most common cancer of the eye. The loss of chromosome 3 (M3) is associated with a high risk of metastases. M3 tumors are more infiltrated by T-lymphocytes than low-risk ...disomic-3 (D3) tumors, contrasting with other tumor types in which T cell infiltration correlates with better prognosis. Whether these T cells represent an antitumor response and how these T cells would be primed in the eye are both unknown. Herein, we characterized the T cells infiltrating primary UMs. CD8+ and Treg cells were more abundant in M3 than in D3 tumors. CD39+PD-1+CD8+ T cells were enriched in M3 tumors, suggesting specific responses to tumor antigen (Ag) as confirmed using HLA-A2:Melan-A tetramers. scRNAseq-VDJ analysis of T cells evidenced high numbers of proliferating CD39+PD1+CD8+ clonal expansions, suggesting in situ antitumor Ag responses. TCRseq and tumor-Ag tetramer staining characterized the recirculation pattern of the antitumor responses in M3 and D3 tumors. Thus, tumor-Ag responses occur in localized UMs, raising the question of the priming mechanisms in the absence of known lymphatic drainage.
To evaluate tipapkinogene sovacivec (TG4001), a viral immunotherapeutic vaccine expressing human papillomavirus (HPV)16 E6/E7 non-oncogenic proteins and IL-2, in combination with avelumab in HPV16+ ...cancer patients.
In this open-label, phase Ib/II, multicenter study, HPV16+ advanced cancer patients received subcutaneous TG4001 at two dose levels (DL) in phase Ib and at the recommended phase II dose (RP2D) in phase II weekly for 6 weeks, then every 2 weeks (q2Wk) until 6 months, thereafter every 12 weeks, in combination with avelumab q2Wk starting from day 8. Exploratory end-points included immunomonitoring from sequential tumour and blood samples.
Forty-three patients, mainly heavily pretreated (88% ≥ 1 previous line), were included in the safety analysis, with a majority of anal cancer (44%). No dose-limiting toxicities were reported, and DL2 (5 × 107 Plaque forming units (PFU)) was selected as the RP2D. Treatment-related adverse events to TG4001 occurred in 93% of patients, mostly grade 1/2, with grade 3 anaemia in one patient and no grade 4/5. Overall response rate (ORR) was 22% (8/36) and 32% (8/25) in all and patients without liver metastases, respectively. Median progression-free survival (PFS) and Overall Survival (OS) were 2.8 months (95% CI: 1.4–5.6) and 11.0 months (95% CI:7.5–16.7) in the total population and 5.6 months (95% CI:1.6–9.6) and 13.3 months (95% CI:8.7–32.7) in patients without liver metastases. Antigen-specific T-cell response was identified in 7/11 patients by IFNγ ELISpot.
TG4001 in combination with avelumab is safe, demonstrated antitumour activity in heavily pre-treated HPV16+ cancer patients, and is currently being evaluated in a randomised phase II trial in patients with incurable anogenital cancer and limited hepatic involvement.
NCT03260023.
•TG4001 is an immunotherapeutic vaccine expressing HPV16 E6/E7 proteins and IL-2.•TG4001 is assessed for the first time in combination with avelumab in HPV16+ cancer.•Combination of TG4001 with anti–PD-L1 avelumab showed a manageable safety profile.•TG4001 plus avelumab showed activity in heavily pre-treated HPV16+ anogenital cancer.•The new combination strategy of TG4001 with avelumab warrants further investigations.
BackgroundSpecific immune cell responses against oncogenic antigens are major determinants to achieve long-term disease control for HPV-related malignancies. We developed TG4001, a viral based ...vaccine against the HPV E6 and E7 antigens. Following the demonstration of its safety in phase Ib, we aimed to evaluate the antitumor activity and immune priming effects of TG4001 in combination with the PD-L1 inhibitor avelumab in HPV-related malignancies in phase II (NCT03260023).MethodsPatients (pts) with previously treated R/M HPV-16+ cancers received TG4001 at 5x107 pfu SC weekly for 6 weeks, every 2 weeks up to M6, and every 12 weeks thereafter in combination with avelumab IV at 10mg/kg every 2 weeks. PBMC and tissue samples were collected longitudinally prior to and during the treatment period. Specific T cell response was assessed using ex-vivo IFNg-ELISPOT, and changes in the tumor microenvironment by phenotyping of immune infiltrate and transcriptomic analyses of immune related genes.Results34 pts with anal (15), oropharyngeal (8), cervical (6) or vulvar/vaginal (5) cancer, were enrolled. Median age was 61 years; the majority (88%) had received at least 1 prior line of chemotherapy (CT) with 32% having received ≥ 2 lines. 8 pts achieved confirmed response according to RECIST 1.1 (1 CR, 7 PR, ORR 23.5%). Responses were observed in all primary tumor types and across all lines of prior therapy. Liver metastases had a profound impact on outcome: ORR was 34.8% and PFS 5.6 months in pts without liver metastases (n=23) versus 0% and PFS of 1.4 months in pts with liver metastases (n=11). Consistent with phase Ib data, the combination had a favorable safety profile.11 pts were evaluable for T-cell response at day (D) 43. 7/11 patients had vaccine-induced reactive T cells against E6, E7 or both. In particular, in the patient with CR, lesions disappearance was accompanied by the development of a strong T-cell response against E6 and E7. This response developed as early as D43 and sustained at 6 months after initiation of therapy, consistent with the durable disease-control. Increased infiltrates, expression of immune related genes and higher PD-L1 protein expression were observed across all patients suggesting a remodeling of the tumor microenvironment consistent with a switch toward a ‘hot tumor’ phenotype.ConclusionsOur study suggests that immunotherapeutic combination of TG4001 and avelumab shows valuable tumor activity in pts with previously treated advanced HPV-16+ cancers. These results warrant validation in a larger cohort of patients.Trial RegistrationNCT03260023
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