Patients with HPV16+ cervical cancer and high T-cell responses to an HPV16 vaccine survived longer.
Major Finding: Patients with HPV16+ cervical cancer and high T-cell responses to an HPV16 vaccine survived longer.
Concept: Vaccine dose and the inclusion of PEGylated type I IFN had no effect on tumor shrinkage or survival.
Impact: This trial should prompt larger studies and work to identify biomarkers of strong T-cell response.
Although some clinical success has been achieved with vaccines in premalignant lesions caused by human papillomavirus type 16 (HPV16), responses to vaccine monotherapy in HPV16-induced cancers is limited by cancer-induced immunosuppression. In a study of 77 patients with advanced, recurrent, or metastatic HPV16+ cervical cancer, Melief, Welters, and colleagues tested the effects of an HPV16 vaccine (ISA101) with standard carboplatin–paclitaxel chemotherapy with or without PEGylated type I IFN, with vaccine administration timed for optimal chemotherapy-mediated alleviation of immune dysfunction. Most patients (98.9%) reported chemotherapy-induced side effects, but few were deemed attributable to vaccine treatment. Vaccine-related side effects were mainly systemic allergic reactions, which affected 15.3% of patients and were serious in 6.9% of patients (almost all in the group receiving the highest vaccine dose), and injection-site reactions, which were not serious and affected 69.4% of patients. In the 64 patients evaluable for T-cell response, all exhibited responses specific to the HPV16 oncoproteins E6 and E7 without generally enhanced immune function. Notably, although vaccine dose did not affect the amount of tumor shrinkage or overall survival (OS), patients who mounted strong (greater than median) HPV16-specific immune responses to the vaccine exhibited greater OS than patients with weak (less than median) responses, with median OS values of 16.8 and 11.2 months in each group, respectively. The inclusion or exclusion of PEGylated type I IFN had no impact on tumor size or OS. In all, this study demonstrated that the HPV16 vaccine ISA101 in combination with carboplatin–paclitaxel chemotherapy is generally well tolerated, with a safety profile similar to that of chemotherapy alone. Limitations of the study include the small number of patients included and the lack of a chemotherapy-only control arm. Research to better establish the clinical efficacy of ISA101 and identify biomarkers predicting strong immune response is warranted, and a randomized, placebo-controlled trial examining ISA101′s synergy with anti–PD-1 (observed elsewhere) in patients with HPV16+ recurrent or metastatic oropharyngeal cancer is in progress.
Melief CJM, Welters MJP, Vergote I, Kroep JR, Kenter GG, Ottevanger PB, et al. Strong vaccine responses during chemotherapy are associated with prolonged cancer survival. Sci Transl Med 2020;535:eaaz8235.
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