Therapeutic vaccination of tumor patients with cytokine gene-transfected tumor cells leads to tumor regression in animal models but has so far not resulted in significant clinical benefit. We and others demonstrated that tumor cells transfected to mediate overexpression of a cytokine gene activate immunologic effector cells for an improved proliferation rate and significantly higher antitumoral cytotoxic activity. Here, we performed a pilot study of therapeutic vaccination in patients with metastatic disease. Autologous tumor cells were simultaneously transfected with novel minimalistic, immunogenically defined, gene expression constructs (MIDGE) for overexpression of the two cytokines interleukin 7 (IL-7) and GM-CSF and newly designed double stem-loop immunomodulating oligodeoxyribonucleotides (d-SLIM) as a Th1-promoting and NK cell-stimulating adjuvant. Transfection was performed ex vivo by ballistomagnetic gene transfer. Patients received four subcutaneous injections of at least 1 x 10(6) of their expression-modulated and immunomodified autologous tumor cells. Ten patients have been enrolled in the study protocol. In all patients no adverse effects could be detected. IL-7 and interferon gamma levels were elevated in the serum of the patients after treatment. Interestingly, cytotoxicity of patient-derived PBLs increased significantly during treatment. All 10 patients had progressive disease when entering our protocol. One complete, one partial, and one mixed response with progression of abdominal metastases and regression of lung metastases were observed. Two patients showed a stable disease after treatment and five patients remained in progressive disease. Our observations confirm the capability of autologous expression-modified and immunomodulated tumor cell vaccines to stimulate a strong immune response in patients with metastatic cancer even in the presence of a large tumor burden.

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Human papillomavirus (HPV) infection identified as a definitive human carcinogen is increasingly being recognized for its role in carcinogenesis of human cancers. Up to 38%–80% of head and neck squamous cell carcinoma (HNSCC) in oropharyngeal location (OPSCC) and nearly all cervical cancers contain the HPV genome which is implicated in causing cancer through its oncoproteins E6 and E7. Given by the biologically distinct HPV-related OPSCC and a more favorable prognosis compared to HPV-negative tumors, clinical trials on de-escalation treatment strategies for these patients have been studied. It is therefore raised the questions for the patient stratification if treatment de-escalation is feasible. Moreover, understanding the crosstalk of HPV-mediated malignancy and immunity with clinical insights from the proportional response rate to immune checkpoint blockade treatments in patients with HNSCC is of importance to substantially improve the treatment efficacy. This review discusses the biology of HPV-related HNSCC as well as successful clinically findings with promising candidates in the pipeline for future directions. With the advent of various sequencing technologies, further biomolecules associated with HPV-related HNSCC progression are currently being identified to be used as potential biomarkers or targets for clinical decisions throughout the continuum of cancer care.