Relationship Between Human Papillomavirus and Penile Cancer

Implications for Prevention and Treatment

Laura C. Kidd; Sharon Chaing; Juan Chipollini; Anna R. Giuliano; Philippe E. Spiess; Pranav Sharma

Disclosures

Transl Androl Urol. 2017;6(5):791-802. 

In This Article

Current Therapies Against HPV

Targeted Therapies

While well-established treatment recommendations exist for penile cancer and its metastatic manifestations, HPV-specific targeted therapies remain a promising area of active investigation. Unfortunately, therapeutic HPV vaccine research is lacking, but investigation of nanoparticles might possibly yield an effective drug delivery system to make this a reality.[99,100] Otherwise, a majority of available research has been done in head and neck SCC. For example, HPV-positive HNSCCs have demonstrated improved prognosis over HPV-negative tumors[101] and even appear differently on CT imaging, based on texture.[102] They are more radiosensitive,[101] leading to the development of a multicenter phase II/III RCT investigating outcomes of lower radiation dose in HPV-positive tumors.[103]

Additionally, HPV-positive HNSCCs show markedly increased intratumoral immune cell infiltrate, as well as decreased Cox-2 and increased programmed cell death protein-1 (PD-1) mRNA expression.[104] In fact, a study on mice suggested that the use of HPV vaccine to upregulate PD-1 expression acted in synergism with PD-1 blockade to enhance antitumor efficacy.[105] Furthermore, PD-1 and its ligand, programmed cell death ligand 1 (PD-L1), are elevated in high risk-associated HPV CIN lesions and are associated with impaired cell-mediated immunity.[106] Likewise, favorable response in metastatic cervical cancer has been demonstrated in early studies with use of HPV tumor-infiltrating T-cells, with persistence of clinical benefit at 1 month.[107] Nivolumab, an anti-PD-1 monoclonal antibody has shown improved outcomes in HNSCC treatment after platinum-based chemotherapy,[108] and ipilimumab, a CTLA-4 inhibitor, is currently in clinical trials, given its success in melanoma. Another study showed downregulation of antigen presentation of HPV E7 peptides in HNSCC, suggesting a target for immunotherapy, as well as highlighting the goal of stimulating antigen presentation.[109] Another study showed that HPV-16 E6 protein could be targeted by engineered T cells, another potential target for therapeutics.[110]

Research specifically in penile cancer is limited, but expression of PD-L1 has been found to be higher in non-high-risk HPV penile tumors, with low levels associated with absent lymph node metastases and better prognosis.[111] A study of 148 penile SCCs showed increased HER3 expression in HPV-positive tumors and higher phosphorylated EGFR in HPV-negative tumors.[112] Interestingly, another study found low levels of miRNA-146a, a downregulator of EGFR, in HPV-positive tumors, suggesting a mechanism of EGFR upregulation in HPV-positive patients.[113] Other studies have demonstrated aberrant DNA methylation,[114] and differential miRNA and mRNA[115] levels based on whether penile tumors were HPV-negative or positive, yielding more potential targets.

While there are several biomarkers under investigation, the majority of research is still in HPV-related cancers other than penile SCC. However, the potential is evident, and with time and more translational research, diagnostic and therapeutic targets will likely become available in the near future.

Clinical Trials

There are currently several clinical trials investigating targeted therapies for HPV-related cancers. These include anti-HPV T-cells (NCT02280811, NCT02379520, NCT02858310), a novel therapeutic vaccine in combination with platinum-based chemotherapy (NCT02526316), nivolumab versus combination therapy (NCT02488759) and an investigational drug (NCT01807546).

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