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Table 2. Ongoing clinical trials
Category of therapy Trial number (clinicaltrials.gov) - name/description
Oncolytic viruses NCT02626000 (MASTERKEY232/KEYNOTE-137) - Talimogene Laherparepvec + Pembro in recurrent/metastatic
HNSCC
NCT00625456 - Safety study of recombinant vaccinia virus to treat refractory solid tumors
NCT03740256 - Attenuated vaccinia virus (GL-ONC1) in combination with cisplatin and radiation therapy in
locoregionally advanced HNSCC
Cancer vaccines NCT03633110 - Safety, tolerability, immunogenicity, and antitumor activity of GEN-009 adjuvanted vaccine
NCT03548467 - Safety, feasibility, efficacy of multiple dosing with VB10.NEO immunotherapy in patients with LA or
metastatic solid tumors
NCT02432963 - p53MVA vaccine (modified vaccinia virus ankara vaccine expressing p53) + Pembro in solid tumors
after failed prior therapy
NCT02955290 - Human EGF-rP64K/montanide ISA 51 vaccine (CIMAvax) + nivolumab in advanced HNSCC and non-
small cell lung cancer
NCT02544880 - PDE5 inhibition via Tadalafil to enhance anti-tumor mucin 1 (MUC1) vaccine efficacy in patients with
HNSCC
NCT03946358 - Combination of UCPVax vaccine and Atezolizumab for the treatment of human papillomavirus positive
cancers (VolATIL)
NCT00021424 - Recombinant fowlpox-TRICOM vaccine therapy in stage IV HNSCC
NCT03418480 - Phase I/II vaccine dose escalation study with intradermal injections of HPV anti-CD40 RNA vaccine
(HARE-40) in patients with advanced HPV 16 + cancers
NCT03260023 - TG4001 and Avelumab in patients with HPV-16 positive recurrent or metastatic malignancies (including
OPSCC)
NCT00257738 - 0804 GCC: MAGE-A3/HPV 16 vaccine for squamous cell carcinoma of the head and neck
NCT02002182 - DXS 11-001 vaccination prior to robotic surgery, HPV-positive OPSCC
Immunomodulatory NCT03689192 - Arginase-1 peptide vaccine in patients with metastatic solid tumors
NCT02752074 (Keynote-252/ECHO-301) - A phase 3 study of pembrolizumab + epacadostat or placebo in subjects with
unresectable or metastatic melanoma
NCT02740270 - Phase I/Ib study of GWN323 alone and in combination with PDR001 in patients with advanced
malignancies and lymphomas
NCT02274155 - Anti-OX40 antibody in head and neck cancer patients
T-cell therapy NCT03578406 - HPV-E6-specific anti-PD1 TCR-T cells in the treatment of HPV-positive NHSCC or cervical cancer
HNSCC: head and neck squamous cell carcinoma; OPSCC: oropharynx squamous cell carcinoma; LA: locally advanced; HPV: human
papillomavirus

and there are multiple ongoing trials investigating vaccines in this subset (NCT03418480, NCT03260023,
NCT00257738, NCT02002182).

Both oncolytic viruses and vaccine therapy aim to promote a tumor specific adaptive immune response.
Additional novel therapeutics have also been developed to try to remove the inhibitory signals that
suppress an already active immune response.

One example of this strategy is the targeting of MDSCs, as multiple studies have shown these cells to be
present in high abundance in HNSCC [38,75] . In vivo studies have shown that elimination of MDSCs from the
[76]
tumor microenvironment results in decreased Tregs and increased activity of CTLs . As discussed above,
Arg, NOS, and IDO are thought to play a role in MDSC mediated Treg function; thus, drugs targeting these
pathways are of particular interest. Phosphodiesterase-5 inhibitors are known to reduce both NOS and Arg
production and a recent clinical trial leveraged the already FDA approved drug Tadalafil for use in HNSCC.
In this randomized, double blinded, placebo controlled trial, patients with previously untreated (primary or
recurrent) HNSCC received either tadalafil or placebo for 10 or more days prior to definite treatment. This
study revealed decreased MDSC and Treg populations in the tadalafil treated cohort compared to placebo
controls as well as increased CTL activity. Subgroup analysis of patients with available tumor specimens
[37]
(n = 6) demonstrated increased tumor specific immunity in the Tadalafil treated group . No measures of
survival outcomes were reported for this study. An additional clinical trial (NCT03689192) evaluating a
vaccine targeting arginase is also currently underway.

Inhibition of IDO in combination with Pembrolizumab has also been under intense study in various
[77]
malignancies . In HNSCC, a phase III clinical trial evaluating IDO inhibitor, Epacadostat in combination