International Award Lecture

Lack of effective therapies remains the biggest problem in the treatment of head and neck cancer (HNC). More recently, antibodies targeting the immune checkpoint molecule (anti-PD1) have been developed and approved for HNC. Although the clinical activity of PD1 inhibitors is promising, most patients remain unresponsive to this therapy with objective response rates of less than 20%. Additionally, emerging data is demonstrating that a significant subset of patients who initially responded to immune checkpoint inhibitors eventually relapsed after a period of response. One of the strategies to boost the immune response from immunotherapies is combining the immune checkpoint inhibitor with a tumor-associated antigen (TAA) vaccine. This will potentially lead to the generation of antigen-specific immune response that is more durable in eradicating cancer cells in patients. We have previously identified two immunogenic TAAs that were highly expressed in HNC patients. This has led to the generation of a DNA vaccine that incorporates the full-length DNA sequences of the two TAAs (DV). The objective of our study was to determine the preclinical efficacy of DV in combination with anti-PD1 by comparing tumor growth, survival, and immune profile in mice. As syngeneic HNSCC models are limited, we used a well characterized B16/F10 melanoma model that has been widely used for immunotherapy studies and is susceptible to checkpoint inhibitors including PD1 antibody. The B16/F10 is transfected with human HLA-A2, and the two target TAA constructs to mimic the expression of these antigens in HNC. This cell line was inoculated subcutaneously into a transgenic mouse model (B6.Cg-Tg(HLA-A/H2-D)2Enge/J) that carried a chimeric HLA-A2. Anti-PD1 treatment was given intraperitoneally at the lower abdomen every 3 days starting from day 3 post-cell inoculation and DV vaccination was performed intramuscularly at both thigh muscles on days 5 and 26 postcell inoculation. Tumor measurements were made every 3-4 days. Upon termination, spleen and tumor were harvested to study the presence of immune activation. We discovered that when DV and anti-PD1 were used as a combination, a significant tumor control is achieved as compared to single treatment and control groups, indicating a synergistic effect of DV with anti-PD1. Additionally, prolonged survival was observed in mice from the combination group. Noteworthy, the combination treated animals showed an increased in antigen-specific responses by the ELISPOT assay, suggesting the tumor control and prolonged survival is due to antigen-specific immune responses. In conclusion, the use of DV and anti-PD1 has shown great potential in the combinatorial approach of immunotherapeutic, in which the two agents work synergistically in controlling tumor growth in mice model.