Abstract
Myeloid Derived suppressor cells (MDSCs) play a key role in the progression and recurrence of human malignancies and in restraining the efficacy of adjuvant therapies. We have previously shown that Tadalafil lowers MDSCs and regulatory T cells (Treg) in the blood and in the tumor, primes a tumor specific immune response, and increases the number of activated intratumoral CD8+T cells in patients with primary Head and Neck Squamous Cell Carcinoma (HNSCC). However, despite these important immune modulatory actions, to date no clinically significant effects have been reported following PDE5 inhibition. Here we report for the first time interim results of our ongoing phase I clinical trial (NCT02544880) in patients with recurrent HNSCC to evaluate the safety of and immunological effects of combining Tadalafil with the antitumor vaccine composed of Mucin1 (MUC1) and polyICLC. The combined treatment of Tadalafil and MUC1/polyICLC vaccine was well-tolerated with no serious adverse events or treatment limiting toxicities. Immunologically, this trial also confirms the positive immunomodulation of Tadalafil in patients with recurrent HNSCC and suggests an adjuvant effect of the anti-tumor vaccine MUC1/polyICLC. Additionally, image cytometry analysis of scanned tumors indicates that the PDE5 inhibitor Tadalafil in conjunction with the MUC1/polyICLC vaccine effectively reduces the number of PDL1+macrophages present at the tumor edge, and increases the number of activated tumor infiltrating T cells, suggesting reversion of immune exclusion. However, this analysis shows also that CD163 negative cells within the tumor upregulate PDL1 after treatment, suggesting the instauration of additional mechanisms of immune evasion. In summary, our data confirm the safety and immunologic potential of PDE5 inhibition in HNSCC but also point to PDL1 as additional mechanism of tumor evasion. This supports the rationale for combining checkpoint and PDE5 inhibitors for the treatment of human malignancies.
Highlights
The incidence of head and neck squamous cell carcinoma (HNSCC) has declined in the last 30 years but this remains a deadly disease with more than 550,000 cases and 380,000 deaths reported annually worldwide [1]
Underglycosylated MUC1 has been proposed as a tumor associated antigen in HNSCC, its expression in recurrent HNSCC has not been analyzed
This analysis supports the notion of underglycosylated MUC1 as a tumor specific antigen in patients with recurrent HNSCC
Summary
The incidence of head and neck squamous cell carcinoma (HNSCC) has declined in the last 30 years but this remains a deadly disease with more than 550,000 cases and 380,000 deaths reported annually worldwide [1]. Despite advances in diagnostic imaging, surgical ablative, and complex reconstructive techniques, radiation therapy, and chemotherapy, recurrence remains high and outcomes often poor for advanced stage disease. The lower probability of long-term cancer control, combined with higher toxicity of current treatment modalities in this setting (advanced stage recurrence at a fully treated site), often makes cure a less central, or even unachievable, goal of patient care. For patients with resectable recurrent tumor, surgical salvage remains the firstline and often only available treatment in previously irradiated patients. The addition of chemoradiotherapy as reirradiation to salvage surgery improved locoregional control and disease-free survival, no differences were observed in overall survival because of more treatment-related deaths, distant metastases, and second primary tumors among the re-irradiated patients [3]
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