Background: Oropharyngeal HNSCCa is frequently associated with HPV. We hypothesize that immunotherapy with INO-3112 will generate immune responses in patients (pts) with HPV+ HNSCCa.
Methods: This Phase I/IIa trial included pts with p16+ locally advanced HNSCCa, ECOG PS 0-1. INO-3112 was delivered IM along with electroporation using the CELLECTRA® device, every 3 weeks x 4 doses. Cohort 1 (C1) pts received INO-3112 pre and post-surgery; Cohort 2 (C2) pts received INO-3112 post cisplatin-based definitive chemoradiation. Primary and secondary endpoints were safety and immunogenicity. Pre- and post INO-3112 tissue samples (C1) were assessed for tumor infiltrating lymphocytes (TILs) using immunohistochemistry for CD8, FoxP3, PD-L1 and Granzyme B. Peripheral immune responses were assessed by ELISA to measure HPV16/18 specific antibody levels, and by IFNg ELISpot to measure HPV16/18 specific T cell magnitudes at each dosing visit and every 3 months (mos).
Results: As of March 2017, 22 pts were treated, completing accrual. C1: n=6, C2: n=16; 20 male, median age 57.5 years (32-76); primary tumor location: base of tongue=10, tonsil=12; never smoker=10. All pts are alive, median follow up is 16.4 mos (1-26). INO-3112 was well-tolerated with no related Grade 3-5 adverse events. In 5 C1 pts post immunotherapy, an increase in CD8+ infiltration into tumor was noted in 2 pts (1.6-3.6 fold) and a decrease in FoxP3+ was noted in the other 3 (1.8-2.1 fold). This resulted in positive shift in CD8+/FoxP3+ ratio in neoplastic tissue in 4/5 pts. Furthermore, increased PD-L1 and granzyme B expression was noted in 3/5 subjects (one PD-L1 alone, one Granzyme B alone and one for both PD-L1 and Granzyme B). Peak mean/median antibody responses to HPV16 E7 and HPV18 E7 antigens for 19 evaluable pts were 1:1235/1:150 and 1:2853/1:450, respectively. As compared to baseline, 18 evaluable pts showed elevated HPV16/HPV18 specific T cell activity (by IFNɤ ELISpot), with peak mean/median responses of 179.99/68.33 SFU per 106 PBMC (HPV16) and 107.18/53.3 SFU per 106 PBMC (HPV18). Persistent cellular responses > 100 SFU/106 PBMC were noted out to 12 mos. 3 out of 22 pts have progressed; 1 pt received Nivolumab for progressive disease, and remains in complete response.
Conclusion: These data show that INO-3112 generates HPV-specific peripheral humoral and cellular immune responses that may persist out to 12 months and influences the composition of CD8+ and FoxP3+ immune infiltration into tumor tissue in HPV+ HNSCCa.