Abstract CT143: A phase I/II trial of cetuximab in combination with interleukin-12 administered to patients with unresectable primary or recurrent squamous cell carcinoma of the head and neck
Authors: McMichael Elizabeth , Campbell Amanda , Duggan Megan , Noel Tiffany , Davis Melanie , Opheim Kallan , Levine Kala , Atwal Lakhvir , Olaverria Salavaggione Gonzalo , Gansu Akansha , Uppati Sarvani , Paul Bonnie , Olencki Thomas , Teknos Theodoros , Savvides Panayiotis , Liu Stephen , Carson William 
Published: July 2016

Abstract
Introduction: Preclinical investigations demonstrated that IL-12 significantly enhances the lytic actions and cytokine production of NK cells against cetuximab-coated HER1-positive SCCHN cell lines via synergistic activation of the MAP kinase pathway regardless of tumor cell HPV infection status. This phase I/II trial evaluated the combination of IL-12 with cetuximab to enhance NK cell effector mechanisms in patients with unresectable primary or recurrent squamous cell carcinoma of the head and neck.
Patients/Methods: The phase I dose escalation portion of the trial included 6 patients that received 500 mg/m2 cetuximab i.v. on day 1 of a 2 week cycle with either 0.2 mcg/kg or 0.3 mcg/kg IL-12 given s.c. on days 2 and 5 of the 2 week cycle, beginning with cycle 2. The phase II portion of the trial included 17 patients that received a combination of 500 mg/m2 cetuximab i.v. plus 0.3 mcg/kg IL-12 s.c. (MTD) following the phase I schema. Correlative immune studies using patient blood and plasma obtained prior to and during therapy included measurement of antibody-dependent cytotoxicity (ADCC), serum cytokine analysis, determination of NK cell FcγRIIIa polymorphisms, and myeloid derived suppressor cell (MDSC) frequency.
Results: 23 patients with unresectable primary or recurrent SCCHN were accrued (22 male, 1 female, avg. age 60.2 yrs). The combination therapy was well tolerated. Grade 4 AST and ALT increase was the only adverse event reported in the phase I portion which accrued 6 patients. The MTD was determined to be 0.3 mcg/kg s.c. 15 patients achieved stable disease for an average of 35 weeks (range 6-87). 60% of patients showed heightened ADCC from a baseline reading by the end of cycle 4, averaging an increase of 8.6% lysis. but there was not correlation with overall survival. Patients with progression-free survival (PFS) greater than 100 days showed an increased secretion of IFNγ, IP-10, MIP-1α, and TNF-α in sera from baseline to end of cycle 5, increasing by 81.7%, 53.3%, and 29.6% respectively. 6 patients carried the VV high affinity NK cell FcγRIIIa polymorphism, and PBMCs from these patients were able to better lyse cetuximab-coated SCCHN tumor cells compared to 10 patients with the FF low affinity receptor (25.7% lysis compared to 5.4% lysis at the 25:1 E:T ratio). MDSCs comprised an average of 5.3% of circulating cells. An analysis of MDSC incidence revealed that 15 of 23 majority of patients had a greater percentage of the monocytic subset of MDSCs versus the granulocytic MDSC subset, and these patients achieved an average of 28 weeks of progression free survival (PFS), compared to 13 week PFS in patients with a higher granulocytic MDSC population.
Conclusions: These findings suggest that the addition of IL-12 to cetuximab may lead to enhanced efficacy through the induction of anti-tumor immunity.
Citation Format: Elizabeth McMichael, Amanda Campbell, Megan Duggan, Tiffany Noel, Melanie Davis, Kallan Opheim, Kala Levine, Lakhvir Atwal, Gonzalo Olaverria Salavaggione, Akansha Gansu, Sarvani Uppati, Bonnie Paul, Thomas Olencki, Theodoros Teknos, Panayiotis Savvides, Stephen Liu, William Carson. A phase I/II trial of cetuximab in combination with interleukin-12 administered to patients with unresectable primary or recurrent squamous cell carcinoma of the head and neck. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT143.