Abstract 5514: Safety and immunogenicity of vaccination with MART-1 (27-35), gp100 (209-217, 210M), and tyrosinase (368-376, 370D) peptides given in-oil-adjuvant with TLR-9 agonist PF-3512676 and GMCSF for HLA-A2+ patients with inoperable stage III or stage IV melanoma
Authors: Tarhini Ahmad A. , Leng Siyang , Schlesselman James J. , Lin Yan X. , Gooding William E. , Moschos Stergios , Yin Yan , Sander Cynthia , Kirkwood John M. 
Published: June 2012

Abstract
Purpose: Although promising, the induction of potent CD8+ T cell responses by tumor vaccines remains a major challenge. There remains an urgent need for improved tumor immunization employing more potent immunological adjuvants. Our research objective is to determine the safety and immunogenicity of vaccination emplying a potent adjuvant PF-3512676 and local GMCSF in-oil with peptides of three well characterized lineage antigens.
Experimental Procedures: Using continuous monitoring of safety along with a two-stage design for immunological efficacy, up to 20 immune-response evaluable patients were planned to be enrolled. ELIspot is used as the primary immunologic assay. Based on E1696 trial, our objective was to increase the response rate to ≥60%. Provided toxicity is acceptable, 10 patients were to be enrolled in stage 1. With 4 or more “responses”, an additional 10 patients were to be enrolled in stage 2. (Design characteristics: α = 0.098 one sided test; power = 91%; 65% chance of stopping by the end of stage 1 if the underlying immunologic response rate is only 30%). Clinical activity was measured by RECIST. A secondary component was to define the maturation compartment for antigen-reactive T cells by flow cytometry as this was hypothesized to be influenced by PF-3512676 and GM-CSF.
Results: The first stage has been completed with 12 subjects enrolled. Patients’ age range was 38-74, 9 had cutaneous primary and 3 unknown, 3M1a, 4M1b, 5M1c, 8 male and 4 female, ECOG PS 1(11) and 0(1). All had prior treatment and 5 had history of treated brain metastases. Two patients had only baseline blood collected for immune monitoring and therefore were not evaluable for the primary immune monitoring endpoint. Both had disease progression (PD). Among the 10 subjects immunologically evaluable (3M1a, 4M1b, 3M1c, 7 cutaneous and 3 unknown primary), 1 had partial response (PR) by RECIST, 4 stable disease (SD), 5 PD. Median OS was 523 days (90%CI=344,-), median PFS was 112 days (90%CI=55, 165). Five out of 10 subjects had +ve peripheral immune response by ELIspot (number of reactive CD8+ T cells against any of the HLA A2-restricted peptides MART-1, gp100, and tyrosinase doubles as compared to baseline, and for which the increment is at least 10 spots). Elispot positive patients included 1PR, 1SD, 3PD. ELIspot negative included 3SD, 2PD. The treatment was safely administered in all patients and there were no grade 3 or higher regimen-related adverse events.
Conclusion: This study has met the primary immunologic response endpoint at completion of stage I accrual, demonstrating successful immunization of at least 4 out of 10 subjects. Treatment in stage II continues with the full data expected to be presented at the AACR meeting.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5514. doi:10.1158/1538-7445.AM2011-5514