A phase I dose escalation trial of MAGE-A3- and HPV16-specific peptide immunomodulatory vaccines in patients with recurrent/metastatic (RM) squamous cell carcinoma of the head and neck (SCCHN)

Abstract

Background: We conducted a phase I dose escalation study to evaluate the safety and immunologic response to peptide immunomodulatory vaccines GL-0810 (HPV16) and GL-0817 (MAGE-A3) in HPV16 and MAGE-A3-positive RM-SCCHN patients, respectively.

Methods: Three dose levels (500, 1,000, and 1,500 µg) of GL-0810 or GL-0817 with adjuvants Montanide (1.2 ml) and GM-CSF (100 µg/m2) were administered subcutaneously q2 weeks for a total of four vaccinations in HPV16 and MAGE-A3-positive RM-SCCHN patients, respectively.

Results: Nine and seven patients were enrolled in the HPV16 and MAGE-A3 cohorts, respectively. No dose-limiting toxicities were observed, and toxicity was predominantly local and grade 1 (erythema, pain, and itching at the injection site). In those patients who received all four vaccinations, 80 % (4/5) of the HPV16 cohort and 67 % (4/6) of the MAGE-A3 cohort developed antigen-specific T cell and antibody responses to the vaccine. Significant concordance between T cell and antibody responses was observed for both groups. No clear dose-response correlation was seen. All patients progressed by RECIST at first repeat imaging, except for one patient in the MAGE-A3 500 µg cohort who had stable disease for 10.5 months. The median PFS and OS for the MAGE-A3 cohorts were 79 and 183 days, respectively, and for the HPV16 cohort 80 and 196 days, respectively.

Conclusions: GL-0810 and GL-0817 were well tolerated in patients with RM-SCCHN with T cell and antibody responses observed in the majority of patients who received all four vaccinations.

Fig. 1

Consort diagram

Fig. 2

ELISPOT and ELISA results from HPV16-positive patients who had a response to vaccine. ELISPOT Assay: Collection of peripheral blood mononuclear cells (PBMCs) occurred before and after vaccination at time points shown in Figure 2. T cell reactivity measurements were carried out against human papillomavirus (HPV16)—Trojan- and individual Trojan-specific HLA class I (HPV–CTL) and Class II (HPV–HTL) using interferon-γ (IFN-γ) ELISPOT assays. Control values are shown without subtraction from experimental values. ELISPOT assays were performed with in vitro stimulation. Number of spots per 100,000 PBMCs is shown on the Y-axis. Antigen concentration was 10 μg/ml. Due to variation in response, some figures contain different increments for the Y-axis. ELISA Assay: HPV16-Trojan-specific immunoglobulin G (IgG) antibody response was evaluated before and after vaccination at time points shown in Figure 2. Absorbance data on the Y-axis represent mean optical density (OD) results from triplicate wells from three different plasma dilutions. a HPV16 500 µg cohort. b HPV16 1,000 µg cohort. c HPV16 1,500 µg cohort. *Patient 003 did not have a T cell response

Fig. 3

ELISPOT and ELISA results from MAGE-A3-positive patients who had a response to vaccine. ELISPOT Assay: Collection of peripheral blood mononuclear cells (PBMCs) occurred before and after vaccination at time points shown in Figure 3. T cell reactivity measurements were carried out against MAGE-A3—Trojan- and individual Trojan-specific HLA class I (MAGE–CTL) and Class II (MAGE–HTL) using interferon-γ (IFN-γ) ELISPOT assays. Control values are shown without subtraction from experimental values. ELISPOT assays were performed with in vitro stimulation. Number of spots per 100,000 PBMCs is shown on the Y-axis. Antigen concentration was 10 μg/ml. Due to variation in response, some figures contain different increments for the Y-axis. ELISA Assay: MAGE-A3-Trojan-specific immunoglobulin G (IgG) antibody response was evaluated before and after vaccination at time points shown in Figure 3. Absorbance data on the Y-axis represent mean optical density (OD) results from triplicate wells from three different plasma dilutions. a MAGE-A3 500 µg cohort. b MAGE-A3 1,000 µg cohort. c MAGE-A3 1,500 µg cohort. *Patient 004 did not have a T cell response