Trial to evaluate the immunogenicity and safety of a melanoma helper peptide vaccine plus incomplete Freund’s adjuvant, cyclophosphamide, and polyICLC (Mel63)

• DOI: 10.1136/jitc-2020-000934
• Publication Date: 2021-01-21T16:16:26Z
• Authors: Craig L Slingluff...; Gina R Petroni; Kimberly A Chiane...; Nolan A Wages; Walter C Olson; Kelly T Smith; Kathleen Haden; Lynn T Dengel; Anna Dickinson; Caroline Reed; Elizabeth M Gaughan; William W Grosh; Varinder Kaur; Nikole Varhegyi; Mark Smolkin; Nadejda V Galeassi; Donna Deacon; Emily H Hall
• Keywords: CD4-Positive T-Lymphocytes; Male; Freund's Adjuvant; Administration, Oral; Cancer Vaccines; T-Lymphocytes, Regulatory; Antibodies; 03 medical and health sciences; 0302 clinical medicine; Humans; Polylysine; Cyclophosphamide; Melanoma; RC254-282; Neoplasm Staging; Clinical/Translational Cancer Immunotherapy; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; 16. Peace & justice; Combined Modality Therapy; Lipids; 3. Good health; Poly I-C; Treatment Outcome; Carboxymethylcellulose Sodium; Administration, Metronomic; Vaccines, Subunit; Female

BackgroundPeptide vaccines designed to stimulate melanoma-reactive CD4+ T cells can induce T cell and antibody (Ab) responses, associated with enhanced overall survival. We hypothesized that adding toll-like receptor 3 agonist polyICLC to an incomplete Freund’s adjuvant (IFA) would be safe and would support strong, durable CD4+ T cell and Ab responses. We also hypothesized that oral low-dose metronomic cyclophosphamide (mCy) would be safe, would reduce circulating regulatory T cells (T-regs) and would further enhance immunogenicity.Participants and methodsAn adaptive design based on toxicity and durable CD4+ T cell immune response (dRsp) was used to assign participants with resected stage IIA-IV melanoma to one of four study regimens. The regimens included a vaccine comprising six melanoma peptides restricted by Class II MHC (6MHP) in an emulsion with IFA alone (Arm A), with IFA plus systemic mCy (Arm B), with IFA+ local polyICLC (Arm C), or with IFA+ polyICLC+ mCy (Arm D). Toxicities were recorded (CTCAE V.4.03). T cell responses were measured by interferon γ ELIspot assay ex vivo. Serum Ab responses to 6MHP were measured by ELISA. Circulating T-regs were assessed by flow cytometry.ResultsForty-eight eligible participants were enrolled and treated. Early data on safety and dRsp favored enrollment on arm D. Total enrollment on Arms A-D were 3, 7, 6, and 32, respectively. Treatment-related dose-limiting toxicities (DLTs) were observed in 1/7 (14%) participants on arm B and 2/32 (6%) on arm D. None exceeded the 25% DLT threshold for early closure to enrollment for any arm. Strong durable T cell responses to 6MHP were detected ex vivo in 0%, 29%, 67%, and 47% of participants on arms A-D, respectively. IgG Ab responses were greatest for arms C and D. Circulating T-regs frequencies were not altered by mCy.Conclusions6MHP vaccines administered with IFA, polyICLC, and mCy were well tolerated. The dRsp rate for arm D of 47% (90% CI 32 to 63) exceeded the 18% (90% CI 11 to 26) rate previously observed with 6MHP in IFA alone. Vaccination with IFA+ polyICLC (arm C) also showed promise for enhancing T cell and Ab responses.