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The effectivenes of cancer vaccines in inducing CD8(+) T-cell responses remains a challenge, resulting in a need for testing more potent adjuvants. Our objective was to determine the safety and immunogenicity of vaccination against melanoma-related antigens employing MART-1, gp100, and tysosinase paptides combined with the TLR9 agonist PF-3512676 and local granulocyte macrophage-colony stimulating factor in oil emulsion. Using continuous monitoring of safety and a 2-stage design for immunologic efficacy, 20 immune response evaluable patients were targetted. Vaccinations were given subcutaneously on days 1 and 15 per cycle (1cycle=28 d) for up to 13 cycles. Interferon-γ enzyme-linked immunosorbent spot was used as the primary assay measuring the frequency of peripheral antigen-specific CD8(+) T cells at days 50 and 90 compared with baseline (target ≥ 9/20 immunologic responses). Clinical responses were measured by Response Evaluation Criteria In Solid Tumors every 8 weeks. Twenty-two (including 20 immune response evaluable) melanoma patients were enrolled. All had American Joint Committe on Cancer stage IV (5M1a, 6M1b, 11M1c) and most had previously received therapy. Eight had previously treated brain metastases. An average of 3.5 cycles of vaccination per patient was administered. Clinical response data were available for 21 patients. There were 2 partial response and 8 stable disease lasting 2-7 months. One patient with ongoing partial response continued on treatment. At a median follow-up of 7.39 months (range, 3.22-20.47 mo), median progression-free survival was 1.9 months (90% confidence interval, 1.84-3.68) and median overall survival was 13.4 months (90% confidence interval,11.3-∞). No regimen-related grade 3/4/5 toxicities were observed. There were 9/20 patients with positive enzyme-linked immunosorbent spot at day 50 and/or day 90. Our adjuvant regimen combining PF-3512676 and granulocyte macrophage-colony stimulating factor was safe and is worthy of further testing with these or alternative peptides, potentially in combination with antibodies that target immunoregulatory checkpoints.

A patient with metastatic melanoma who had progressive disease after prior surgical resections, high dose interleukin-2, and anti-cytotoxic T lymphocyte antigen-4 antibody received sequential treatments with autologous tumor infiltrating lymphocytes that recognized the gp100 melanocyte differentiation antigen. Although no clinical response was seen when cells were administered alone, an objective clinical response to therapy was seen with tumor infiltrating lymphocytes administered together with a highly immunogenic fowlpox vaccine expressing a gp100: 209-217 (210M) epitope. Persistence of the transferred antigen-specific lymphocytes in the peripheral blood was observed only after adoptive cell therapy plus administration of vaccine. Cell proliferation in vitro was further stimulated by additional vaccine and interleukin-2. The patient has an ongoing partial response at 10 months after the last treatment.

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

CRA9011 Background: In a phase II study, 13 (42%) of 31 patients with metastatic melanoma receiving high-dose (HD) IL-2 plus gp100:209–217(210M) peptide experienced objective responses (S.A. Rosenberg, et al, Nature Medicine 4: 321–327, 1998). Other studies showed a lower response rate (RR) but no randomized studies have been done. Methods: A prospective randomized phase III trial was conducted at 21 centers with 185 patients. Eligibility: stage IV or locally advanced stage III cutaneous melanoma, HLA A0201, no brain metastases, eligible for HD IL-2, and no previous HD IL-2 or gp100:209–217(210M). Arm 1 received HD IL-2 alone (720,000 IU/kg/dose) and Arm 2 gp100:209–217(210M) peptide + Montanide ISA followed by HD IL-2. The primary objective was clinical response. Secondary objectives were toxicity, disease free/progression free survival, immunologic response and quality of life. Central HLA typing, pathology review, and blinded response assessment were done at the NIH. Central data monitoring was done by The EMMES Corp. and a Data Safety Monitoring Board. Results: Numbers of patients enrolled, treated, and evaluable for response in Arm 1 were 94, 93, and 93 respectively; in Arm 2 91, 86, and 86. Toxicities were consistent with HD IL-2 ± vaccine. Investigator assessed RR showed significant improvement in overall RR for Arm 2=22.1% vs 9.7% (P=0.0223, Chi-Square) and progression free survival (PFS) in favor of Arm 2=2.9 months (1.7–4.5) vs 1.6 (1.5–1.8) (P=0.0101). Median overall survival favors Arm 2=17.6 months (11.8–26.6) vs 12.8 (8.7–16.3) (P=0.0964). Blinded response review is ongoing. Conclusions: RR and PFS were superior with peptide vaccine and HD IL-2 compared to HD IL-2 alone. This represents the first evidence of clinical benefit of vaccination in patients with melanoma. [Table: see text]

7502 Background: The role of peptides targeting multiple CD8 T cell epitopes of lineage antigens expressed in melanoma, and of systemic immunomodulators IFNα2b and GM-CSF have here been first evaluated in a multicenter cooperative group trial. Methods and Results: ECOG has completed accrual of 120 patients to a factorial 2 × 2 evaluation of vaccination q 2 weeks with three melanosomal peptides MGT, (A) alone, (B) +GM-CSF 250 mcg daily for 14/28 days each month or, (C) +IFNα2b10 MIU/M2 TIW (D) +both IFNα2b and GM-CSF. Candidates were PS 0,1 with normal organ functions, measurable disease and HLA-A2 expression. The primary endpoint of immune response has been measured by ELISPOT assay directly from the PBL without in vitro stimulation. Toxicities have been chiefly vaccine site discomfort, and expected IFNα2b and GM-CSF toxicity. ELISPOT assays are complete through month 3 for 71/120 cases. Immune response is documented in 26/71 evaluable pts (37%; 95% CI 25%–49%) with increase of ≥26 spots/50,000 T cells. A...