Summary Preferentially expressed antigen in melanoma (PRAME) and prostate-specific membrane antigen (PSMA) are tumor-associated antigens implicated in cellular differentiation, genetic stability, and angiogenesis. MKC1106-PP is an immunotherapeutic regimen cotargeting PRAME and PSMA, comprised of a recombinant plasmid (pPRA-PSM encoding fragments derived from both antigens) and 2 peptides (E-PRA and E-PSM derived from PRAME and PSMA, respectively). This multicenter study evaluated MKC1106-PP with a fixed plasmid dose and 2 different peptide doses, administered by intralymph node injection in a prime-boost sequence in human leukocyte antigen-A*0201 and tumor-antigen-positive patients with progressing metastatic solid tumors who had failed standard therapy. Immune monitoring was done by tetramer and enzymatic-linked immune spot analysis. The treatment was well tolerated, with no significant differences in safety, immune response, and clinical outcome relative to peptide doses. Fifteen of 24 evaluable patients showed an immune response, as defined by the expansion of PRAME-specific or PSMA-specific T cells in the blood. There were no partial or complete responses by the Response Evaluation Criteria in Solid Tumors. Seven patients showed stable disease (SD) for 6 months or longer, or prostate specific antigen decline: 4 of 10 with prostate carcinoma, 2 of 2 with renal clear cell carcinoma, and 1 of 10 with metastatic melanoma. In addition, there was an association between the induction and persistence of antigen-specific T cells in blood above baseline levels and disease control, defined as SD for 6 months or longer. These results support further development of MKC1106-PP in specific clinical indications.

Nineteen patients with stage IV melanoma were treated in an escalating dose, phase 1 trial of a DNA plasmid vaccine pSEM. The plasmid encoded T-cell epitopes from differentiation antigens Melan-A/melanoma antigen recognized by T cells (MART)-1 and tyrosinase, encompassing amino acids 26-35 and 31-70 from Melan-A/MART-1, and 1-9 as well as 369-377 from tyrosinase. End points of the trial were safety, tolerability, and melanoma antigen-specific immunity by tetramer assay. Intralymph nodal infusions of the vaccine were given 4 times, every 2 weeks over 96 hours each to groin lymph nodes. Vaccine doses were 500, 1000, and 1500 microg of DNA per infusion. Disease evaluation was performed 8 weeks after treatment initiation. The vaccine was well tolerated, with only grade I/II toxicity observed and no dose limiting toxicity at the highest dose of 1500 microg per infusion. Immune response defined prospectively was seen in 4/19 patients, and 5/19 had evidence of preexisting immunity to Melan-A/MART-1. No immune responses to tyrosinase was seen. There was a correlation between time to progression (TTP) and Melan-A/MART-1 immunity (preexisting or induced) for all patients. There was no association between TTP and immune competence assayed by ex vivo polyclonal stimulation of peripheral blood mononuclear cells. No clinical responses were seen. DNA plasmid pSEM vaccine was well tolerated when administered intranodally by 96-hour infusion to patients with stage IV melanoma, and was immunogenic, but did not induce regression of established disease. The association of TTP with preexisting or induced Melan-A immunity supports future attempts to induce potent immunity to this antigen.

Purpose: The goal of this study was to test the safety and activity of a therapeutic vaccine, MKC1106-MT, in patients with metastatic melanoma. Experimental Design: MKC1106-MT comprises a plasmid (pMEL-TYR) and two peptides (E-MEL and E-TYR), corresponding to Melan A and tyrosinase, administered by intra–lymph node injection in a prime-boost sequence. All 18 patients were HLA-A*0201 positive and received a fixed priming dose of plasmid and a low or a high peptide dose. Enumeration of antigen-specific T cells was done prior to and throughout the treatment. Patients who did not exhibit disease progression remained on study and could receive up to eight cycles of treatment. Results: The MKC1106-MT regimen was well tolerated and resulted in an overall immune response rate of 50%. The treatment showed disease control, defined as stable disease that lasted for 8 weeks or more in 6 of 18 (33%) of the patients: 14% and 46% in the low and high peptide dose, respectively. Interestingly, four patients, all with tumor burden largely confined to lymph nodes and Melan A–specific T cells at baseline, showed durable disease control associated with radiologic evidence of tumor regression. There was no noticeable correlation between the expansion of antigen-specific T cells in blood and the clinical outcome; yet, there was evidence of active tumor-infiltrating lymphocytes (TIL) in two regressing lesions. Conclusions: MKC1106-MT showed immunogenicity and evidence of disease control in a defined patient population. These findings support further development of this investigational agent and the concept of therapeutic vaccination in metastatic melanoma. Clin Cancer Res; 17(9); 2987–96. ©2011 AACR.

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