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A randomized pilot trial testing the safety and immunologic effects of a MAGE-A3 protein plus AS15 immunostimulant administered into muscle or into dermal/subcutaneous sites

2015; Springer Science+Business Media; Volume: 65; Issue: 1 Linguagem: Inglês

10.1007/s00262-015-1770-9

1432-0851

Craig L. Slingluff, Gina R. Petroni, Walter C. Olson, Mark E. Smolkin, Kimberly A. Chianese‐Bullock, Ileana S. Mauldin, Kelly T. Smith, Donna H. Deacon, Nikole Varhegyi, Sean B. Donnelly, Caroline M. Reed, Kristy J. Scott, Nadejda V. Galeassi, William W. Grosh,

Immune Cell Function and Interaction

Methods to induce T cell responses to protein vaccines have not been optimized. The immunostimulant AS15 has been administered with the recombinant MAGE-A3 protein (recMAGE-A3) i.m. but not i.d. or s.c. This study tests hypotheses that the i.d./s.c. route is safe and will increase CD4+ and CD8+ T cell responses to MAGE-A3. Twenty-five patients with resected stage IIB-IV MAGE-A3+ melanoma were randomized to immunization with recMAGE-A3 combined with AS15 immunostimulant (MAGE-A3 immunotherapeutic) either i.m. (group A, n = 13) or i.d./s.c. (group B, n = 12). Adverse events were recorded. Ab responses to MAGE-A3 were measured by ELISA. T cell responses to overlapping MAGE-A3 peptides were assessed in PBMC and a sentinel immunized node (SIN) after 1 in vitro stimulation with recMAGE-A3, by IFN-γ ELISPOT assay and by flow cytometry for multifunctional (TNF-α/IFN-γ) responses. Both routes of immunization were well tolerated without treatment-related grade 3 adverse events. All patients had durable Ab responses. For all 25 patients, the T cell response rate by ELISPOT assay was 30 % in SIN (7/23) but only 4 % (1/25) in PBMC. By flow cytometry, multifunctional CD8+ T cell responses were identified in one patient in each group; multifunctional CD4+ T cell response rates for groups A and B, respectively, were 31 and 64 % in SIN and 31 and 50 % in PBMC. The MAGE-A3 immunotherapeutic was well tolerated after i.d./s.c. administration, with trends to higher CD4+ T cell response rates than with i.m. administration. This study supports further study of AS15 by i.d./s.c. administration.