RESUMEN
Whereas systemic IL12 is associated with potentially life-threatening toxicity, intratumoral delivery of IL12 through tavokinogene telseplasmid electroporation (tavo) is safe and can induce tumor regression at distant sites. The mechanism by which these responses are mediated is unknown but is presumed to result from a cellular immune response. In a phase II clinical trial of tavo (NCT01502293), samples from 29 patients with cutaneous melanoma with in-transit disease were assessed for immune responses induced with this treatment. Within the blood circulating immune cell population, we found that the frequencies of circulating PD-1+ CD4+ and CD8+ T cells declined with treatment. Circulating immune responses to gp100 were also detected following treatment as measured by IFNγ ELISpot. Patients with a greater antigen-specific circulating immune response also had higher numbers of CD8+ T cells within the tumor. Clinical response was also associated with increased intratumoral CD3+ T cells. Finally, intratumoral T-cell clonality and convergence were increased after treatment, indicating a focusing of the T-cell receptor repertoire. These results indicated that local treatment with tavo can induce a systemic T-cell response and recruit T cells to the tumor microenvironment.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Electroporación/métodos , Interleucina-12/uso terapéutico , Melanoma/inmunología , Melanoma/terapia , Plásmidos/administración & dosificación , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/terapia , Microambiente Tumoral/inmunología , Adyuvantes Inmunológicos/uso terapéutico , Antígenos de Neoplasias/inmunología , Biomarcadores/sangre , Biomarcadores/metabolismo , Humanos , Inmunidad Celular/efectos de los fármacos , Inmunoterapia/métodos , Interferón gamma/inmunología , Melanoma/metabolismo , Estadificación de Neoplasias , Seguridad del Paciente , Neoplasias Cutáneas/metabolismo , Resultado del Tratamiento , Melanoma Cutáneo MalignoRESUMEN
Inexpensive retinyl acetate has been subjected to transesterification followed by allylic oxidation to give retinal in 98% yield as a 92:8 mixture of all-trans/13-cis isomers after chromatographic separation. More convenient methods of isolating the all-trans isomer have also been employed.