RESUMEN
The ability to genetically modify T cells is a critical component to many immunotherapeutic strategies and research studies. However, the success of these approaches is often limited by transduction efficiency. As retroviral vectors require cell division for integration, transduction efficiency is dependent on the appropriate activation and culture conditions for T cells. Naive CD8(+) T cells, which are quiescent, must be first activated to induce cell division to allow genetic modification. To optimize this process, we activated mouse T cells with a panel of different cytokines, including interleukin-2 (IL-2), IL-4, IL-6, IL-7, IL-12, IL-15 and IL-23, known to act on T cells. After activation, cytokines were removed, and activated T cells were retrovirally transduced. We found that IL-12 preconditioning of mouse T cells greatly enhanced transduction efficiency, while preserving function and expansion potential. We also observed a similar transduction-enhancing effect of IL-12 preconditioning on human T cells. These findings provide a simple method to improve the transduction efficiencies of CD8(+) T cells.
Asunto(s)
Linfocitos T CD8-positivos/fisiología , Interleucina-12/farmacología , Virus de la Leucemia Murina de Moloney/genética , Transducción Genética , Animales , Proteínas del Linfoma 3 de Células B , Linfocitos T CD8-positivos/efectos de los fármacos , Células Cultivadas , Expresión Génica , Humanos , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Anticancer vaccines have been extensively studied in animal models and in clinical trials. While vaccination can lead to tumor protection in numerous murine models, objective tumor regressions after anticancer vaccination in clinical trials have been rare. B16 is a poorly immunogenic murine melanoma that has been extensively used in anticancer vaccination experiments. Because B16 has been widely used, different vaccination strategies can be compared. We reviewed the results obtained when B16 was treated with five common vaccine types: recombinant viral vaccines, DNA vaccines, dendritic cell vaccines, whole-tumor vaccines, and peptide vaccines. We also reviewed the results obtained when B16 was treated with vaccines combined with adoptive transfer of tumor antigen-specific T cells. We found several characteristics of vaccination regimens that were associated with antitumor efficacy. Many vaccines that incorporated xenogeneic antigens exhibited more potent anticancer activity than vaccines that were identical except that they incorporated the syngeneic version of the same antigen. Interleukin-2 enhanced the antitumor efficacy of several vaccines. Finally, several effective regimens generated large numbers of tumor antigen-specific CD8(+) T cells. Identification of vaccine characteristics that are associated with antitumor efficacy may aid in the development of more effective anticancer vaccination strategies.
Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Traslado Adoptivo , Animales , Ensayos Clínicos como Asunto , Células Dendríticas , Humanos , Melanoma Experimental/tratamiento farmacológico , Ratones , Vacunas de ADN/uso terapéutico , Vacunas de Subunidad/uso terapéutico , Vacunas Sintéticas/uso terapéutico , Vacunas Virales/uso terapéuticoRESUMEN
Leukemia is susceptible to immune-mediated therapies such as allogeneic stem-cell transplantation, donor lymphocyte infusion, and interferon. The clinical effectiveness of these immune-based modalities has encouraged interest in vaccine therapies for leukemia. Substantial progress has recently been made in basic immunology, allowing scientifically based vaccination strategies to be developed. The discovery of leukemia- specific and leukemia-associated antigens will allow antigen-specific therapeutic strategies to be developed. Vaccination with genetically modified leukemia cells and the use of dendritic cells in various vaccination approaches are all promising avenues of study for development of effective leukemia vaccines.