RESUMEN
Direct injection of therapies into tumors has emerged as an administration route capable of achieving high local drug exposure and strong anti-tumor response. A diverse array of immune agonists ranging in size and target are under development as local immunotherapies. However, due to the relatively recent adoption of intratumoral administration, the pharmacokinetics of locally-injected biologics remains poorly defined, limiting rational design of tumor-localized immunotherapies. Here we define a pharmacokinetic framework for biologics injected intratumorally that can predict tumor exposure and effectiveness. We find empirically and computationally that extending the tumor exposure of locally-injected interleukin-2 by increasing molecular size and/or improving matrix-targeting affinity improves therapeutic efficacy in mice. By tracking the distribution of intratumorally-injected proteins using positron emission tomography, we observe size-dependent enhancement in tumor exposure occurs by slowing the rate of diffusive escape from the tumor and by increasing partitioning to an apparent viscous region of the tumor. In elucidating how molecular weight and matrix binding interplay to determine tumor exposure, our model can aid in the design of intratumoral therapies to exert maximal therapeutic effect.
Asunto(s)
Colágeno/genética , Inmunoterapia/métodos , Interleucina-2/farmacología , Melanoma Experimental/terapia , Receptores Inmunológicos/genética , Neoplasias Cutáneas/terapia , Aloinjertos , Animales , Proteínas Portadoras/genética , Proteínas Portadoras/inmunología , Línea Celular Tumoral , Colágeno/inmunología , Femenino , Biblioteca de Genes , Inyecciones Intralesiones , Interleucina-2/genética , Interleucina-2/inmunología , Interleucina-2/farmacocinética , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/genética , Melanoma Experimental/mortalidad , Ratones , Ratones Endogámicos C57BL , Péptidos/genética , Péptidos/inmunología , Tomografía de Emisión de Positrones , Unión Proteica , Ingeniería de Proteínas/métodos , Receptores Inmunológicos/inmunología , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Albúmina Sérica/genética , Albúmina Sérica/inmunología , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/mortalidad , Análisis de Supervivencia , Carga Tumoral/efectos de los fármacosRESUMEN
The clinical application of cytokine therapies for cancer treatment remains limited due to severe adverse reactions and insufficient therapeutic effects. Although cytokine localization by intratumoral administration could address both issues, the rapid escape of soluble cytokines from the tumor invariably subverts this effort. We find that intratumoral administration of a cytokine fused to the collagen-binding protein lumican prolongs local retention and markedly reduces systemic exposure. Combining local administration of lumican-cytokine fusions with systemic immunotherapies (tumor-targeting antibody, checkpoint blockade, cancer vaccine, or T cell therapy) improves efficacy without exacerbating toxicity in syngeneic tumor models and the BrafV600E /Ptenfl/fl genetically engineered melanoma model. Curative abscopal effects on noncytokine-injected tumors were also observed as a result of a protective and systemic CD8+ T cell response primed by local therapy. Cytokine collagen-anchoring constitutes a facile, tumor-agnostic strategy to safely potentiate otherwise marginally effective systemic immunotherapies.