Cellular immunotherapy: a clinical state-of-the-art of a new paradigm for cancer treatment.

Cancer immunotherapy has opened a new chapter in Medical Oncology. Many novel therapies are under clinical testing and some have already been approved and implemented in cancer treatment protocols. In particular, cellular immunotherapies take advantage of the antitumor capabilities of the immune system. From dendritic cell-based vaccines to treatments centered on genetically engineered T cells, this form of personalized cancer therapy has taken the field by storm. They commonly share the ex vivo genetic modification of the patient's immune cells to generate or induce tumor antigen-specific immune responses. The latest clinical trials and translational research have shed light on its clinical effectiveness as well as on the mechanisms behind targeting specific antigens or unique tumor alterations. This review gives an overview of the clinical developments in immune cell-based technologies predominantly for solid tumors and on how the latest discoveries are being incorporated within the standard of care.

Dendritic cells phenotype fitting under hypoxia or lipopolysaccharide; adenosine 5'-triphosphate-binding cassette transporters far beyond an efflux pump.

This study examines adenosine 5'-triphosphate-binding cassette (ABC) transporters as a potential therapeutic target in dendritic cell (DC) modulation under hypoxia and lipopolysaccharide (LPS). Functional capacity of dendritic cells (DCs) (mixed lymphocyte reaction: MLR) and maturation of iDCs were evaluated in the presence or absence of specific ABC-transporter inhibitors. Monocyte-derived DCs were cultured in the presence of interleukin (IL)-4/granulocyte-macrophage colony-stimulating factor (GM-CSF). Their maturation under hypoxia or LPS conditions was evaluated by assessing the expression of maturation phenotypes using flow cytometry. The effect of ABC transporters on DC maturation was determined using specific inhibitors for multi-drug resistance (MDR1) and multi-drug resistance proteins (MRPs). Depending on their maturation status to elicit T cell alloresponses, the functional capacity of DCs was studied by MLR. Mature DCs showed higher P-glycoprotein (Pgp) expression with confocal microscopy. Up-regulation of maturation markers was observed in hypoxia and LPS-DC, defining two different DC subpopulation profiles, plasmacytoid versus conventional-like, respectively, and different cytokine release T helper type 2 (Th2) versus Th1, depending on the stimuli. Furthermore, hypoxia-DCs induced more B lymphocyte proliferation than control-iDC (56% versus 9%), while LPS-DCs induced more CD8-lymphocyte proliferation (67% versus 16%). ABC transporter-inhibitors strongly abrogated DC maturation [half maximal inhibitory concentration (IC50 ): P-glycoprotein inhibition using valspodar (PSC833) 5 µM, CAS 115104-28-4 (MK571) 50 µM and probenecid 2·5 µM], induced significantly less lymphocyte proliferation and reduced cytokine release compared with stimulated-DCs without inhibitors. We conclude that diverse stimuli, hypoxia or LPS induce different profiles in the maturation and functionality of DC. Pgp appears to play a role in these DC events. Thus, ABC-transporters emerge as potential targets in immunosuppressive therapies interfering with DCs maturation, thereby abrogating innate immune response when it is activated after ischaemia.

Inmunoterapia en el melanoma maligno diseminado / Immunotherapy of diseminated malignant melanoma

Se ha demostrado que la quimioterapia es incapaz de aumentar la supervivencia de los enfermos de melanoma metastásico, cuya media de supervivencia es de 6-9 meses. Las observaciones, tanto clínicas como de laboratorio, sugirieron que la respuesta inmunitaria podía influenciar el curso de esta enfermedad y estimularon la utilización de modificadores de la respuesta biológica en su tratamiento. Las estrategias inmunoterapéuticas ya probadas en clínica que se han mostrado más eficaces son: las citocinas recombinantes solas o combinadas con agentes quimioterapéuticos (bioquimioterapia), las vacunas terapéuticas y la infusión de células antitumorales. Es muy difícil establecer comparaciones sobre la eficacia de las distintas pautas inmunoterapéuticas publicadas, debido a las diferencias existentes en la composición de los grupos de enfermos en cada estudio (número y ubicación de las metástasis). En conjunto, los tratamientos con dosis altas de IL-2, de IFN- 2 y bioquimioterapia, han proporcionado incrementos modestos de la supervivencia de estos enfermos , hasta los 9-11 meses, pero lo más destacable es que entre un 4 y un 10 por ciento de los enfermos así tratados, lograron alcanzar remisiones completas y de larga duración. El aspecto negativo de estos tratamientos, es que conllevan una toxicidad muy elevada, que limita su aplicabilidad. Las vacunas terapéuticas son mucho menos tóxicas, pero solamente son efectivas cuando la masa tumoral es pequeña. Empleando vacunas terapéuticas, el grupo de Morton y cols. logró incrementar la media de supervivencia de los enfermos metastásicos hasta los 23 meses. La utilización de células dendríticas "cargadas" con antígenos de melanoma, es prometedora, pero es necesario optimizar diversos aspectos de su preparación. De forma similar, es preciso encontrar un método práctico de preparación de las proteínas autólogas de estrés térmico. Finalmente, no ha sido posible demostrar la eficacia clínica de la infusión de células con probada actividad antitumoral in vitro. (AU)