Protein release from gelatin matrices

DNA-polycation nanospheres as non-viral gene delivery vehicles

Biodegradable Polymers for Protein and Peptide Drug Delivery

Advances in our understanding of the molecular events of antigen recogni­ tion by T cells and T cell activation are opening up new approaches to cancer immunotherapy. The identification and cloning of cytokines provide one impor­ tant set of tools for manipulating immunologic responses. For cancer therapy, cytokines such as interleukin-2 have been administered systemically. However, systemic administration of cytokines ignores the paracrine nature of their ac­ tion. Recently, an alternative approach has been explored that produces high concentrations of cytokines local to the tumor cells. This is achieved either by transduction of the tumor cells the cytokine gene or by mixture of the tumor cells with cytokine containing biodegradable polymer microspheres. Under these circ umstances, the locally released cytokine produces a strong local inflammatory response specific to the particular cytokine. In some cases, a potent tumor-specific T cell response results, capable of mediating regression of systemi c tumor de­ posits. This paracrine delivery of cytokines can therefore be considered as a new type of adjuvant in the design of vaccines for cancer as well as microbial infections.

Paracrine Cytokine Adjuvants in Cancer Immunotherapy

Previously, we reported that killing tumor cells in vivo with the HSV thymidine kinase/ganciclovir system generates potent antitumor immunity, determined in part by the mechanism by which the cells die and by the levels of inducible heat shock protein (hsp) expression induced during the process of cell death. Here, we show that induction of hsp70 expression induces an infiltrate of T cells, macrophages, and predominantly dendritic cells (DCs) into the tumors as well as an intratumoral profile of Th1 cytokine expression (IFN-gamma, TNF-alpha, and IL-12) and enhances immunogenicity via a T cell-mediated mechanism. In addition, the protection conferred by hsp70 is both tumor and cell specific. We also demonstrate that hsp70 targets immature APC to make them significantly more able to capture Ags. This is likely to optimize cross-priming of the infiltrating APC with tumor Ags, which are simultaneously being released by the dying cells. In addition, using an Myc epitope-tagged hsp70 expression vector, we present evidence that hsp70 released from dying tumor cells is taken up directly into DCs and may, therefore, be involved in direct chaperoning of Ags into DCs. Taken together, our data suggest that hsp70 induction serves to signal the immune system of the presence of an immunologically relevant (dangerous) situation against which an immune reaction should be raised.

Heat shock protein 70 induced during tumor cell killing induces Th1 cytokines and targets immature dendritic cell precursors to enhance antigen uptake.

Experimental studies using murine tumor models have demonstrated that potent systemic immunity can be generated using tumor vaccines engineered by gene transfer to secrete certain cytokines. The underlying physiological principle behind these strategies involves the sustained release of high doses of cytokine at the site of the tumor. In some cases, this paracrine approach appears to enhance tumor antigen presentation and avoids systemic cytokine toxicity. The widespread clinical use of autologous cytokine gene transduced tumor vaccines may be limited by the technical difficulty and labor intensity of individualized gene transfer. We have therefore explored an alternate approach to generating sustained release of cytokines local to the tumor cells. High doses of granulocyte-macrophage colony-stimulating factor encapsulated in cell-sized gelatin-chondroitin sulfate microspheres were mixed with irradiated tumor cells prior to s.c. injection. This vaccination scheme resulted in systemic anti-tumor immune responses comparable to granulocyte-macrophage colony-stimulating factor gene transduced tumor vaccines.

https://cancerres.aacrjournals.org/content/canres/53/24/5841.full.pdf

Controlled Release, Biodegradable Cytokine Depots: A New Approach in Cancer Vaccine Design

Die kontrollierte freisetzung von pharmazeutisch aktiven substanzen in der immuntherapie

L'invention concerne un procede pour stimuler une reponse immunitaire systematique sur une cellule tumorale ou un antigene associe a un pathogene. Ce procede consiste a administrer un melange d'un vehicule a liberation controlee contenant un agent renforcant l'immunite et un antigene.

Rosa Azhari

Papers

Controlled Release, Biodegradable Cytokine Depots: A New Approach in Cancer Vaccine Design

Die kontrollierte freisetzung von pharmazeutisch aktiven substanzen in der immuntherapie

Liberation controlee de substances pharmaceutiquement actives pour l'immunotherapie