""""""""Our goal is to develop anti-cancer vaccines based on recombinant and synthetic forms of tumor associated antigens (TAA) recognized by immune cells. We have focused our efforts on developing vaccines for the treatment of patients with metastatic cancer by using mouse models. Our approach is """"""""""""""""reductionistic"""""""""""""""" in that it is based on an understanding of the interactions between the immune system and tumor cells on a molecular level. This approach is possible because TAA have now been cloned."""""""" """"""""Although a widely efficacious tumor vaccine is not yet available, a great deal of progress has been made in the development of effective cancer vaccines, especially those designed to treat metastatic malignant melanoma. The success of vaccines designed to target melanocyte differentiation antigens that are expressed by melanoma cells may require an understanding of the mechanisms behind breaking tolerance to """"""""""""""""self"""""""""""""""" antigens that has for the most part been obtained from experiments in mice. To explore the immunological effects of the """"""""""""""""self"""""""""""""""" nature of melanocyte differentiation antigens, we have developed a new set of models that employ the mouse homologs for melanocyte differentiation antigens. Like their human counterparts, the mouse homologs are expressed in normal melanocytes from unmanipulated C57BL/6 mouse as well as in mouse melanomas. In one system designed to model the human situation with more fidelity, mouse gp100 was cloned from the spontaneous B16 mouse melanoma and evaluated the functional characteristics of mouse gp100-reactive T cells in the recognition and destruction of B16 in vivo. Autoreactive T cells have been induced and the epitope within the mouse gp100 molecule, as well as the restricting MHC class I molecule, have been identified. Using the mouse gp100 model, it is clear that immunogens containing a """"""""""""""""self"""""""""""""""" peptide with enhanced binding to its restricting MHC class I molecule can be more effective in the elicitation of auto-reactive T cells."""""""" """"""""We have used mouse models to evaluate large panels of molecularly defined adjuvants. They have revealed that interleukins (IL) -2 and -12 are extremely potent in its ability to increase the efficacy of cancer vaccines. Other key non-cytokine immunomodulators include key molecules involved in co-stimulation. One of these, CD40 and its ligand, a member of the TNF family, naturally forms homotrimers shown to be important in B cell activation, the production of Type 1 cytokines by T helper cells and in the generation of cytotoxic memory responses. We have found that the addition of CD40L trimer to DNA vaccination can significantly increase anti-tumor efficacy in mice. FLT3 ligand can induce the apparent growth and differentiation of functional dendritic cells and has been reported to have anti-tumor effects but its role, if any, in the augmentation of recombinant and synthetic anti-cancer vaccines has yet to be demonstrated in experimental models (our own unpublished data)."""""""" The most well defined costimulators for T cells remain B7-1 (CD80) and B7-2 (CD86) which can be induced on antigen presenting cells (APC). Whether B7 family molecules trigger the activation or inhibition is dependent on its interaction with molecules on the T cell: engagment of CD28 is associated with proliferation and differentiation while and encounter with CTLA-4 may trigger functional unresponsiveness. The blockade of the engagement of CTLA-4 has been reported to potentiate immune responses to tumor cells. """"""""Despite advances in the development of new immunotherapies, many patients do not respond favorably to vaccination leading many to speculate that tumors may actively evade immune destruction. Examples of tumor escape from treatment are well known from the field of chemotherapy and include the induction of the expression of the multi-drug resistance gene. It was recently been reported that Fas ligand (FasL/CD95L) expression by melanoma cells was also involved in immune escape. FasL expression has been reported in areas of immune privilege such as the eye and testis. Some authors argued that expression of FasL by melanoma cells indicated that the tumor bed was also an """"""""""""""""immune privileged"""""""""""""""" site. To investigate the expression of FasL by melanomas, a panel of early passage cell lines were screened. None of the 19 human melanoma lines we tested killed the Fas+ targets in a sensitive functional assay. Furthermore, none of the 26 human melanoma cell lines expressed FasL mRNA as evaluated by RT-PCR. Thus, our unpublished data do not support a role for FasL expression in the escape of melanoma cells from immune destruction. Nevertheless, there is abundant evidence from our laboratory and others that melanoma cells do escape immune recognition by a variety of mechanisms. For example, we have observed and previously reported on the selective loss of b2-microglobulin, MHC class I expression and loss of antigen processing capability."""""""" """"""""We have focused our efforts in vector delivery on """"""""""""""""naked"""""""""""""""" plasmid DNA (ie. DNA without a viral coat) because they are relatively safe and easy to engineer. However, because they are generally not as potent as recombinant viruses at eliciting immune responses capable of destroying tumors, we have focused on improving the efficacy of DNA vaccines. Most recently, we have made great progress in the development of """"""""""""""""self-replicating"""""""""""""""" nucleic acid-based immunogens. We have used these immunogens in the treatment of established tumors expressing experimental antigens in mice. We continue to improve the function of recombinant anti-cancer vaccines in the laboratory with the goal of translating these findings into clinical trials.""""""""
Showing the most recent 10 out of 23 publications
