for future application of this technology in CTL mediated tumor immunotherapy

For future application of this technology in ctl

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for future application of this technology in CTL-mediated tumor immunotherapy. Initial application of Lm vaccines in tumor immunotherapy After confirming the potential of Lm -based vectors to induce robust CTL responses against foreign antigens, Paterson and colleagues applied this technology to the then nascent field of tumor immunotherapy ( Pan et al., 1995a ). Much like infected cells, tumor cells can be recognized and lysed by antigen-specific CTLs ( Freedman et al., 1972 ). Therefore, to assess the poten- tial for Lm -based vaccines to induce effective anti-tumor CTL responses, the team utilized the previously constructed Lm - NP vaccine strain along with tumor cell lines that expressed NP as a model tumor antigen ( Pan et al., 1995a ). When mice were vaccinated with the Lm -NP vaccine, it provided prophy- lactic protection against tumor formation after challenge. In addition, after first allowing for tumors to form and estab- lish, therapeutic intervention was effective at reducing tumor volume. This regression by Lm -NP correlated with infiltration of T cells into the tumor after vaccination and was abrogated after antibody-mediated depletion of T cells. A subsequent study by Jensen and colleagues also found Lm -based vaccines to be effective as a prophylactic against cottontail rabbit papilloma virus (CRPV) induced papillomas, a model for virus-induced malignant transformation ( Brandsma, 1994 ). After previous suc- cess generating virus-specific CTL responses with recombinant Lm , they developed a novel Lm strain expressing the CRPV E1 antigen, E1-r Lm , that induced cellular immune responses against E1 and protected the rabbits from papilloma forma- tion ( Shen et al., 1995; Slifka et al., 1996; Jensen et al., 1997 ). Therefore, the summation of these studies validated Lm as a viable platform for the delivery of TAAs in both a prophylactic and therapeutic setting. The promise demonstrated by these ini- tial vaccines resulted in the development of numerous Lm -based immunotherapies, many outlined in this review, that continues to this day. MECHANISMS OF Lm -BASED VACCINE VECTORS FOR TUMOR IMMUNOTHERAPY Early studies demonstrated the powerful potential of Lm -based immunotherapies for cancer but the mechanisms governing their efficacy are still under investigation. We describe, in detail below and depicted in Figure 2 , important advances in our understand- ing of Lm -based immunotherapy efficacy that continue to guide its development. ENHANCED PROCESSING AND PRESENTATION OF Lm -DELIVERED ANTIGENS The initial rationale for the use of Lm as a vaccine vector was to harness its ability to deliver antigens efficiently to both the MHC Class I and II presentation machinery and induce robust T-cell responses to Lm-derived antigens ( Naher et al., 1985; Lukacs and Kurlander, 1989; Brunt et al., 1990; Schafer et al., 1992; Hsieh et al., 1993 ). However, recent studies suggest that the robust CD8 + T cell responses to Lm -derived antigens are not simply due to proficient cytosolic delivery. In fact, Lm -derived antigens appear to be processed and presented on MHC Class I by a ded-

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