The Technology
Adoptive T cell therapy has the potential to enhance antitumor immunity, augment vaccine efficacy, and limit graft-versus-host disease. One strategy is the idea of activating and re-directing endogenous T cells, and one way to do this is to use bispecific antibodies (BsAb) comprising anti-CD3 and anti-tumor antigen moieties. Unfortunately, this is frequently associated with severe toxicity due to the release of a plethora of inflammatory cytokines. A refinement of this strategy is to retarget an existing population of CTL of a single specificity, such as for a particular viral antigen. This has the great potential advantage in that it avoids the use of anti-CD3 which is non-discriminatory in terms of T-cell recruitment and can trigger cells which are not helpful as effectors but which contribute to the cytokine release syndrome which hamper this approach. Recent studies in mice using the MHC targeting approach applied to the murine system indeed indicated that the MHC targeting approach is less toxic and that mice bearing tumors did not exhibit the cytokine syndrome compared to the bi-specific CD3 construct. The toxicity imposed by the CD3 bi-specific approach due to the cytokine burst induced by global T cell recruitment does not only force toxicity issues and administration problems (continuous infusion of very low doses is required to control toxicity) but also limits the maximal tolerated dosage (MTD) of the drug. To overcome the above limitations, the research lab created a novel therapeutic strategy that recruits potent effector CD8+ T cells to the tumor site by a newly designed fusion protein that is composed of a tumor-targeting antibody fused to a class I human HLA molecule that carries a potent immunogenic peptide such as a viral-derived epitope. Using this approach, the research lab previously shown that a single chain antibody fused to a human MHC (HLA 2A) complex with viral peptides, is able to recruit CD8 T cells and inhibit the growth human cancer xenografts in Nude mice that received specific CD8 T cell lines by adoptive cell transfer. This innovative scientific approach aims to overcome immune tolerance of tumors and elicit specific and potent tumor immunity by targeted recruitment of an allogeneic T cell response through antibody-mediated targeting of mismatches class I MHC-peptide complexes to the tumor site.
Advantages
- Recruitment or engagement of a highly potent allogeneic T cell response for tumor rejection
- Facilitating the potent allogeneic tumor rejection response in a tumor and site-specific manner
Applications and Opportunities
- Cancer immunotherapy
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