Immunotherapy is the modulation of a patient's immune system to treat illness. Unfortunately many T cell based attempts have failed due to the fact that existing tumor-specific T cells are mostly anergic or tolerized and ex vivo generated T cells are often exhausted secondary to repetitive stimulation. A promising alternative approach includes bispecific antibody technology to redirect non-tumor specific T cells to kill tumors. This has been accomplished through use of the conserved TCR CD3 complex and an antibody specific to the tumor to redirect T cells to kill tumors. Here we propose a novel nanoparticle based approach to selectively recruit antigen-specific cytotoxic T cells and re-direct them to kill tumors, termed ATR (Antigen-specific T cell Redirectors). The long-term goal is to develop these new platform technologies to redirect antigen-specific T cells. Our objective here is to develop prototypic nanoparticle based systems to mediate redirected lysis by both murine and human antigen-specific cytotoxic T lymphocytes, CTL, to kill tumor cells that otherwise would not be recognized. Our central hypothesis is that ATR nanoparticles decorated with HLA-Ig, or MHC-Ig, and anti-tumor specific antibodies can be used to replace current approaches for redirected lysis by T cells. The rationale for the proposed research is that this knowledge can then be used to devise new innovative immunotherapeutic approaches not only for B cell tumors but also for other cancers that can be targeted with antibodies or antibody-like molecules as part of an ATR system. Guided by our preliminary data, we will analyze the following aims: 1) Generation and in vitro testing of ATR mediated T cell redirected lysis and 2) ATR facilitated redirected killing of tumors in vivo. In vivo experiments will include both murine/human hybrid mouse models and an immunocompetent murine tumor model. The proposed research is significant, because it has potential advantages over current bispecific antibody approaches as discussed in the application including increased efficacy, less side effects and potential use in conjunction with antigen-specific immunization to increase the targeted CTL populations. Ultimately, we expect to increase our understanding of tumor immunotherapy through T cell redirection and its potential clinical applications.
The research is relevant to public health as the proposed experiments will address development of a new approach for treatment of hematological malignancies using a nanoparticle based approach redirecting antigen-specific cytotoxic T cells to kill human lymphoma cells. If successful, this approach can be used for redirecting lysis of other cancers and immune modulation in general. Thus, the proposed research is relevant to the part of NIH's mission that pertains to enhancing fundamental knowledge that will impact on immune therapy for cancer and other diseases.
| Schappert, Anna; Schneck, Jonathan P; Suarez, Lauren et al. (2018) Soluble MHC class I complexes for targeted immunotherapy. Life Sci 209:255-258 |
| Hickey, John W; Isser, Ariel Y; Vicente, Fernando P et al. (2018) Efficient magnetic enrichment of antigen-specific T cells by engineering particle properties. Biomaterials 187:105-116 |
