The long-term objective is to eradicate large well-established solid tumors by adoptively transferred tumorspecificCD8+ T cells. Success depends on CD8+ T cells: (i) eliminating the majority of cancer cells bydirect antigen-specific (perforin-dependent) killing and (ii) destroying non-malignant tumor stroma which inconjunction with radiation, chemo- or hormone therapy eliminates cancer cell variants responsible forrecurrences. These objectives are obtainable, but have used transgenic CD8+ T cells for adoptive therapy,cancer cells expressing a tumor-specific antigen, tumor-bearing hosts lacking regulatory T cells, and atransplanted tumor model. The challenge is to demonstrate how these conditions will apply (and can beapplied) to the elimination of autochthonous tumors in animals and then in patients. Thus, Aim 1 is todetermine the requirements and limitations for adoptively transferred T cells to eradicate or arrest large wellestablishedtumors. First it will be determined whether adoptively transferred T cells that eradicate largeestablished transplanted tumors can also destroy autochthonous tumors growing in the same host andexpressing the same antigen. The capability of the autochthonous tumors to sensitize stroma with antigenreleased from the cancer cells is also tested.
In Aim 2, it will be tested whether stromal sensitization andstromal destruction occurs in different tumor types and whether peripheral T cells can be made effective todestroy tumor stroma by reprogramming these T cells with TCRs from self-reactive poorly lytic T cells.Some cancers harbor sufficient antigen, and in Aim 3, release of this antigen from the cancer cells bytherapeutic manipulations will be attempted to load and sensitize the stroma. If cancer cells express too littleantigen to sensitize stroma, loading of the stroma with exogenous antigen will be attempted. Finally, byoptical imaging of well-established large tumors through a window opening, the real-time sequence of eventswill be analyzed that occur when adoptively transferred T cells encounter cancer cells and cancer stroma.This may reveal the primary targets of adoptively transferred T cells destroying large established tumors andthe mechanisms of cancer variant destruction.These mouse models study novel concepts and use engineered reagents to destroy solid tumors of sizesthat are detectable in patients and that escape conventional immunological therapies even in rodents. Theplan is to establish principles and to develop novel approaches as a guide for the development of noveltherapies to eradicate established solid tumors in patients.
| Arina, Ainhoa; Karrison, Theodore; Galka, Eva et al. (2017) Transfer of Allogeneic CD4+ T Cells Rescues CD8+ T Cells in Anti-PD-L1-Resistant Tumors Leading to Tumor Eradication. Cancer Immunol Res 5:127-136 |
| Kammertoens, Thomas; Friese, Christian; Arina, Ainhoa et al. (2017) Tumour ischaemia by interferon-? resembles physiological blood vessel regression. Nature 545:98-102 |
| Tang, Haidong; Zhu, Mingzhao; Qiao, Jian et al. (2017) Lymphotoxin signalling in tertiary lymphoid structures and immunotherapy. Cell Mol Immunol 14:809-818 |
| Arina, Ainhoa; Idel, Christian; Hyjek, Elizabeth M et al. (2016) Tumor-associated fibroblasts predominantly come from local and not circulating precursors. Proc Natl Acad Sci U S A 113:7551-6 |
| Blankenstein, Thomas; Leisegang, Matthias; Uckert, Wolfgang et al. (2015) Targeting cancer-specific mutations by T cell receptor gene therapy. Curr Opin Immunol 33:112-9 |
| Smith, Sheena N; Harris, Daniel T; Kranz, David M (2015) T Cell Receptor Engineering and Analysis Using the Yeast Display Platform. Methods Mol Biol 1319:95-141 |
| Corrales, Leticia; Glickman, Laura Hix; McWhirter, Sarah M et al. (2015) Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. Cell Rep 11:1018-30 |
| Gajewski, Thomas F; Corrales, Leticia (2015) New perspectives on type I IFNs in cancer. Cytokine Growth Factor Rev 26:175-8 |
| Spaapen, Robbert M; Leung, Michael Y K; Fuertes, Mercedes B et al. (2014) Therapeutic activity of high-dose intratumoral IFN-? requires direct effect on the tumor vasculature. J Immunol 193:4254-60 |
| Woo, Seng-Ryong; Fuertes, Mercedes B; Corrales, Leticia et al. (2014) STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41:830-42 |
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