Exploiting the Natural Signaling Power of T Cell Receptors to Fight Cancer
T Cells and Immunotherapy
The immune system is critical for our defense against infectious diseases and cancer. The immune response to these challenges relies on specialized T cells recognizing and killing infected or malignant cells. Unfortunately, cancer cells have found many ways to evade and subvert this process. In recent decades, many of the mechanisms by which cancer cells escape our T cells have been identified. With these new insights, the field of cancer immunotherapy is rapidly advancing with several drugs already approved, some of which show high response rates in patients.1
T cells have long been recognized as the most potent killers of tumor cells. Several companies have therefore equipped T cells with chimeric antigen receptors (CARs) that bypass the TCR signaling complex and allow binding to specific cancer surface antigens. This therapeutic approach has achieved impressive response rates in certain hematological cancers although questions remain around durability and toxicity.2-5 CAR-T cells, which by design incorporate only a single TCR subunit, also struggle to show efficacy against solid tumors. Possible reasons include inadequate and limited signaling as well as the immunosuppressive tumor microenvironment. We believe we can overcome these limitations by engineering T cells that are powered by the full signaling capacity of natural TCR complexes.
The Importance of T Cell Receptor
The TCR on T cells is responsible for recognizing cancer-associated peptide antigens presented by the major histocompatibility complex (MHC) on the surface of cancer cells. It gives T cells the capacity to see both intracellular and extracellular targets. After binding its target on cancer cells, the TCR transduces and amplifies a highly complex signaling cascade that causes a series of downstream events inside T cells. The TCR is one of the most complex receptors known. Studies by our scientists, collaborators and others in the field have demonstrated that each of the six different TCR subunits plays a unique and critical role in the signaling and activation of T cells.6,7 The TCR signals through a total of ten Immunoreceptor Tyrosine-based Activation Motifs (ITAMs) that upon ligation of the TCR are differentially phosphorylated to amplify signal strength and modulate duration. The multiplicity of TCR subunits and their functional interactions therefore allows for a large variety of cellular responses that are only possible with all TCR subunits present on the cell surface.8,9 We believe that signaling through the complete TCR complex is necessary to unleash the full capacity of T cells in cancer therapy, particularly in the more hostile immunosuppressive microenvironment of solid tumors.
Our Proprietary TRuC™ Platform
The TRuC™ platform is designed to power T cells through the complete TCR complex. This is made possible by proprietary T cell receptor fusion constructs that contain an antigen recognition domain directly connecting the TCR with a surface target on cancer cells. When TRuC™-T cells encounter a target cancer cell they are activated to rapidly kill. Our unique approach provides for a more natural T cell response because the entire TCR is employed and not just one selected subunit.
Our research team at TCR2 has systematically investigated combinations of target binding domains with TCR subunits and identified several TRuC™ variants that power T cells with high killing activity. We have demonstrated cancer cell killing by TRuC™-T cells that recognize different target antigens across multiple tumor types and therefore believe our platform will be broadly applicable for cancer therapy. We have also developed combinations of TRuC™ variants with elements designed to sustain the immunotherapeutic response and counteract the immunosuppressive tumor microenvironment.
Advantages of TRuC™ Therapy
Our unique approach offers several opportunities:
- Stronger and more comprehensive activation of reprogrammed T cells by using the full signaling capacity of a complete TCR complex
- MHC-independent recognition of cancer surface antigens
- Recruitment of all co-stimulatory receptors that naturally associate with the TCR in the immunological synapse
- Measures to counter T cell exhaustion and the immunosuppressive tumor microenvironment
We believe that these features of TRuC™-T cells are essential to achieve sustained clinical efficacy in a wide range of cancers, including solid tumors.
1 Hodi, F. S. et al. (2016). Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. The Lancet. Oncology, 17(11), 1558–1568
2 Turtle, C. J. et al. (2016). Immunotherapy of non Hodgkins lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Science Translational Medicine, 8(355), 355ra116-355ra116
3 Bonifant, C. L. et al. (2016). Toxicity and management in CAR T-cell therapy. Molecular Therapy — Oncolytics, 3(February), 16011
4 Maude, S. L. et al. (2014). Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia. New England Journal of Medicine, 371(16), 1507–1517
5 Maus, M. V., & June, C. H. (2016). Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy. Clinical Cancer Research, 22(8), 1875–1884
6 Ardouin, L. et al. (1999). Crippling of CD3-zeta ITAMs does not impair T cell receptor signaling. Immunity, 10(4), 409–420
7 Minguet, S., Swamy, M., Alarcón, B., Luescher, I. F., & Schamel, W. W. A. (2007). Full Activation of the T Cell Receptor Requires Both Clustering and Conformational Changes at CD3. Immunity, 26(1), 43–54
8 Guy, C. S. et al. (2013). Distinct T cell receptor signaling pathways drive proliferation and cytokine production in T cells. Nature Immunology, 14(3), 262–270
9 Hwang, S. et al. (2015). TCR ITAM multiplicity is required for the generation of follicular helper T-cells. Nature Communications, 6, 6982