A NOVEL TRuC™ PLATFORM FOR SOLID AND HEMATOLOGIC CANCERS WITHOUT THE NEED FOR HLA MATCHING 

T Cell Therapy: Harness the Power of Living Immune Cells to Fight Cancer

The immune system is critical for our defense against infection and cancer. Growing insight into the mechanisms by which the immune system fights cancer has led to a recent explosion of immunotherapies being developed and several drugs approved showing high response rates in patients1. In particular, companies are now able to engineer living T cells with chimeric antigen receptors (CARs) or engineered T cell receptors (TCRs) to recognize specific cancer antigens and kill tumor cells.

Complete TCR Complex on T Cell is Needed to Address Solid Tumors

T cells are the most potent killers of tumor cells with activities driven by the TCR complex. Upon binding to specific tumor antigens, TCR transduces a highly complex signaling cascade that triggers downstream activities including proliferation, activation, migration, cytokine release, persistence and cell killing. Each of the six different subunits of the TCR and their phosphorylation motifs (ITAMs) play a unique and critical role in signaling the T cells.2,3 By engaging the complete TCR complex, T cells can unleash their full range of weapons against cancer, the totality of which is particularly critical in the context of the hostile immunosuppressive microenvironment present in solid tumors.4-5

Existing CAR and Engineered TCR Therapies Have Key Limitations

While the CAR-T approach has achieved remarkable response rates in certain hematologic cancers and gained two FDA approvals in 2017, persistence and toxicity remain challenging.6-9 Importantly, CAR-T cells have struggled to show efficacy against solid tumors, likely because they do not utilize the complete TCR complex required to trigger all signals involved in T cell activation.

The engineered TCR approach which utilizes the complete TCR has shown clinical activity in solid tumors, but there are major limitations to this approach associated with HLA which is required for TCR to bind to tumor antigen10,11. Specifically, HLA is often downregulated on cancer cells, blinding T cells from recognizing them, and current TCR-T cell approaches are only applicable to individuals expressing specific HLA subtypes (most frequently those expressed by patients of European descent such as HLA-A2) preventing the universal applicability of such technology.

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The TRuC™ Platform Overcomes CAR-T and TCR Limitations

The TRuC™ platform is the first engineered T cell platform to use the complete TCR complex without the need for HLA matching. By conjugating tumor antigen binder (e.g., scFV, sdAb, Fab) to the TCR complex, the TRuC™ construct can recognize highly expressed surface antigens on tumor cells without HLA and employ the complete TCR machinery to drive the totality of T cell functions required for potent, modulated and durable tumor killing.

TRuC™-T cells have demonstrated superior anti-tumor activity in vivo compared to CAR-T cells while releasing a lower level of cytokines. In vivo studies also showed long persistence of TRuC™-T cells in animal models for over 100 days. These data are particularly encouraging for solid tumors where CAR-T cells have not shown significant clinical activity likely due to very short persistence and in hematologic tumors where a high incidence of severe cytokine release syndrome remains a major concern.

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The TRuC™ Platform Has Great Versatility

A key feature of the TRuC™ platform is its flexibility to be modified to address target- and/or indication-specific requirements. Dual-target TruC™ is an example of such a vehicle where two tumor antigens can be targeted by a single TRuC-T cell product to overcome antigen escape mechanisms that are common in certain tumor types.

Each vehicle can also be engineered to carry built-in modulators (accessories) that further potentiate T cell activity in the presence of specific negative elements of the hostile tumor microenvironment.

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Resources

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 Ardouin, L. et al. (1999). Crippling of CD3-zeta ITAMs does not impair T cell receptor signaling. Immunity, 10(4), 409–420

3 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

4 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

5 Hwang, S. et al. (2015). TCR ITAM multiplicity is required for the generation of follicular helper T-cells. Nature Communications, 6, 6982

6 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

7 Bonifant, C. L. et al. (2016). Toxicity and management in CAR T-cell therapy. Molecular Therapy — Oncolytics, 3(February), 16011

8 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

9 Maus, M. V., & June, C. H. (2016). Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy. Clinical Cancer Research, 22(8), 1875–1884

10 Robbins, P. F. et al. (2015). A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clinical Cancer Research, 21(5):1019-27

11 Lu, Y. C. et al. (2017). Treatment of Patients With Metastatic Cancer Using a Major Histocompatibility Complex Class II–Restricted T-Cell Receptor Targeting the Cancer Germline Antigen MAGE-A3. Journal of Clinical Oncology, 35, no. 29 (October 2017) 3322-3329.