Immunotherapy constitutes an exciting and rapidly evolving field, and the demonstration that genetically-modified T cell receptors (TCRs) can be used to produce T lymphocyte populations of desired specificity offers new opportunities for antigen-specific T cell therapy.Overall, TCR-modified T cells have the ability to target a wide variety of self and non-self targets through the normal biology of a T cell. Although MHC-restricted and dependent on co-receptors, genetically engineered TCRs still present a number of characteristics that ensure they are an important alternative strategy to chimeric antigen receptors (CARs), and high affinity TCRs can now be successfully engineered with the potential to enhance therapeutic efficacy while minimising adverse events.This review will focus on the main characteristics of TCR gene-modified cells, their potential clinical application and promise to the field of adoptive cell transfer (ACT), basic manufacturing procedures and characterisation protocols, and overall challenges that need to be overcome so that redirection of TCR specificity may be successfully translated into clinical practice, beyond early phase clinical trials. BackgroundWith roots in the principles of basic immunology, synthetic biology and genetic engineering, the field of adoptive cell transfer (ACT) has become one of the most promising and innovative approaches to treat cancer, viral infections and other immune-modulated diseases.There are currently three main types of ACT using effector T cells 1 : administration of tumour infiltrating lymphocytes (TILs), and gene transfer-based strategies relying on genetic engineering to express either chimeric antigen (Ag) receptors (CARs) -composed of antibody (Ab)-binding domains fused to T cell signalling domains -or engineered T cell receptor (TCR) α/β heterodimers.Genetic modification of autologous T cells to target specific tumour antigens has been developed to overcome the consequences of immune tolerance and offers the possibility to endow the immune system with reactivities not naturally present. This approach has the additional benefit of rapid tumour eradication, which is usually observed with cytotoxic chemotherapy or other targeted therapies rather than the delayed responses that are commonly observed with vaccines and T cell checkpoint therapies. Page 2 of 33Durable anticancer responses have been extensively reported for CARs targeting CD19 in the treatment of acute lymphoblastic leukaemia (ALL), B-cell lymphomas 2 and chronic lymphocytic leukaemia (CLL), and the US Food and Drug Administration (FDA) has recently approved two genetically engineered CD19 CAR T cell products, tisagenlecleucel (Kymriah) 3 and axicabtagene ciloleucel (Yescarta) 4 , for clinical application. Therapeutic TCR gene-modified T cells have demonstrated clinical activity in earlier phase clinical trials but their development currently lags behind CAR T cells 2 . The unique biology of TCR-peptide/MHC recognition may render TCR-modified T cells a more suitable approach for specific t...

TPS9116 Background: Mesenchymal stromal cells (MSCs) migrate to and incorporate into tumour stroma allowing them to act as vehicles for delivering anti-cancer therapies. TNF-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in malignant cells however short biological half-life has its limited therapeutic efficacy. We have transduced umbilical cord MSCs with a lentiviral vector to express TRAIL (MSCTRAIL). These cells trigger apoptosis selectively in cancer cells with evidence of synergistic activity with other systemic anti-cancer therapies. Given their immune-privileged nature we are delivering ex vivo pooled MSCTRAIL from third party donors without tissue matching or immunosuppression. Efficacy has been demonstrated using in vitro co-culture assays and in vivo in orthotopic lung metastasis murine model, showing regression of metastases following treatment with intravenous MSCTRAIL [1]. Methods: TACTICAL is a phase I/II trial assessing safety and efficacy of MSCTRAIL in combination with first line standard of care (SOC); pemetrexed (500mg/m2) and cisplatin (75mg/m2) and/or pembrolizumab (200mg), in treatment naïve patients with stage IIIB/IV metastatic lung adenocarcinoma. Patients have no actionable driver mutations and ECOG performance status 0-1. Phase I is a dose de-escalation study, patients receive SOC on day 1 and 4x108 MSCTRAIL cells on day 2 of a 21 day cycle for 3 cycles. A Bayesian adaptive design will recommend dose reductions if excessive toxicities occur. Primary outcomes are to determine recommended phase II dose along with safety and tolerability of MSCTRAIL. 46 patients will then be randomised into a multi-centre phase II double blind, placebo-controlled trial to receive SOC and either MSCTRAIL or placebo (1:1). Primary outcome is tumour response rate by RECIST (v 1.1) criteria at 12 weeks. Secondary outcomes include, best overall response, duration of response, progression free survival and overall survival. TACTICAL is the first clinical trial of this novel cell and gene therapy and if successful will pave the way for future allogeneic MSC therapy in cancer. 1. Loebinger, M.R., et al., Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res, 2009. 69(10): p. 4134-42. Clinical trial information: NCT03298763.

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