Session Details

Plenary Session 5 - Immune Monitoring and Tumor Escape
Saturday, June 1, 2019 09:15 AM - 10:45 AM
Plenary Hall
Chair:
Patrick Hanley, PhD , Children's National Medical Center, USA

This session focuses on immune monitoring of novel therapies, including using novel biomarkers, factors that impact duration of response, and bioinformatic approaches to mass cytometry and the use of t-SNE and PCA. The session will also evaluate tumor escape in a solid tumor model and the role of TNF in resistance to immunotherapy

Factors Impacting Duration of Response in Adults Treated with CD19 CAR-T Cell Immunotherapy
Cameron Turtle, MBBS, PhD, Fred Hutchinson Cancer Research Center, USA

Lymphodepletion chemotherapy followed by infusion of T cells that are genetically modified to express a chimeric antigen receptor (CAR) targeted to CD19 is a novel therapy for patients with relapsed and/or refractory B cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, and chronic lymphocytic leukemia. We have investigated factors that impact the duration of response in adults receiving CD19 CAR-T cell therapy.

TNF In Anti-Tumour Immunity and Resistance to Immunotherapy
Jane Oliaro, BSc (Hons), PhD, Peter MacCallum Cancer Centre, Australia

Immunotherapies that enhance cytotoxic T cell activity against tumour cells have revolutionised outcomes for cancer patients. However patient responses vary widely, so there is considerable interest in understanding how tumours evade this form of therapy. To investigate this, we carried out a series of CRISPR screens to identify mechanisms of tumour immune evasion from T cell killing. We found that deletion of key genes within the TNF signalling, IFN-gamma signalling, and antigen presentation pathways provided protection of tumour cells from T cell killing, and blunted anti-tumour immune responses in vivo. Our results also highlighted a role for TNF-mediated bystander killing as a potent T cell effector mechanism that can be enhanced by a class of drugs, called smac-mimetics, that inhibit IAPs and can sensitise tumour cells to TNF-induced cell death. Indeed, our studies showed that the smac-mimetic, birinapant, significantly enhanced tumour cell death in the presence of T cells, an effect that was amplified upon checkpoint blockade. Furthermore, birinapant significantly enhanced CAR T cell therapy in a solid tumour setting. Taken together, we identify T cell-derived TNF as a potent anti-tumour effector mechanism that can be enhanced with birinapant, and an opportunity for combination therapy through co-inhibition of immune checkpoints.

In Vivo Dynamics of Adoptively Transferred T Cells - Evidence from Human Trials
Emily Blyth, B.Med(Hons), FRACP, FRCPA, PhD, Westmead Hospital, Australia

Adoptive T cell therapy with pathogen specific T cells for the treatment of immune deficiency following allogeneic haemopoietic stem cell transplant (HSCT) has shown clinical efficacy with little toxicity. Graft manipulation strategies and adoptive cell transfer after HSCT are ever more complex but the biological effects are not well understood. Small patient numbers and complex clinical features pose significant challenges.
We have employed high dimensional mass cytometry and a bioinformatics pipeline to study immune reconstitution in recipients of allogeneic HSCT with and without adoptive T cell therapy using a 37 marker panel producing 75 gated canonical cell subsets per patient sample. We have used bioinformatics tools including t-stochastic neighbour embedding (t-SNE), principle component analysis (PCA) and unsupervised consensus clustering algorithm SC3 to analyse this large dataset. Immunological profiles have been identified that are influenced by clinical parameters such as transplant conditioning, donor source, T cell depletion and post-transplant events, in particular, CMV reactivation, adoptive T cell transfer of pathogen specific T cells and time post-transplant. Immune recovery within each individual can be visualised in detail using spanning-tree progressive algorithm of density normalised events (SPADE) or visualisation of t-SNE (ViSNE).
In order to assess the fate of transferred clones, we have used deep sequencing of TCR- in patients on adoptive T cell therapy trials. Notable differences were seen in TCR diversity and specificity pre-and post-infusion in patients receiving donor-derived cells, and adoptively transferred cells were seen to rapidly engraft. In contrast, patients who received third party T cells did not demonstrate significant engraftment of third-party cells, despite clinical recovery from the targeted infection and immune recovery.
The system level immunological changes form cell therapy interventions can be understood using mass cytometry immune profiling and TCR clone tracking. This technology has numerous potential applications in cancer immunotherapy.