Adoptive T cell therapy is advancing rapidly as an anti-tumor treatment. Determinants of clinical success likely include rigorous selections of target antigens and corresponding receptors, optimization of T cell fitness, as well as strategies enabling T cells to overcome the immune suppressive micro-environment. In addition to the preclinical trajectory, it is important to roll out these therapies quickly in the clinical setting.

Points that are presented during this lecture: Patient study: start of MAGE-C2 TCR T cell clinical trial and, laboratory study: future strategies to enhance efficacy of engineered T cells.

The development of allogeneic cell therapies for cancer holds much promise, with various methods and cell types currently being developed. In this talk, I will update you on our progress towards developing T cells differentiated from IPSC cells, incorporating our SPEAR T cell TCRs, as a therapeutic approach.

Predicting CAR and TCR therapeutic response with legacy techniques including affinity, cytokine release and in vitro killing assays can be difficult. However, cell avidity (or overall cellular binding strength) provides a more complete and physiologically relevant picture of the interaction between T cells and targets and is better at predicting therapeutic response. In this talk we will share case studies demonstrating how cell avidity has been used to better understand downstream functionality.

We are developing neoantigen-specific TCR-engineered T cell therapies for the treatment of solid cancers. Using our proprietary TCR discovery and T cell engineering technologies we are developing fully individualized multi-specificity engineered T cell products that utilize TCRs recognizing patient-specific neoantigens. We are also developing engineered T cell products expressing TCRs that recognize highly-prevalent shared neoantigens such as those resulting from mutations in TP53 and KRAS oncogenic driver genes.

Targeting of solid tumors with “fixed” specificity CARs has shown limited efficacy and questionable benefit/risk profiles.   This presentation will review an alternative approach using a universal CAR and a cocktail of specific TumorTags specific for tumor cells/stromal elements.    Delivery of a universal “TagCAR” construct (ie, anti-FITC) that can be delivered with ex vivo and in vivo technologies paired with TumorTags potentially provides an integrated approach to effective solid tumor therapy.

Relapsed/refractory acute myeloid leukemia (R/R-AML) has a poor prognosis even with hematopoietic stem cell (HSC) transplantation. Surface expression of FLT3 in leukemic cells and in HSCs provides an excellent opportunity for the development of targeted therapy aimed to eradicate FLT3+ R/R-AML and facilitate bone marrow conditioning. We have developed chimeric antigen receptor modified T cells (CAR T) targeting FLT3 and a humanized bispecific antibody (CDX) that recruits T cells to eliminate FLT3-expressing cells.

In solid malignancies, modifiers dependent on individual tumour immune biology may affect pharmacodynamics, including differential trafficking to benign compared with cancer tissue, hampered engagement with target cells, immune suppression and cellular dysfunction due to unfavourable metabolic conditions. Here, we propose a patient-specific assessment of factors affecting on-tumour from off-tumour activity in disparate immunologic environments that impact Adoptive Cell Therapy’s clinical efficacy and may favourably balance the TI for these products.

Gamma delta T lymphocytes hold great promise for the development of new cancer immunotherapies. However, a better understanding of how they recognize and kill cancer cells is required to harness their full anti-tumor potential. I will present the strategy we developed to identify tumor antigens recognized by gamma delta T cells on different types of cancer cells and how they could be used as cell therapy against glioblastoma.

Combination therapies aligning chemotherapy and immunotherapy can improve outcomes over either approach but eradication of solid tumors remains elusive. While chemotherapy reduces tumor mass, increases vascular permeability, disrupts immunosuppressive networks, and upregulates NKG2DL expression, anti-tumor immune effector cells can also be depleted. We show effective synergies achieved with genetic modification of γδ T cell for chemotherapy resistance and concurrent delivery with chemotherapy.

LAVA Therapeutics is using its Gammabody platform to engage Vγ9Vδ2-T cells and a cascade of down-stream immune cells to attack tumor cells expressing PSMA as a novel bispecific antibody therapeutic for the treatment of prostate cancer. The presentation will address the design and selection of the lead candidate as well as pharmacokinetic, non-clinical safety studies of the therapeutic format and its progress to the clinic.

Gamma delta T cells are a unique class of lymphocytes that bridge innate and adaptive immunity. Adaptate has developed antibodies which target Vd1 gamma delta T cells. These antibodies selectively modulate Vd1 gamma delta T cell activity with a potential for superior efficacy and safety compared to conventional immunomodulatory therapies such as pan T cell activators and are being developed primarily for solid tumour indications.

γδ-T cells are innate-like lymphocytes that sense stressed cells and form a part of the immune surveillance mechanism, their infiltration into tumors is associated with a positive prognosis. Butyrophilin-3A (BTN3A), a stress sensing surface protein is required for activation of human γ9δ2-T cells in response to malignant or infected cells. ICT01 is a first-in-class clinical-stage anti-BTN3A monoclonal antibody that selectively activates γ9δ2-T cells. The presentation will cover preclinical discovery, mode of action, and development of ICT01. The clinical development strategy that includes biomarker findings and the latest patient responses in the cancer patients will be presented as well.

Major challenges within the hostile tumour microenvironment, including tumour antigen heterogeneity contribute to CAR treatment limitations in solid tumours. In this talk, a study is discussed looking into the limitations in efficiency of CAR T cell therapy in an antigen-heterogeneous syngeneic tumour model, and whether this can be overcome by CAR T cell induction of bystander effects. 

CAR T cells elicit remarkable efficacy in haematological malignancies, but not other cancers. We postulate that dual CD28 and 4-1BB co-stimulation could enhance potency, enabling effective implementation against solid tumours. Consequently, we designed parallel (p)CARs in which a 2G (CD28+CD3z) CAR is co-expressed with a 4-1BB-containing chimeric co-stimulatory receptor. We found that pCAR T cells consistently resist exhaustion and senescence, enabling superior anti-tumour activity compared to T cells that express traditional linear CARs.

The majority of solid tumours create a hostile microenvironment, with many obstacles preventing the correct function and expansion of immuno-therapeutic agents such as CAR T cells. One of the hurdles is the highly heterogeneous population which together form the solid tumour lesion. Our research focuses on the employment of Adaptor FITC CAR T-cells which have the ability to recognise multiple tumour associated antigens, guided by bispecific adaptor molecules conjugated to Fluorescein.