LAVA Therapeutics is developing a Gammabody that engages V?9Vd2-T cells and a cascade of downstream 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 lead candidate selection as well as our progress to the clinic.

Engaging the innate immune system is a novel approach in immuno-oncology and Affimed’s innate cell engagers (ICE) redirect innate immune cells to kill tumors. Combining ICE with adaptive immuno-therapeutic agents, e.g. checkpoint inhibitors, or with NK cells holds promise to elicit maximum clinical benefit. Early results from a Phase 1/2a study of the ICE AFM13 precomplexed with cord blood-derived NK cells, followed by AFM13 monotherapy, showed highly encouraging response rates.

This talk will feature novel mechanisms of resistance to CAR T therapy, novel target antigens and CAR T cell products for treating multiple myeloma, virus-free transposon-based gene-transfer for CAR T manufacturing, and a novel application for CAR T in fungal infections.

γd T cells are an attractive platform for off-the-shelf, allogeneic CAR T cell therapy. ADI-001, the first CAR-engineered γd T cell product to reach the clinic, consists of allogeneic peripheral blood Vd1 γd T cells expressing a second-generation CAR directed against CD20. We will discuss available clinical data from the ongoing Phase I trial of ADI-001 in patients with Non-Hodgkin’s Lymphoma.

I will present the results of the dose escalation phase of a phase 1 CAR T-cell clinical trial of second generation T4 immunotherapy in patients with relapsed refractory head and neck cancer. Thereafter I will describe two new CAR platforms entitled parallel CAR and adapter CAR with potential for greater impact in relapsed refractory solid tumours.

We recently described that malignant cells overexpress branched N-glycans that protect them from CAR T cell targeting, interfering with proper immunological synapse formation and promoting T cell exhaustion. Disrupting N-glycans synthesis with the glucose/mannose analogue 2DG allows to overcome this barrier and improve CAR T cell efficacy in different solid tumors. Currently, we are trying to expand this scenario by investigating the impact of N-glycosylation blockade on cellular components within the tumor microenvironment.

CAR T-cell therapy has shown significant clinical efficacy in hematological malignancies but not in solid tumors. Using an experimental system of human tumor slices combined with dynamic imaging microscopy, we previously demonstrated that a dense extracellular matrix and tumor-associated macrophages hinder anti-tumor functions of T cells by reducing their migration and interaction with tumor cells. Once CAR T-cells have overcome the obstacles found in the stroma, they need to form productive conjugates with tumor cells. We have recently uncovered a new mechanism by which CAR T cells infiltrate islets of carcinomas in a two-step process dependent on IFNg and ICAM-1. 

Despite the high remission rates achieved against B cell leukemias, CAR T cell therapy is less effective for other tumor types, while there are still challenges hindering its broader usage. Next-generation genetic engineering employing multi-targeting, multi-costimulation, and spatially-controlled activation can overcome the current limitations in efficacy and safety. 

CAR T cell therapy in solid tumors is limited by the access of the therapeutic cell to cancer tissue. Migration of cells is a tightly regulated process involving chemokine receptors and their matching ligands guiding cells to specific sites. We have developed approaches how we can target T cell migration to tumor tissue by means of engineering. I will discuss different translational approaches along these lines.