Enhancing TIL-mediated anti-tumour immunity by reducing the immunosupressive effects of TGF-beta and limiting effector T-cell exhaustion using intrabodies against negative intracellular down-modulators
Adoptive cell therapy using transferred tumour infiltrating lymphocytes (TILs) is limited by the physical barrier created by a restrictive tumour microenvironment (TME) and by T-cell inactivation within the TME. Thus, minimizing the immunosuppressive effects of the TME and overcoming T-cell inactivation is crucial. AVID200 is a potent TGF-beta inhibitor designed by Forbius that selectively neutralizes TGF-beta1 & -beta3 with picomolar potency that reverses immunosupression, fibrosis & renders tumors sensitive to checkpoint blockade. In preclinical models, AVID200 was shown to effectively promote infiltration of TILs, activate cytolytic T cells and increase the responsiveness of immune checkpoint (ICP) inhibitors such as anti-PD-(L)1. ICP blockers (CTLA-4, PD-1, LAG3, TIM3, BTLA and others) have been shown to help restore anti-tumour immunity to a certain extent either alone or in combination therapies. Most of these ICP signal through SHP-1/-2 phosphatases, which have important inhibitory roles in T-cell activation. Accordingly, blocking SHP-1/SHP-2 within T-cells may help overcome their inactivation by targeting different ICP pathways simultaneously.