CAR T cell therapy for the treatment of solid tumors

The importance of CAR T cell therapy in the treatment of haematological malignancies has grown in the past years, with six CAR T cell products approved by the FDA as of 2023. However, in the treatment of solid tumours, CAR T cell therapy has so far not demonstrated efficacy, with most clinical trials failing to improve patient outcome. This is due to a variety of factors including poor infiltration and survival of the CAR T cell product in solid tumour tissues as well as their immunosuppressive microenvironment. Additionally, selection of target antigens in solid tumours is proving more difficult than in haematological disease, with at times significant on-target off-tumour effects. Therefore, despite its promise, no CAR T cell product has been approved for the treatment of solid tumours yet.The past decade has seen a steep increase in preclinical studies aiming at circumventing the challenges CAR T cells face in solid tumours. This has led to several innovative solutions targeting each of the four described axes of CAR T cell failure - difficult antigen selection, poor infiltration, a strong immunosuppressive tumour microenvironment and poor persistence of the transferred T cell product - through cellular engineering, ultimately improving CAR T cell treatment of solid tumours preclinically. While it is still not possible to predict how those approaches will fare in clinical trials, there is certainly reason to expect that first break-throughs of CAR T cell therapy in solid tumours might be on the way.This article summarizes mechanisms leading to CAR T cell failure in solid tumours and the approaches undertaken in engineering CAR T cells to overcome their shortcomings. Preclinical approaches are described and a small outlook is given into which of these approaches are currently being tested in clinical trials.