Die chimäre Antigenrezeptor (CAR)-T-Zell-Therapie ist eine moderne
Krebstherapie, die in Leukämien und Lymphomen beeindruckende Erfolge
verzeichnet. In anderen hämatologischen Erkrankungen und speziell in
soliden Tumoren muss die Wirksamkeit der Therapie weiter verbessert oder
überhaupt erst gezeigt werden. Die Gründe für das
schlechtere Ansprechen sind vielfältig, jedoch wird bereits an
zahlreichen Ansätzen gearbeitet, diese Schwierigkeiten zu umgehen.
Abstract
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.
Schlüsselwörter
CAR-T-Zell-Therapie - solider Tumor - CAR-T-Zell-Design - zelluläre Therapie
Key words
CAR T cell therapy - solid tumour - CAR T cell design - cellular therapy
