Current status and perspective of CAR-T and CAR-NK cell therapy trials in Germany

Abstract

Chimeric antigen receptor (CAR)-T cell therapies are on the verge of becoming powerful immunotherapeutic tools for combating hematological diseases confronted with pressing medical needs. Lately, CAR-NK cell therapies have also come into focus as novel therapeutic options to address hurdles related to CAR-T cell therapies, such as therapy-induced side effects. Currently, more than 500 CAR-T and 17 CAR-NK cell trials are being conducted worldwide including the four CAR-T cell products Kymriah, Yescarta, Tecartus and Breyanzi, which are already available on the market. Most CAR-T cell-based gene therapy products that are under clinical evaluation consist of autologous enriched T cells, whereas CAR-NK cell-based approaches can be generated from allogeneic donors. Besides modification based on a second-generation CAR, more advanced CAR-immune cell therapeutics are being tested, which utilize precise insertion of genes to circumvent graft-versus-host disease (GvHD) or employ a dual targeting approach and adapter CARs in order to avoid therapy resistance caused by antigen loss. In this review, we are going to take a closer look at the commercial CAR-T cell therapies, as well as on CAR-T and CAR-NK cell products, which are currently under evaluation in clinical trials, that are being conducted in Germany.

Fig. 1. Schematic illustration of a CAR-T or CAR-NK cell therapy, which uses primary immune cells.

(1) T or NK cells are isolated from the patient’s or donor’s blood. (2) Subsequently, cells are genetically modified to express chimeric antigen receptors (CARs). (3) CAR-T or CAR-NK cells are expanded until sufficient cell numbers are attained and (4) (re-)injected into the patient’s body, where they can fight cancer cells. CAR constructs possess a targeting module that recognizes tumor antigens and either a single intracellular signaling domain (1. gen) or, one (2. gen), or two (3. gen) additional co-stimulatory domains. In most CAR constructs the targeting module consist of a single-chain variable fragment (scFv). Novel CAR constructs can also possess nanobodies, designed ankyrin repeat proteins (DARPins), ligands, or receptors instead of scFvs for target recognition. Adapter CARs consist of two components: a soluble antigen targeting module (TM) and a CAR which targets this TM. CAR chimeric antigen receptor, DARPins designed ankyrin repeat proteins, gen generation, scFv single-chain variable fragment, TM targeting module. This figure has been created using BioRender.