Although already considered a major hematological success, CAR T‑cell therapies are still at an early stage of development and their various facets offer great opportunities for improvements. As examples, modifications in CAR design allow for the creation of armored CAR T cells (Fig.
1) and products with an incorporated suicide gene that would allow their ablation upon stimulation with a pharmacologic agent in cases of life-threatening toxicity. In general, the possible composition and modifications of CAR domains already now give rise to an unlimited number of possible CAR T‑cell products with specific profiles regarding immunogenicity, expansive capabilities, cytokine secretion, cytotoxicity as well as in-host persistence [
16]. Hence, it will be a long way to define the ideal CAR construct for each entity and patient. Not all patients respond to CAR T‑cell therapy and relapses rates are significant also with this approach. The latter have in some cases been linked to loss of tumor antigen [
17] or immune escape via the PD1-PD-L1 axis [
18]. Efforts to overcome primary or secondary resistance thus include multi or tandem CAR T cells targeting two different tumor antigens (e. g., CD19 and CD22) [
19], or the use of checkpoint inhibitors [
20] or interleukin-15 [
21] to reactivate exhausted CAR T cells. Furthermore, several pharmaceutical agents such as ibrutinib have shown to enhance CAR T‑cell efficacy in preclinical models and their supplemental use is currently being investigated [
22]. Other possible modifications include the type and intensity of the conditioning regimen, the formulation of the CAR T‑cell product (e. g., selection of T‑cell subsets), the administered cell dose, or their use in earlier disease stages [
16]. Finally, advances in genome editing (e. g., CRISPR/Cas9 or TALEN) may allow for the creation of off-the-shelf universal allogeneic CAR T cells with disrupted endogenous TCR expression, thus, diminishing the risk for graft-versus-host reactions [
23,
24].