Obstacles and Coping Strategies of CAR-T Cell Immunotherapy in Solid Tumors

Abstract

Chimeric antigen receptor (CAR) T-cell immunotherapy refers to an adoptive immunotherapy that has rapidly developed in recent years. It is a novel type of treatment that enables T cells to express specific CARs on their surface, then returns these T cells to tumor patients to kill the corresponding tumor cells. Significant strides in CAR-T cell immunotherapy against hematologic malignancies have elicited research interest among scholars in the treatment of solid tumors. Nonetheless, in contrast with the efficacy of CAR-T cell immunotherapy in the treatment of hematologic malignancies, its general efficacy against solid tumors is insignificant. This has been attributed to the complex biological characteristics of solid tumors. CAR-T cells play a better role in solid tumors, for instance by addressing obstacles including the lack of specific targets, inhibition of tumor microenvironment (TME), homing barriers of CAR-T cells, differentiation and depletion of CAR-T cells, inhibition of immune checkpoints, trogocytosis of CAR-T cells, tumor antigen heterogeneity, etc. This paper reviews the obstacles influencing the efficacy of CAR-T cell immunotherapy in solid tumors, their mechanism, and coping strategies, as well as economic restriction of CAR-T cell immunotherapy and its solutions. It aims to provide some references for researchers to better overcome the obstacles that affect the efficacy of CAR-T cells in solid tumors.

Keywords: chimeric antigen receptor T cell; coping strategies; immunotherapy; obstacles; solid tumors.

Graphical Abstract

CAR-T cell immunotherapy has demonstrated notable future opportunities in the mainstream cancer treatment of solid tumors. However, it still has numerous obstacles in the treatment of solid tumors. Only by adopting effective strategies against these obstacles can CAR-T cells exert better curative effects in the treatment of solid tumors.

Figure 1

The development of the CARs. The intracellular structure of first-generation CARs only has one signal structure domain (CD3ζ) without co-stimulatory molecules. The second-generation CARs add one co-stimulatory molecule to the first-generation CAR, e.g, CD28, 4-1BB, OX40 or ICOS. The third-generation CARs contain 2 costimulatory molecules. The fourth-generation CARs are modified by adding NFAT or suicide genes based on the second-generation CARs or the third-generation CARs. The fifth-generation CARs use a “third-party” intermediate system to separate the antigen-binding domain of CARs from the T cell signaling unit.

Figure 2

Combined CARs, Dual-singling CAR and Tandem CAR. (A) Simultaneous or sequential use of 2 or more CAR-T cells treating a similar malignant tumor; (B) Dual-signaling CAR refers to the simultaneous and separate expression of 2 different CARs on similar T cell surface; (C) Two different scFvs are connected hand in hand to form tandem CAR on the surface of the T cell.

Figure 3

AND gate CAR. SynNotch receptor uses the scFv to bind to the corresponding target antigen A, however, the combination of 2 does not trigger the T cells activation. This binding causes the synNotch receptor to split and release the transcriptional activator domain, which enters the nucleus and drives the expression of another B-CAR gene. Subsequently, the surface of the T cell will express B-CARs. At this time, the newly expressed CARs binds to the target antigen B, activating the T cells.

Figure 4

Immune checkpoints and immune checkpoint inhibitors. (A) When these immune checkpoints bind to the corresponding ligands, inhibitory signals transmitted from tumor cells inhibit T cell activation; (B) These immune checkpoint inhibitors specifically bind to the corresponding checkpoints on the T-cell surface or tumor cell surface, thereby blocking the binding of these checkpoints to corresponding ligands, ultimately preventing the transmission of inhibitory signals from tumor cells to T cells.

Figure 5

The trogocytosis of CAR-T cells. The CAR-T cells accidentally ingested surface antigens of tumor cells via trogocytosis, and transferred these antigens to the surface of CAR-T cells, causing them to attack each other, ultimately causing the depletion of the CAR-T cells.

Figure 6

On-switch CAR and iCAR. (A) The on-switch CAR-T cells are initially turned off, activated only with specially designed drugs, then recognize, bind to, and kill the targeted tumor cells. When the drugs are not present, the CAR-T cells return to their off state; (B) When iCAR-T cells bind to the corresponding tumor cells, iCAR-T cells are activated and kill the tumor cells. Nonetheless, when iCAR-T cells combine with normal cells, the iCARs produce inhibitory signals which prevent traditional CARs or TCRs from functioning, thus the normal cells remain undamaged.