Table 3.
A comparison of obstacles and feasible solutions of applying chimeric antigen receptor (CAR) T cells in solid tumors and hematological malignancies.
| Challenges in solid tumors | Feasible solutions | Challenges in hematological malignancies | Feasible solutions |
|---|---|---|---|
| Trafficking to the solid tumor site | Local infusion of CAR T cells (29) | Antigen escape | Targeting two antigens (such as CD19/CD20) via dual CARs (129) |
| Pro-inflammatory chemokine production by CAR T cells (79) | |||
| Engineering tumor site-specific CAR T cells (e.g., hypoxia-inducible factor sensitized and epidermal growth factor receptor sensitized CARs) (100) | |||
| Engineering CAR T cells with chemokine receptors (CXCR2, CCR4) (128) | |||
| The immunosuppressive microenvironment of the malignant tumor: cytokines, immune inhibitory checkpoints, and immune cells | Reduction and inhibition of regulatory T cells by lymphodepletion (113) | B-cell aplasia and multiple infections after infusion | Intravenous immunoglobulin injection (60) |
| Employment of exogenous interleukin (IL)-2, IL-7, and IL-12 for enhancing CAR T cell efficacy (119) | Dual CD19-Dectin-1 CAR T cells (99) | ||
| Programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 blockade by monoclonal antibody (89, 125) | |||
| Administering clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 for engineering PD-1-knockout CAR T cells (68) | |||
| Designing other inhibitory-molecule knockout CAR T cells | |||
| Target antigen heterogenicity and specificity | Dual CARs targeting two antigens simultaneously (97) | Reduced number of CAR T cells in patient’s blood | Multiple infusions of CAR T product (130) |
| Identifying more tumor-specific antigens proprietary for solid tumor | |||
| Administrating glycan-CARs to increase the tumor-specificity of CAR (78) | |||
| Indication of specific CARs for patients with particular antigen expression profile | |||
| Identifying new tumor-unique antigens | |||
| Controlling side effects | Engineering smarter CAR T cells [e.g., inhibitory CARs (iCARs), “on-off switch” CARs, split CARs] (90) | Severe acute side effects | iCARs (90) |
| Predicting cytokine release syndrome (CRS) via specific biomarkers (e.g., IL6, CRP, and IFNγ) (59) | Predicting CRS via specific biomarkers (e.g., IL6, CRP, and IFNγ) (59) | ||
| Administration of anti-IL6 (Tocilizumab) and hydration methods in case of severe toxicity (59) | Administration of anti-IL6 (Tocilizumab) and hydration methods in case of severe toxicity (59) | ||
| Transient expression of CAR (76) | |||
| Limited in vivo persistence | Selecting appropriate T cell subgroups | ||
| Simultaneous infusion of T cell stimulating cytokines (IL-12, IL-15, and IL-18) (59) | |||
| Penetration to the solid tumor stroma | Anti-fibroblast-associated protein-CAR T cells (131) | ||
| Heparanase expressing CAR T cells (HPSE-CAR) (132) | |||