Pharmacologic Control of CAR T Cells

Abstract

Chimeric antigen receptor (CAR) therapy is a promising modality for the treatment of advanced cancers that are otherwise incurable. During the last decade, different centers worldwide have tested the anti-CD19 CAR T cells and shown clinical benefits in the treatment of B cell tumors. However, despite these encouraging results, CAR treatment has also been found to lead to serious side effects and capricious response profiles in patients. In addition, the CD19 CAR success has been difficult to reproduce for other types of malignancy. The appearance of resistant tumor variants, the lack of antigen specificity, and the occurrence of severe adverse effects due to over-stimulation of the therapeutic cells have been identified as the major impediments. This has motivated a growing interest in developing strategies to overcome these hurdles through CAR control. Among them, the combination of small molecules and approved drugs with CAR T cells has been investigated. These have been exploited to induce a synergistic anti-cancer effect but also to control the presence of the CAR T cells or tune the therapeutic activity. In the present review, we discuss opportunistic and rational approaches involving drugs featuring anti-cancer efficacy and CAR-adjustable effect.

CAR T Cell Immunotherapy That Revolutionary Breakthrough in Human Oncology Treatment: A Review

“…It is important to note that, to date, all CAR studies have, in any case, identified extreme grade 3 or 4 clinical AEs and passed. In the present survey, novel, imaginative ways to deal with managing the flexibility of CAR-T cells by consolidating rather than with exogenous pharmacologic medication (see Table 3 for an outline) [65]. The in vivo process eliminates.…”

“…This treatment also means more and often unexpected aspects, and patients will need careful observation and counseling during the effects and initial verification. Although it is elegant and able to protect patients from unwanted effects, it can be expensive and, when compared to patient-compatible CAR drug costs, may be a small amount of the total treatment cost [65].…”

“…The FDA and EMA approved those drugs, so they can easily be transferred to use in the clinic. Hopefully, future CAR/drug trials will show efficient clinical results in the near future [65].…”

“…N/A non-available. AML acute eyelid leukemia; B ALL precursor B acute lym-phoid leukemia; Bcl-xL: Bcl extra-large; Bcl-2: B cell lymphoma 2; C2H2: Cys 2 -His 2 ; CLL: chronic lymphoid leukemia; CAIX carbonic anhydrase IX; CRS cytokines release syndrome; CRBN: cerebelon; EGFR (epidermal growth factor receptor); FKBP: FK506 binding protein; FLT3: fms-like tyrosine kinase 3; FRB (FKBP-rapamycin-binding); GD2: disialoganglioside; GBM: globalism multiform; GM-CSF granulocyte-macrophage colony stimulating factor; HCV: Hepatitis C Virus; HER-2: epidermal growth factor receptor 2; hRBP4: human retinol retinal binding protein 4; IFN-γ: interferon gamma; iMC: ineducable MyD88/CD40; La/SS-B: human nuclear auto-antigen La/SS-B; LD3: human apolipoprotein E4 E; LID: ligand-induced dimerization; MDM2: mouse double minute 2 homolog; MDSC (myeloid-derived suppressor cells); Meso: mesothelin; NHL (non-Hodgkin lymphoma); Nos: nitric oxides; PD-1 (programmed cell death protein 1); PKC: protein kinase C; PSCA: prostate stem cell antigen; RCC: renal cell carcinoma; PSMA (prostate-specific membrane antigen); scFv: single-chain variable fragment; zip: leucine-zipper; SMAC (second mitochondria-derived activator of caspase); tCD34: truncated CD34; TNF-α (tumor necrosis factor alpha); tNGFR (truncated nerve growth factor receptor) [65].…”

Knowns and Unknowns about CAR-T Cell Dysfunction

“…They showed that transient “resting” of CAR-T cells improved functionality and may help mitigate exhaustion both functionally and epigenetically, even in “aged” CAR-T cells with constant tonic signaling lasting up to 45 days [ 154 ]. They demonstrated that dasatinib, an FDA-approved multikinase inhibitor [ 155 ], has a similar effect on CAR-T cells underlining its potential clinical application. However, the authors emphasize that their findings contradict those of mouse models in which a late (>14 days) “rescue” of T cells from their cognate antigen did not result in their reinvigoration [ 5 , 11 ].…”