Remote controlling of CAR-T cells and toxicity management: Molecular switches and next generation CARs

Abstract

Highlight The emergence of CAR-T cell therapy with its exciting results attained in patients with relapsed and refractory hematological malignancies is considered as the biggest advance in cellular cancer immunotherapy. However, severe side effects and toxicity stir concerns regarding the safety of CAR-T cell treatments.Most of CAR-T cell therapies are currently autologous small-scale treatments for patients suffering from B cell malignancies due to the safety concerns about the potential development of a GVHD in allogeneic therapies. So, allogeneic therapies have been less effective than autologous ones. High cost and highly variable manufacturing processes are other limitations on the way of CAR-T cell therapy. In contrast to the unprecedented responses achieved through using CD19-CAR-T cells in the treatment of ALL, this type of treatment has not shown the same results in the battle against solid tumors that is partly related to different characteristics and microenvironment of solid tumors that limit the success of CAR-T cell therapies in patients with solid tumors. Immune checkpoint therapies with previously reported reproducible beneficial effects in 20–30% of patients with different incurable cancers have serious side effects and considerable cost of repeated administration. Also, recently most patients have not responded effectively to these therapies. In contrast, CAR-T cell therapy has two characteristics that may compensate for the limitations of immune checkpoint therapies. Firstly, only one administration of the engineered T cells is needed for long lasting effectiveness of the therapy. Secondly, more than 90% of patients suffering from ALL respond to CAR-T cell therapy, a result which is not obtained through administration of the immune checkpoints. Future development of CAR-T cell technology should address concerns related to the safety of the treatment and improve toxicity management. Also, it should extend the application of technology in diseases where its effectiveness has been demonstrated and opt for more targets and cancers.

Interleukin Inhibitors in Cytokine Release Syndrome and Neurotoxicity Secondary to CAR-T Therapy

“…CAR-T therapy is an innovative and effective therapeutic option for the treatment of hematological malignancies refractory to previous treatment lines or multiple relapses [1][2][3][4][5][6][7][8][9][10]12,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]32,34,[37][38][39][40][41][42][43][44][45][46].…”

Bispecific Antibodies in Cancer Immunotherapy: A Novel Response to an Old Question

“…The endogenous switches comprehend molecular strategies of the immune synapsis such as target-antigen recognition or expression of immune regulation singles such as PD-1 or CTL-4 (i.e SynNotch switches). The exogenous switches include antibodies or derived proteins with multiple binding sites that could lead to a more specific union of the CRA-T cell with its target [88].…”

Targeted Therapy in the Treatment of Pediatric Acute Lymphoblastic Leukemia—Therapy and Toxicity Mechanisms

“…Management begins with its proper diagnosis and is based on supportive therapy. CRS evasion can be obtained via the proper dosage of infused CART-T cells or the molecular “switch” approach (temporary change of CART-T targeting that enables the monitoring of its cellular activity) [ 72 ]. Mild CRS can be managed with antipyretics and intravenous fluids.…”