Reduce the side effects of cell therapy! Pfizer's research team uses this small molecule as a "switch"

The cell therapy of chimic antigen-treated T (CAR-T) cells has developed rapidly in recent years and has made great achievements in hematoma treatment.
But at present, CAR-T cell therapy still needs to solve a series of problems, such as how to enhance the lethal activity of CAR-T cells, relieve tumor immunosuppression, bring CAR-T cells into solid tumors, and enhance the safety of CAR-T cell therapy.
often accompanied by CAR-T cells include cytokine storms, off-target effects, and neurotoxicity, which can threaten patients' lives in severe cases.
This cytokine storm has long been considered one of the main obstacles to CAR-T cell therapy because when CAR-T cells are entered into the patient's body, a large number of immune cells are activated and rapidly multiply, causing excessive cascade release of cytokines such as IL-6, IL-1, IL-12, TNF-α, IFN-α, GM-CSF, and ultimately cytokine storms.
over-immune response mediated by these cytokines can cause clinical manifestations such as fever, myalgia, low blood pressure, dyspnea, blood clotting disorders, and end-organ dysfunction.
To design safer CAR-T cell therapies, one of the strategies commonly used by researchers today is to install a "safety switch" on CAR-T to press the safety switch in time for adverse reactions to avoid side effects.
a more commonly used method is to use a "suicide switch" to guide the procedural apoptosis of CAR-T cells under certain conditions, but this method reduces side effects while also pre-terminating anti-tumor efficacy.
other method that is currently more commonly used is to design CAR-T cells with secondary inactivation modules that can be activated with specific external stimuli without the risk of permanently reducing the therapeutic effect.
but these modules have large loads, and it is difficult to deliver loads by relying on retrovirus and lysovirus.
team from Pfizer has designed a single-module CAR that can be activated under certain conditions, with tumor antigens that are directly regulated by FDA-approved small molecule drugs, ultimately regulating CAR-T cell activity.
CAR-T cells using this CAR structure showed tumor cell-specific cytotoxicity comparable to traditional CAR-T therapies, but the cytotoxicity reversivity decreased when small molecule drugs were added.
this makes it possible to continuously regulate CAR-T cell activity during treatment, depending on the characteristics of the adaptive disorder.
results were published recently in the scientific journal Nature Communications.
, the researchers used VHH, a camel antibody with unique properties, as a stent to design a single-module CAR activated under certain conditions.
CAR's basic structure consists of a tumor-related antigen (TAA) binding region (usually derived from the scFV segment of the monoclonal antibody antigen binding region), an extracellulated hinge area (Hinge area), a transmembrane region, and an intraocyte immunoreceptogen active sequence (ITAM).
has evolved to the fourth generation through continuous technical iterations, but the off-cell TAA part hasn't changed much.
different TAAs can act as target antigens for CAR-T cells, acting as a target antigen for CAR-T and playing a key role in CAR specificity, effectiveness, and subsequent safety.
this study, TAA identified the FDA-approved small molecule drug methotrexate (MTX) directly regulated.
researchers also tested indicators such as antigen-specific cytotoxicity of new CAR-T cells, secretion of cytokines such as IL-2 and IFN-γ, cell proliferation, and other indicators in in-body experiments, which are not significantly different from traditional CAR-T cells, but the activity of new CAR-T cells can be achieved through MTX regulation.
in mice, the new CAR-T cells showed the same tumor suppression as traditional CAR-T cells, and their tumor suppression was regulated by MTX.
, several start-ups are focusing on the development of different CAR-T switches and related innovative therapies, including Bellicum Pharmaceuticals, Precigen and BioAtla.
we look forward to finally having a new CAR-T therapy stand out for the benefit of the vast majority of patients.
: s. Park, S., Pascua, E., Lindquist, K.C. et al. Direct control of CAR T cells through small molecule-regulated antibodies. Nat Commun 12, 710 (2021).