What's the pharmacological control of CAR T cells?

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What’s the pharmacological control of CAR T cells?

Chimeric antigen receptor (CAR) modified T cell therapy appeared as an innovative cancer immunotherapy about 20 years ago and was approved for the treatment of certain B cell malignancies four years ago.

T cells are genetically modified to express a receptor that replaces the function of the endogenous T cell receptor (TCR) to specifically bind to a specific tumor antigen. CAR is a synthetic molecule that is limited to surface antigen recognition.

After binding, it will aggregate and stimulate immune cell function. Although different CAR generations have been developed to improve effector function and persistence, the receptors are all composed of extracellular recognition domains, transmembrane anchoring domains, and intracellular signaling domains.

The extracellular module usually consists of a single-chain variable fragment (scFv) of an antibody and a hinge region. The transmembrane domain ensures the distribution of CAR on the plasma membrane and is connected to the intracellular domain. The intracellular domain is composed of a combination of signal domains of the TCR mechanism.

Therefore, the redirected CAR T cells are activated upon antigen attack, and specifically kill the tumor through cytokine release and cytotoxicity. Therefore, we can distinguish two main factors that affect the success of treatment: the quality of the targeted antigen and the efficacy of intracellular stimulation.

One of the first CAR targets is CD19, a pan-B lymphocyte marker, which has obtained a huge response in exploratory research and translated into clinical benefits for relapsed and refractory B-cell malignancies. It should be noted that careful administration of epitope refining or injection products can turn dangerous CARs into effective drugs.

In addition to the problems related to target recognition, many other parameters may hinder the success of CAR treatment, including product manufacturing, transportation, penetration, activation, and durability.

Innovative attempts to control these factors have been carried out through molecular modification of the signal tail or in combination with related receptors, and have been discussed elsewhere. Another option is to use compounds and approved drugs for exogenous intervention. In fact, in the past decade, drug intervention and CAR therapy have been the center of many studies.

What's the pharmacological control of CAR T cells?

In this review, we will discuss the following five pharmacological methods, including the combination of CAR T cells and anticancer drugs, adverse reaction neutralizing drugs, and drugs used in synthetic systems biology to improve CAR clinical results (Figure 1 ):

(I) Combination of anti-cancer methods.

A variety of pharmacological methods have been combined with CAR T cells. These include compounds that sensitize cancer cells to apoptosis, tyrosine kinase inhibitors (TKIs), and histone deacetylase inhibitors.

(Ii) Mitigating adverse effects.

Cytokine release syndrome (CRS) and neuroinflammation are the main adverse events of CAR treatment. Strategies designed to counteract these effects include antagonists or neutralizing monoclonal antibodies (mAbs) against cytokines and their receptors (such as anti-IL-6R tocilizumab), IL-1 receptor antagonists (IL-1R ) Or a drug-derived product that inhibits macrophages (nitric oxide).

(Iii) CAR T cell elimination.

In the case of AE, these transgenic methods encoding suicide switches or mAb selectable markers aim to eradicate effector cells by irreversibly removing cell therapy products. Vectors expressing CAR constructs are also designed to have tracking (for example, truncated CD34 or nerve growth factor receptor) and removal systems (for example, CD20 mimotopes fused with CD8 stems for rituximab-mediated Antibody-dependent cytotoxicity). An important method initially developed together with other adoptive cell transfer methods is the use of suicide genes that can induce apoptosis in CAR T cells.

(Iv) Reversible control of CAR.

Synthetic biology systems have been used to design CARs with response elements that exogenously control CAR T cell functions (for example, drug-induced dimerization of the split CAR form, drug-induced CAR targeting proteasome degradation). These methods are reversible; therefore, they are superior to the suicide genes discussed above.

What's the pharmacological control of CAR T cells?

(V) Regulate CAR specificity.

These methods mainly express CAR, in which the extracellular module is designed to combine with the soluble recognition module provided by additional exogenous sources.

CAR T cells show unprecedented effects in the treatment of cancer, otherwise there is no cure. However, the treatment is still not optimal. This is partly due to the nature of the product, which is a “living medicine”, indicating that its control may vary depending on the source (patient health) and quality. It is worth mentioning that all CAR studies so far have identified at least serious grade 3 or 4 clinical AEs and/or patient deaths. In this review, we emphasized novel and innovative ways of dealing with versatility by combining CAR T cells with exogenous drugs (see Table 1 for an overview).

What's the pharmacological control of CAR T cells?

The first obvious use is to combine the sensitization effect of drugs on tumor cells with CAR therapy to further synergize the effects of the two therapies. The arm should give full play to its potential to alleviate tumor resistance mechanisms and counteract unlicensed TME.

However, dual treatment also means more and often unexpected side effects, and the patient needs to be carefully monitored during initial validation. Another important use of drug combinations has been found in the method of inducing suicide of immune cells. Although elegant and able to protect patients from adverse effects, medications can be expensive.

However, compared with the production of patient-compatible transgenic T cells, drug costs may only account for a small part of the total treatment costs.

We predict that more advanced switching technologies will emerge, in which valuable therapeutic materials will be saved by carefully adjusting the activity of CAR rather than by destroying the product. Adjusting the therapeutic effect of CAR will be an important step in the personalized adaptation of “living medicine”.

Consistent with this, several groups have used FDA and EMA approved drugs that can be easily transferred to clinics to control CAR function. This creates a positive synergy between systems biologists and immunotherapists, with the goal of identifying innovative systems with specific pharmacological partners.

In short, the success of CAR therapy depends on better control of the product and individualized treatment. We have discussed a strategy here: combining drugs with CAR treatment, and observed that this strategy is innovative, elegant and feasible. Therefore, we hope to see future CAR/drug trials show effective clinical results in the near future.

Refereence:

For more details, see the original DOI:10.3390/ijms22094320

What’s the pharmacological control of CAR T cells?

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