Toxicity of cell therapy: Mechanisms Manifestations and Challenges

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Toxicity of cell therapy: Mechanisms, Manifestations and Challenges

Toxicity of cell therapy: Mechanisms Manifestations and Challenges. Tumor adoptive cell therapy (ACT), including tumor infiltrating lymphocytes (TILs), T cell receptor engineered T cells (TCR-T) and chimeric antigen receptor engineered T cells (CAR-T), has been shown to treat cancer The significant clinical benefits.

However, all of these ACT therapies have clinically mild to life-threatening toxicity. Common ACT-related toxicities include cytokine release syndrome (CRS) caused by immune activation, nervous system toxicity, targeted/non-tumor or non-targeted toxicity, and related to lymphatic depletion pretreatment and high-dose IL-2 administration toxicity.

This article summarizes the clinical manifestations of adverse events related to ACT treatment and discusses the underlying pathological mechanisms; in addition, it also discusses the challenges and opportunities of managing ACT-related toxicity to illustrate how to improve ACT without affecting the effectiveness of treatment The safety of treatment.

Currently, adoptive cell therapy (ACT) is mainly divided into three categories:

(1) Tumor infiltrating lymphocytes (TILs) are separated from the patient’s tumor sample, then amplified in vitro, and then perfused into the patient.

(2) T cells engineered with T cell receptor (TCR) specific tumor antigens,

(3) T cell genetic engineering using chimeric antigen receptors (CARs), which are synthetic receptors that target homologous tumor-specific antigens.

Compared with traditional cancer treatment methods such as radiotherapy, chemotherapy, and even molecular targeted therapy, the use of tumor-reactive T cells to eradicate tumor cells with ACT can more accurately target tumors and generally reduce toxicity.

However, ACT also induces inflammation-related adverse events, which may be life-threatening. The toxicity of conventional treatment drugs usually decreases after treatment is stopped. According to reports, in some cases, the transferred T cells can exist in patients for up to several years, and the complexity of managing expected and unexpected ACT-related toxicity far exceeds that of traditional drugs.

Cytokine release syndrome (CRS) is a common type of toxicity that occurs in all three ACT treatments. The most common immune-related toxicity associated with ACT injection is CRS. CRS is caused by the activation of T cells by recognizing homologous antigens expressed by tumors, which is directly related to the activation of metastatic T cells. CRS is usually related to the progress of ACT treatment, and the expansion of CAR-T cells in the body may be related to more severe CRS grades and other immune-related toxicities.

In CAR-T cell therapy, the first-generation CAR-T cells have been reported to have insufficient cytokine release and weak anti-tumor response, while the second-generation CAR-T cells with costimulatory domains are shown in hematological malignancies. Significantly enhanced anti-tumor activity and higher cytokine release emphasizes the importance of balancing the rapid anti-tumor response and the potential cytotoxicity produced by metastatic T cells.

The treatment of CRS toxicity is still challenging. Studies have shown that systemic use of corticosteroids can quickly reverse symptoms, but high-dose corticosteroids can weaken the efficacy of CAR-T cells. Recent studies have shown that serum IL-6 level is one of the key factors related to the severity of CRS toxicity.

Neurotoxicity, also known as CAR-T cell-related brain injury syndrome (cre), is another common adverse event associated with CAR-T, TCR-T and TIL treatment. Cre toxicity is always reversible, but it may be rapid Development to a higher severity requires close monitoring of the patient.

The severity of targeted/extra-tumor toxicity depends on the amount of antigen expressed on the tissue/organ and the importance of the tissue/organ. If the transplanted T cells quickly damage key organs, it may be life-threatening. In this case, the choice of tumor antigen may be the most critical factor in determining the success of CAR-T or TCR-T therapy.

Sometimes, the antigens expressed on normal tissues can cross creatively with the tumor antigens targeted by the transferred T cells. This toxicity is called off-target toxicity. This is usually caused by unexpected molecular mimics of antigens. There are only limited reports of this toxicity in CAR-T and TCR-T therapies.

TIL adoptive transfer is usually combined with high-dose IL-2 and lymphocyte depletion to support the expansion and survival of T cells. High-dose IL-2 administration and lymphopenia can also cause adverse events. High-dose IL-2 can cause a variety of systemic toxicity in a dose-dependent manner.

Most IL-2 related toxicities can be reduced by stopping treatment within 2-5 days. The most critical toxicity management is to decide when to stop the next dose. Toxicity usually peaks in about 4-6 hours in most patients, and It disappears gradually before the next dose. Heart rate, oxygen saturation, and blood pressure should be closely monitored until it returns to the baseline level before the next administration.

Patients are usually pretreated for lymphatic clearance before adoptive transplantation of TILs, CAR-T and TCR-T. Lymphatic clearance pretreatment programs include cyclophosphamide alone, cyclophosphamide combined with fludarabine or pentostatin, and whole body irradiation ( TBI), high-intensity regulation of lymphatic consumption can lead to a variety of toxic reactions. It has been reported that, compared with cyclophosphamide alone, the addition of fludarabine to cyclophosphamide improves the persistence of CAR-T cells, but has a higher level of CRS and neurotoxicity.

In general, ACT has shown promising clinical results in various types of cancer, but is also associated with minimal to life-threatening adverse events, including CRS, neurotoxicity, off-target toxicity, off-target toxicity, and high doses IL-2 or lymphatic wasting related toxicity.

Patients using ACT need to be closely monitored to manage these expected or other unexpected adverse events. In terms of CRS and neurotoxicity, there is an urgent need to reach a consensus on the general toxicity classification system of each drug, which makes it possible to compare the toxicity of different ACT treatment regimens in different clinical trials.

In order to better judge the severity of CRS, more clinically detectable CRS-related markers should be identified as preventive strategies to improve the safety of ACT treatment. It is also necessary to conduct a systematic analysis to look at the immunosuppressive strategies for the treatment of CRS. Identifying new tumor-associated antigens that are least expressed in healthy tissues is the key to overcoming the off-target toxicity induced by ACT.

In short, with the in-depth understanding of the pathological mechanism of cell therapy-related toxicity, ACT may become a safe and controllable general strategy in the future.

Toxicity of cell therapy: Mechanisms Manifestations and Challenges