September 25, 2021

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Immunotherapy: Related toxicity of Eight categories of CAR-T treatment

Immunotherapy: Related toxicity of Eight categories of CAR-T treatment

Immunotherapy: Related toxicity of Eight categories of CAR-T treatment.  The good response of CAR-T in hematological malignancies makes it an important strategy for tumor immunotherapy. However, treatment-related side effects are a problem that CAR-T treatment must face. This article systematically sorts out eight types of CAR-T treatment-related toxicities.

Immunotherapy: Related toxicity of Eight categories of CAR-T treatment. 

Schematic diagram of toxicity related to CAR-T treatment (Reference 1)

01. Cytokine release syndrome

The definition of cytokine release syndrome (CRS) is the rapid activation of a large number of immune cells, leading to high levels of systemic inflammatory cytokines, which in turn cause body damage. It is one of the main side effects associated with CAR-T cell therapy.

Typically, CRS occurs on the 2nd to 14th days after CAR-T cell treatment, and the subsequent time is sufficient for CAR-T cells to expand, circulate to the tumor site and perform their initial effector functions, including the production of cytokines. CRS rarely occurs more than 2 weeks after CAR-T cell infusion, and usually resolves within 2 to 3 weeks after the onset of CRS. CRS has high levels of serum cytokines and inflammatory markers, especially IL6, IFN-γ, ferritin and C-reactive protein.

Clinically, symptoms include high fever and flu-like symptoms, which can develop into hypotension, capillary leakage, hypoxia, and multiple organ dysfunction.

The following table is the commonly used ASTCT clinical grading standards:

Immunotherapy: Related toxicity of Eight categories of CAR-T treatment. 

The management of CRS usually involves the use of active supportive treatment, including antipyretic, analgesia, supplemental oxygen and intravenous fluids, and direct measures to weaken immunity (moderate to severe). IL-6 monoclonal antibody (tocilizumab) is used in clinical practice. It is widely used. Corticosteroids are also widely used, but theoretically they may affect the effect of anti-tumor CAR-T cells.

02. Neurotoxicity

Following CRS, neurotoxicity is the second most common adverse event associated with CAR-T cell therapy.

The term used previously was CAR-T-related encephalopathy syndrome (CRES). However, after the publication of the new ASTCT consensus recommendation report in 2019, the term ICANS (Immune Effector Cell Associated Neurotoxic Syndrome) was adopted. As compared with CRS, ICANS has a different time and response to intervention.

For ICANS, ASTCT also has clinical scoring standards, as follows

Immunotherapy: Related toxicity of Eight categories of CAR-T treatment. 

03. Related toxicity caused by leaching

Different from early CAR-T treatment, now before CAR-T treatment, lymphocytes will be removed, which can reduce the number of regulatory T cells, increase the availability of cytokines, especially IL-2, and reduce immune rejection, thereby enhancing CAR-T effect.

Fludarabine and cyclophosphamide are the most commonly used regimens, and their toxicity includes neutropenia, leukopenia, anemia, and thrombocytopenia. They also increase the chance of infection. Its duration may vary significantly depending on the condition of the previous treatment and the patient’s hematopoietic reserve function.

Long-term neutropenia, that is, the CAR-T cell injection lasts for more than 3 weeks. After any cytokine release syndrome (CRS) is resolved, the use of myeloid cell growth factor can be considered.

04. Off-target toxicity

CAR and non-target molecules in normal tissues cross-react, causing toxic effects.

At present, there are not many cases of off-target toxicity reported in CAR-T clinically. On the contrary, there are reports of off-target toxicity caused by TCR-T. The possible reason is that most of the scFv used by CAR are high-affinity monoclonal antibodies, and many antibody drugs themselves have been used clinically, which has proved to be safe, thus ensuring the safety of CAR-T. However, for some new target CARs that are used in humans for the first time, it is still necessary to pay attention to their off-target toxicity.

05. Non-tumor targeted toxicity (On-Target Off-Tumor)

Non-tumor targeted toxicity is usually caused by the target being a shared target, which is also expressed in normal tissues and will be recognized and attacked by CAR-T. This type of side effect is more common in CAR-T, and its severity is related to the expression and criticality of the target in normal tissues.

CAR-T cell treatment of hematological malignancies shows that the extra-tumor toxicity is not so serious. In CD19 CAR-T cell treatment of r/rB-ALL and r/rLBCL, B cell dysplasia will occur after CAR-T cell implantation.

However, the consequences of B cell dysplasia can be dealt with, and plasma cell CD19 expression has been down-regulated, so the body’s humoral immunity can be maintained to a certain extent. B-cell dysplasia is a sign of CAR-T persistence. On the contrary, premature loss of B-cell dysplasia after CD19 CAR-T cell treatment is associated with an increased risk of recurrence. Using different costimulatory domains, B cell recovery time is different, using CD28 CD19 CAR-T requires 2 months, and using 4-1BB CD19 CAR-T requires 11 months.

06. On-Target On-Tumor Toxicity

CAR-T recognizes the toxicity caused by tumor cell target molecules. The rapid destruction of a large number of tumor cells, as their contents are suddenly released into the blood, will cause metabolic disorders and affect organ functions. This phenomenon is called tumor lysis syndrome.

Although not common, tumor lysis syndrome has been reported in patients with chronic lymphocytic leukemia and B-ALL.

07. Allergic reactions

Most CARs currently in clinical use use mouse-derived scFv sequences for antigen recognition. The patient’s immune system may recognize that the components of these mice are foreign, which can trigger the risk of allergic reactions, especially when CAR-T cells are used repeatedly. Allergic reactions require continuous observation, rapid diagnosis and treatment. Immune response will reduce the durability of CAR-T.

With the use of more and more whole-person scFv, this type of risk will be reduced.

08. Insertion mutation

Because CAR is a genetically modified product, theoretically there is a certain possibility of insertion mutation. However, according to current observations, this side effect has basically not occurred. At present, safer methods such as transposons have also begun, and clinical trials of gene transduction are underway.

Summary


CAR-T treatment will produce related immune cell treatment side effects. In addition to the well-known cytokine release syndrome (CRS) and neurotoxicity, it is also necessary to consider the side effects (such as infections), off-target effects, and non-target effects caused by Qinglin itself.

Tumor targeting, or tumor lysis syndrome caused by tumor lysis may also endanger the life of the patient. As a genetically modified product, allergic reactions and the possibility of potential insertion mutations also need to be considered.

(source:internet, reference only)


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