Eight categories of CAR-T treatment-related toxicity

The good response of CAR-T in hematological malignancies makes it an important strategy for tumor immunotherapy
.

However, treatment-related toxic and side effects are problems that CAR-T treatment must face.
This article systematically sorts out eight types of CAR-T treatment-related toxicities
.

Diagram of CAR-T treatment-related toxicity (Reference 1) The related toxicity caused by Qinglin is different from early CAR-T treatment.
Now before CAR-T treatment, lymphocytes will be cleared, which can reduce the number of regulatory T cells and increase cytokines, especially The availability of IL-2 reduces immune rejection, thereby enhancing the role of CAR-T
.

Fludarabine and cyclophosphamide are the most commonly used regimens, and their toxicities include hematological toxicity such as neutropenia, leukopenia, anemia and thrombocytopenia, and 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
.

Off-target toxicity CAR cross-reacts with non-target molecules in normal tissues, 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 in CAR are high-affinity monoclonal antibodies, and many antibody drugs themselves have been used clinically, which proves 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
.

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
.

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
.

Allergic reactions Most CARs currently in clinical applications 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
.

Cytokine release syndrome (CRS) is defined as the rapid activation of a large number of immune cells, leading to high levels of systemic inflammatory cytokines, which in turn causes body damage
.

It is one of the main side effects associated with CAR-T cell therapy
.

Typically, CRS occurs on the 2 to 14 days after CAR-T cell therapy, 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: CRS management 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 Mab (tocilizumab) is widely used clinically
.

Corticosteroids are also widely used, but theoretically they may affect the effect of anti-tumor CAR-T cells
.

Neurotoxicity is the second most common adverse event related to CAR-T cell therapy after CRS
.

The term previously used 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.
Insertion mutations are as follows.
Because CAR is a genetically modified product, there is theoretically a certain possibility of insertion mutations
.

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
.

The editor concludes that CAR-T therapy will produce related immune cell therapy 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) and off-target caused by Qinglin itself.
Effects, non-tumor targeting effects, 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
.

References 1.
Andrea Schmidts et al, Toward Better Understanding and Management of CAR-T Cell–Associated Toxicity, Annu.
Rev.
Med.
2021.
72:7.
1–7.
182.
Lee DW, Santomasso BD, Locke FL, et al.
2019 .
ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells.
Biol.
Blood Marrow Transplant.
25:625–383.
Scholler J, Brady TL, Binder-Scholl G, et al.
2012.
Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells.
Sci.
Transl.
Med.
4:132ra53 The copyright statement welcomes personal forwarding and sharing
.

Any other media or website that needs to reprint or quote the copyrighted content of this website must obtain authorization and indicate "Reposted from: Aogu" in a prominent position
.