What are side effects of TCR-T and how to control them?

What are side effects of TCR-T and how to control them?

What are side effects of TCR-T and how to control them?  ACT using genetically engineered T cells has shown high sensitivity, but some serious adverse events have occurred in some clinical studies.

Optimal TCR affinity in engineered T cells is critical, therefore, receptor affinity can determine the safety/effectiveness of T cell therapy. For example, in melanoma and neuroblastoma, some preclinical studies have shown that T cells have advanced strength and long-lasting anti-tumor effects.

In a recent multi-target cell-based immunotherapy, patients received CARTs/TCRs for certain tumorigenic antigens, such as interventional studies of tumor-specific CAR-T/TCR combined with cyclophosphamide or fludarabine (NCT03638206; NCT03941626). At the same time, within 30 days after the last infusion, treatment-related adverse events were monitored according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03. The increase in TCR expression and the high frequency of TCR-modified T cells in the graft improves the anti-tumor efficacy of TCR-modified T cells. In addition, the combination of TCR therapy and radiation therapy has further improved the efficiency of TCR therapy (Table 2).

Due to the presence of targeted extra-tumor toxicity, affinity has become a major obstacle to the clinical success of ACT. When using antigen-specific receptors, in terms of efficacy, the affinity should be high enough to properly activate T cells. On the other hand, low-affinity TCR interactions are sufficient to activate T cells, but strong affinity is required to maintain T cell expansion. In phase I/II ACT clinical trials, low-affinity engineered T cells showed safer characteristics, but their anti-tumor response was weaker.

Therefore, optimal affinity is a key factor in the safety/effectiveness of ACT. Recently, the reversible Ni2+-nitrilotriacetic acid histidine tag (NTAmers) technology has been developed to effectively isolate high-affinity cytotoxic T cells. By recognizing the TCR-pMHC interaction of T cells, engineered T cells can be separated into high-affinity and low-to-moderate affinity subtypes. Here, advanced affinity monitoring technology is needed to ensure safe treatment.

Herpes simplex virus thymidine kinase

Immunotherapy using T lymphocytes is an attractive strategy for the treatment of many malignant tumors. However, due to the side effects and off-target of T cell immunotherapy, it is necessary to find a safety switch mechanism based on engineered T cells. Many clinical trials attempt to use suicide genes to eliminate potentially harmful cells. The thymidine kinase gene derived from herpes simplex virus I (HSV-TK) is one of the most common suicide genes. Therefore, the transcriptional connection between HSV-TK and the cell division gene (CDK1) has been designed and quantified based on a mathematical model to determine the safety of the therapy. The cell batch and homozygous HSV-TK-CDK1 in the suicide system can increase the safe cell level (SCL) while ensuring the safety range of clinical validation.

When graft versus host disease (GvHD) occurs, serious complications related to hematopoietic allografts may occur. Due to T cell transplantation, this can cause tissue and organ damage. T cell transplantation can identify host histocompatibility in about 80% of patients. To prevent GvHD, T cells have been genetically modified with the suicide gene HSV-TK using the prodrug ganciclovir (GCV) (Figure 5). The safety switch (suicide gene) has special value in long-term cell-dependent immunotherapy. They also avoid off-target interactions of T cells.

Suicide genes can control the treatment process and can be initiated through early clinical intervention. For example, in clinical trials, when HSV-TK-modified T cells migrate to unexpected locations, they can be monitored by positron emission tomography (PET)/CT.

Figure 5 HSV-TK/GCV system and inducible caspase-9 system. The herpes simplex virus-thymidine kinase/ganciclovir (HSV-TK/GCV) system can eliminate tumorigenic cells, it is effective and specific to induced pluripotent stem cells (iPSC), and can kill HSV-TK expression has been silenced Cell. The HSV-TK/GCV system is used as a safety switch, which produces a toxic compound to kill the transduced cells. Another method of suicide gene therapy is to introduce inducible caspase-9 (iC9) into iPSC. The dimerization of iC9 activates iC9, which then triggers the caspase cascade to eliminate iPSC-derived tumors. Specific chemical inducers of dimerization (CID) induce iC9.

There are several restrictions. First, previous studies have observed that a small number of patients with HSV-TK engineered T cells lose sensitivity to GCV. Secondly, the prodrug GCV will not only activate HSV-TK to prevent its administration, but it can also be used as an antiviral drug for other indications, such as cytomegalovirus (CMV) infection. Finally, HSV-TK engineered T cells have potential immunogenic activity.

The autoimmune response that activates the suicide gene may lead to the elimination of transduced T cells, thus reducing their therapeutic efficiency. The newly engineered T cells urgently need non-immunogenic suicide genes with low toxicity, stable expression and high elimination strength.

Inducible Caspase-9

Although HSV-TK has shown safety in cell-based immunotherapy, it needs to convert phosphorylated nucleoside analogues into DNA synthesis to completely eliminate tumor cells. Specifically, cancer cell therapy and regenerative medicine require rapid removal of injected cells. An original inducible T cell safety switch was brought to the donor T cell called caspase-9 (Figure 5).

Inducible caspase-9 is a fusion of human inducible caspase-9 (iC9). It is a modified human FK binding protein that can be activated by the small molecule compound AP1903. This process depends on the mitochondrial apoptotic pathway. After the prodrug was administered, the iC9-mediated cell clearance increased to 90% within half an hour. The iC9 suicide gene has low immunogenicity and will trigger a reduced immune response to transgenic cells. This is to maintain a stable cell level in the patient’s body.

In one study, after one to two weeks of treatment with AP1903, polyclonal iC9-positive T cells were detected in peripheral blood, with specific reactivity. Therefore, the iC9 cell suicide system has been shown to be activated to protect T cell-based immunotherapy and expand its clinical application. IC9-based safety switches have been shown to have better potential than pre-existing suicide genes for cell therapy. In previous studies, it has been reported that iC9-T cells deplete their allogeneic reaction components in vitro. A new study shows that iC9 allodepletion can be performed in vivo, and iC9-T cells can be eliminated within 30 minutes after AP1903 is absorbed .

The transferred T cells can also secrete pro-inflammatory cytokines, leading to the life-threatening GvHD-related cytokine release syndrome (CRS). CRS is caused by increased levels of cytokines including IL-6 and IFN-γ. Immunosuppressants, such as tocilizumab as an anti-IL-6 receptor, can reverse this situation with or without corticosteroids.

The results show that iC9 activation is sufficient to promote allogeneic clearance and treatment of GvHD, so as to quickly resolve CRS. Although the iC9 system is designed to prevent the side effects of T cell immunotherapy, any transgene integration is mutagenic and potentially carcinogenic. Therefore, it is important to assess its potential risks and benefits.

In short, TCR-T ACT has a good potential for the treatment of cancer. TCR adjustment is essential for T cell reactivity, immune response and its clinical impact on foreign antigens. The engineered TCR for specific antigens also improves the efficiency of immunotherapy. The safety of transgenic T cells used in ACT is also critical.

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