List of Genetically Engineered Immune Cell Therapies and Their Pain Points

Immune-cell therapy uses components of the immune system to treat a variety of diseases, including cancer, autoimmune diseases and chronic inflammatory conditions, and is a highly promising therapeutic approach.

The immune cells used in this therapy can be divided into two main categories according to whether they have been genetically engineered or not. The unmodified ones mainly include regulatory T cells (Treg), tumor infiltrating lymphocytes (TIL), and cytotoxic T lymphocytes (CTL). The genetically engineered ones mainly include chimeric antigen receptor T cells (CAR-T), T cell receptor T cells (TCR), and chimeric antigen receptor natural killer cells (CAR-NK).

This article will detail the characteristics and current technical barriers of several genetically engineered immune cell therapies.

1. TCR-T Therapy

TCR-T treats tumors by screening and identifying TCR sequences that can specifically bind target antigens, using genetic engineering to transfer them into T cells (or heterologous T cells) derived from the patient's peripheral blood, and then transfusing the modified T cells back into the patient's body so that they specifically recognize and kill antigen-expressing tumor cells. The technology targets solid tumors.

Pain points of TCR-T therapy:

1. The technical barriers. The selection of TCR targets and optimization of affinity are difficult.

2. Tumor escape. The activation of TCR-T relies on MHC (major histocompatibility complex) molecules to present tumor antigens to TCR-T, which requires co-stimulatory signals, etc. The cell activation process is difficult and tumor cells are prone to escape from its killing.

3. Limitations of the applicable population. Due to the diversity of MHC in the population and the need for MHC molecules for the targeted killing of tumor cells by TCR-T, TCR-T therapies cannot be developed as a universal type.

2. CAR-NK Therapy

NK cells are mainly derived from bone marrow CD34+ lymphocytes, and their role in the human body is to kill virus-infected cells and tumor cells, NK cells do not need to rely on MHC molecules to function. Since many tumor cells themselves inhibit the synthesis of MHC molecules, this prevents immune cells such as B cells, T cells and macrophages from recognizing the cells, leading to immune escape of tumor cells. Instead, these cells that do not secrete MHC molecules are killed by NK cells.

The activity of NK cells depends on the balance of stimulatory and inhibitory signals rather than antigen specificity. There are five main sources of NK cells currently used in clinical practice: human peripheral blood (PB), umbilical cord blood (UCB), human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs), and the NK-92 cell line.

Pain points of NK cells:

1. Short duration of action. In the absence of interleukin (IL) 2 and IL15, NK cells do not survive long in vivo.
2. Complex NK subpopulations. The composition of NK cell subpopulations is complex, and it is unknown which NK cell subpopulations to use to achieve the best therapeutic effect.

3. Immature research. Current research on engineered CAR-NK cells is limited to preclinical and early clinical, and further research is needed on the safety risks of using CAR-NK in humans.

3. CAR-T Therapy

By introducing an artificially designed CAR molecule into T cells, a new targeted activation function is given to T cells, and then these modified CAR-T cells are infused back into patients, these CAR-T cells are no longer MHC-restricted and can be activated only by combining with targeted antigens, thus killing tumor cells efficiently.

Pain points of CAR-T therapy:

1. Poor effect on solid tumor. CAR-T cells input into patients are easily blocked outside the solid tumor, and can hardly enter inside the tumor, so the killing effect on solid tumor is limited.
2. Off-target effect. CAR-T targets tumor-associated antigens that are not tumor cell-specific, and normal cells may also be attacked.
3. Poor accessibility. CAR-T preparation process takes 2-3 weeks, so this time is not allowed for advanced patients. Some patients' body does not allow to obtain enough healthy T cells, and the quality of CAR-T cells eventually obtained varies from patient to patient.
4. Poor stability. The introduced CAR receptor is an exogenous molecule with certain immunogenicity, and the body will produce antibodies against CAR, which will affect the survival of CAR-T cells. In addition the scFV in CAR molecules is unstable and prone to self-aggregation, which triggers cytokine release syndrome (CRS).

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