Principles and types of cells for cell therapy
Systemic administration of cytokines for the treatment of malignant tumors often causes severe intoxication. To avoid this, adoptive immunocytotherapy is used — the patient's cells are extracted, activated in a test tube with the necessary cytokines, and then returned back.
Main types of effector cells:
- LAK cells (lymphokine-activated killer cells). Derived from NK cells upon exposure to IL-2 for 5–7 days. They acquire the ability to destroy a wide range of tumor cells.
- CIK cells. Mononuclear cells or CD8+ T cells serve as the starting material. They are treated with anti-CD3 antibodies and a cytokine cocktail (IL-2, IL-1, IFNγ). This results in the selective proliferation of T lymphocytes, transforming them into potent cytotoxic cells.
- TIL cells (tumor-infiltrating lymphocytes). Initially, they have a defective receptor complex (impaired expression of ζ-chains). In vitro, cytokines (TNFα, IFNα, IFNγ, IL-2) restore their structure and restore high antitumor activity.
Combination with gene therapy
Treatment efficacy is enhanced by combining cellular and gene technologies. Cells (such as tumor, stromal, or TIL cells) are pre-transfected with genes encoding antitumor substances, such as IFNγ, TNFα, IL-2, or IL-12.
When introduced back into the tumor, these modified cells begin actively secreting cytokines. This ensures targeted drug delivery directly to the lesion site, minimizing systemic toxicity.
In the treatment of primary immunodeficiencies, gene therapy also shows results, although its use is limited. The most famous example is the treatment of SCID with adenosine deaminase deficiency. The patient's bone marrow cells are transfected with the healthy ADA gene and returned to the body, which, upon successful engraftment, eliminates the genetic defect.
Therapeutic dendritic cell (DC) vaccines
The development of therapeutic vaccines is a promising approach for treating tumors, autoimmune pathologies, and allergies. Dendritic cells serve as the main "working tool" here.
To obtain the required number of DCs in vitro, monocytes are most commonly used (they are more accessible than stem cells) by culturing them with GM-CSF and IL-4. The choice of DC type depends on the goal:
- Oncological vaccines. Require immune enhancement. Mature myeloid DCs (DC1) stimulated with IL-12 or IFNγ are used.
- Allergy and autoimmunity vaccines. The goal is to suppress hypersensitivity. Immature myeloid or plasmacytoid DCs (DC2) treated with IL-10 are used.
Then the cells are "loaded" with the required antigen (tumor-specific, allergen, or autoantigen) and administered to the patient.
Briefly: answers to topical questions
What viral and non-viral vectors are used for delivering the ADA gene into bone marrow cells in gene therapy for SCID?
For delivering the ADA gene in gene therapy for SCID, sources indicate a retroviral DNA vector. Information on the use of non-viral or other viral vectors for this purpose is absent. One methodological description involves harvesting lymphocytes, introducing the normal ADA gene in vitro using a retroviral DNA vector, and transplanting the modified lymphocytes back into the patient. For autologous bone marrow cells, the source indicates transfection with the ADA gene followed by transplantation, but does not specify the vector type.
What surface markers (CD molecules) begin to be expressed by mature myeloid dendritic cells compared to immature ones?
Compared to immature precursors, mature myeloid dendritic cells begin to express co-stimulatory molecules and specific maturation markers.
During maturation, the following surface markers appear on their membrane:
- CD80 — a co-stimulatory molecule required for interaction with T lymphocytes;
- CD86 — a co-stimulatory molecule performing a similar function;
- CD83 — a specific marker of mature myeloid dendritic cells.
Additionally, during maturation, the expression of MHC class II molecules on the membrane increases significantly.
LCT — Treatment with Specific Therapies: L - LAK (from NK cells), C - CIK (from CD8+ T cells), T - TIL (tumor-infiltrating).
Class and exam questions
What is the main advantage of adoptive immunocytotherapy?
This method avoids the systemic toxic effects of high cytokine doses on the body, as the immune cell activation process is carried out in vitro.
Where are TIL cells obtained from if they are difficult to access?
When tumors invade serous cavities, an adequate amount of TIL cells can be harvested from the accumulating exudate (ascites).
Why are type DC1 dendritic cells used in cancer vaccines?
Mature myeloid DCs (DC1) are necessary to stimulate a potent antitumor response, while DC2 are used to suppress immune reactions.
What else to study on this topic
- Mechanisms of ζ-chain restoration in TIL cells
- Use of regulatory T cells for GVHD prevention
- The role of PAMP-containing stimulators and TLRs in cancer vaccines
- Gene therapy for X-linked SCID (transfer of the γ(c)-chain gene)
- Use of hematopoietic stem cells to replace immunopoiesis
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