Adoptive cell transfer (ACT) is the transfer of cells into a patient. The cells may have originated from the patient or from another individual. The cells are most commonly derived from the immune system with the goal of improving immune functionality and characteristics. In autologous cancer immunotherapy, T cells are extracted from the patient, genetically modified and cultured in vitro and returned to the same patient. Comparatively, allogeneic therapies involve cells isolated and expanded from a donor separate from the patient receiving the cells.

In the 1960s, lymphocytes were discovered to be the mediators of allograft rejection in animals. Attempts to use T cells to treat transplanted murine tumours required cultivating and manipulating T cells in culture. Syngeneic lymphocytes were transferred from rodents heavily immunized against the tumour to inhibit growth of small established tumours, becoming the first example of ACT.

Description of T cell growth factor interleukin-2 (IL-2) in 1976 allowed T lymphocytes to be grown in vitro, often without loss of effector functions. High doses of IL-2 could inhibit tumour growth in mice. 1982, studies demonstrated that intravenous immune lymphocytes could treat bulky subcutaneous FBL3 lymphomas. Administration of IL-2 after cell transfer enhanced therapeutic potential.

Mechanisms of action

Cell therapy is targeted at many clinical indications in multiple organs and by several modes of cell delivery. Accordingly, the specific mechanisms of action involved in the therapies are wide-ranging. However, there are two main principles by which cells facilitate therapeutic action

In melanoma, a resected melanoma specimen is digested into a single-cell suspension or divided into multiple tumour fragments. The result is individually grown in IL-2. Lymphocytes overgrow. They destroy the tumours in the sample within 2 to 3 weeks. They then produce pure cultures of lymphocytes that can be tested for reactivity against other tumours, in co-culture assays. Individual cultures are then expanded in the presence of IL-2 and excess irradiated anti-CD3 antibodies. The latter targets the epsilon subunit within the human CD3 complex of the TCR. 5–6 weeks after resecting the tumour, up to 10¹¹ lymphocytes can be obtained

Stem, progenitor, or mature cell engraftment, differentiation, and long term replacement of damaged tissue. In this paradigm multipotent or unipotent cells differentiate into a specific cell type in the lab or after reaching the site of injury (via local or systemic administration). These cells then integrate into the site of injury, replacing damaged tissue, and thus facilitate improved function of the organ or tissue.

Cells that have the capacity to release soluble factors such as cytokines, chemokines, and growth factors act in a paracrine or endocrine manner. These factors facilitate self-healing of the organ or region by inducing local (stem) cells or attracting cells to migrate towards the transplantation site. The delivered cells (via local or systemic administration) remain viable for a relatively short period (days-weeks) and then die. This includes cells that naturally secrete the relevant therapeutic factors, or which undergo epigenetic changes or genetic engineering that causes the cells to release large quantities of a specific molecule.

Applications

The adoptive transfer of autologous tumour infiltrating lymphocytes or genetically re-directed peripheral blood mononuclear cells has been used experimentally to treat patients with advanced solid tumours, including melanoma and colorectal carcinoma, as well as patients with CD19-expressing hematologic malignancies, cervical cancer, lymphoma, leukemia, bile duct cancer and neuroblastoma, lung cancer, breast cancer, sarcoma, melanoma, relapsed and refractory CD19+ B cell malignancies, including B cell acute lymphoblastic leukemia (B-ALL) harbouring rearrangement of the mixed lineage leukemia

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Immunotherapy: Open Access

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