How Gene Therapy Targets Follicular Lymphoma

Follicular lymphoma (FL) is a type of non-Hodgkin lymphoma that originates from abnormal B cells in the lymph nodes. It is characterized by the presence of neoplastic follicles, which are clusters of transformed B cells surrounded by a mantle of normal lymphocytes. While FL is generally indolent and slow-growing, it can eventually transform into a more aggressive form known as diffuse large B-cell lymphoma (DLBCL).

Gene therapy is an innovative treatment approach that aims to target and rectify the genetic abnormalities responsible for FL development. By manipulating or introducing functional genes, gene therapy seeks to restore normal cellular function, induce tumor cell death, enhance the immune response against cancer cells, or modulate the tumor microenvironment.

One promising strategy in FL gene therapy involves targeting the translocation t(14;18). This chromosomal rearrangement fuses the BCL2 gene from chromosome 18 with the immunoglobulin heavy chain (IgH) locus on chromosome 14. The resulting fusion gene, BCL2-IgH, leads to the overexpression of BCL2, an anti-apoptotic protein that inhibits programmed cell death. This dysregulation promotes FL cell survival and resistance to chemotherapy.

A common gene therapy approach for FL focuses on introducing a chimeric antigen receptor (CAR) T-cell therapy. CAR T cells are engineered T cells that express a synthetic receptor that recognizes a specific antigen on cancer cells. In FL, CAR T cells are designed to target the CD20 antigen, which is expressed on the surface of B cells, including FL cells.

The engineered CAR T cells recognize and bind to the CD20 antigen on FL cells, triggering the activation of the T cells. Once activated, these T cells release cytotoxic molecules, such as perforin and granzymes, that induce apoptosis or programmed cell death in FL cells. This targeted approach selectively eliminates FL cells while sparing normal cells.

Another gene therapy strategy for FL involves RNA interference (RNAi). RNAi utilizes short interfering RNA (siRNA) molecules to silence or suppress the expression of specific genes. In FL, siRNA can be designed to target the BCL2 gene, thereby reducing the production of the anti-apoptotic BCL2 protein. This approach aims to restore apoptosis and enhance the susceptibility of FL cells to chemotherapy or other treatments.

Furthermore, gene therapy approaches are being explored to modulate the tumor microenvironment in FL. This involves introducing genes or genetic modifications that alter the interactions between FL cells and their surrounding immune cells and stromal cells. By re-educating the immune system or modifying the microenvironment, gene therapy can enhance anti-tumor immune responses and improve treatment outcomes.

Gene therapy offers significant potential for the targeted and effective treatment of FL. By manipulating specific genetic alterations or modulating the tumor microenvironment, gene therapy strategies can induce tumor cell death, enhance immune surveillance, and improve patient outcomes. However, further research and clinical trials are necessary to optimize gene therapy approaches, address safety concerns, and ensure long-term efficacy in FL treatment.