In a discussion on immunotherapies in the treatment of cancers, the most appropriate place to begin is with the monoclonal antibodies. These are a type of molecularly targeted cancer therapy we spoke of at the end of our last blog. They are designed to interact with specific targets and as such are the foundation of precision medicine. They target proteins that control how cancer cells grow, divide, and spread. As researchers learn more about the DNA changes and proteins that drive cancer, they are better able to design promising treatments that target these proteins.
Most targeted therapies are either “small-molecule drugs” (molecules small enough to enter cells easily, so they are used for targets that are inside cells) or monoclonal antibodies. Some monoclonal antibodies (Blog #21) are also immunotherapeutic because they help turn the immune system against the cancer. An example would be monoclonal antibodies that mark cancer cells so that the immune system will better recognize and destroy them. An example is rituximab that binds to a protein called CD20 on B cells and some types of cancer cells, causing the immune system to kill them. Other monoclonal antibodies called immune checkpoint inhibitors (see Blog #21) bring T cells close to cancer cells, helping the immune cells to kill the cancer cells. An example is blinatumomab (Blincyto), that binds to both CD19, a protein found on the surface of leukemia cells, and CD3, a protein on the surface of T cells. This process helps the T cells get close enough to the leukemia cells to respond to and kill them (Fig. 6.1).
Up to this point, we have described numerous immunotherapeutic approaches developed to redirect and/or augment immune functions against tumor cells. The application of adoptive cell transfer therapy (ACT therapy – simply the transfer of cells, usually immune cells [autologous – from self or allogenic – from another], with the goal of improving immune function) for the treatment of malignant cancers has now been expanded by the use of T lymphocytes “engineered” to express chimeric antigen receptors (CARs) to produce genetically engineered CAR-T as was described back in Blog #25.
As with CAAR-T cell therapy (see Blog #25), CAR-T cell therapy (Figure 6.3) begins by removing a patient’s lymphocytes and transducing them with a DNA plasmid vector (a DNA molecule distinct from the cell’s DNA used as a tool to clone, transfer, and manipulate genes or stem cells) that encodes specific tumor antigens. These modified and targeted lymphocytes are then reintroduced into the patient’s body (similar to CAAR-T) through a single infusion to attack tumor cells. This treatment has been used in cancer treatment for more than 25 years, resulting in four generations of improving therapy that has generated effective therapeutic responses for up to 4 years in some studies. A recent report (February 2022) documented 2 patients with chronic lymphocytic leukemia (CLL) treated with CAR-T therapy 10 years ago remaining in remission. This suggests the therapy to be a “cure” (remember how careful we have to be with that word) for CLL. Based upon the high rates of initial cancer remission and durable responses in many patients receiving CAR-T cell therapy, the ACT field has expanded with CAR-T cell therapy now being applied against numerous other B cell-associated antigens with encouraging clinical response data being reported. Again, as previously described about the combination of stem cells with CRISPR-Cas9, so too can CAR-T cell therapies be expanded in combination with CRISPR-Cas9 and stem cell transplantation.
Discussion Questions:
Monoclonal antibodies attack cancer cells in numerous ways. Can you describe some of the direct and indirect methods by which monoclonals attack cancer cells?
CAR-T and CAAR-T therapies use similar methods of T cell transduction and reinfusion. For what treatment purposes are each of the therapies used?
تعليقات