(Selected Tables and Figures referenced, but not present in this blog
can be found in their corresponding Science Version blogs)
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 and in previous blogs and podcasts. 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 molecules small enough to enter cells easily (called “small-molecule drugs”) so they are used for targets that are inside cells, or they are 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. One type of monoclonal antibody binds to a protein on the B cells along with 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. One type of monoclonal binds to a protein found on the surface of leukemia cells and 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 increase immune functions against tumor cells. Another way is the transfer of cells, usually immune cells [from self or from another], with the goal of improving immune function for the treatment of malignant cancers. This approach 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) 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 transfer of cells has expanded with CAR-T cell therapy and is now being applied against numerous other cancer-producing 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.
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