Oncology

CRISPR and Cancer: A Path Forward in Oncology

Cancer, one of the leading causes of mortality worldwide, has long been a formidable opponent in the medical field. Traditional treatments such as chemotherapy, radiation, and surgery have improved survival rates, but they often come with significant side effects and are not always effective, particularly against advanced or resistant cancers. In recent years, however, breakthroughs in genetic engineering have opened up new avenues for cancer treatment, offering hope for more effective and personalized therapies. One of the most promising tools in this new era of cancer treatment is CRISPR-Cas9, a powerful technology that allows scientists to edit genes with unprecedented precision.

Figure 1. Mesothelin-specific CAR T cells attacking a cancer cell. (Credit: Prasad Adusumilli / Memorial Sloan Kettering)

A Path Forward in Oncology

Cancer is fundamentally a genetic disease, characterized by mutations that lead to uncontrolled cell growth and the formation of tumors. These mutations can be inherited, but more commonly, they occur sporadically due to environmental factors, lifestyle, or errors in DNA replication. The ability of CRISPR to target and modify specific genes makes it an ideal tool for addressing the genetic mutations that drive cancer.

Researchers are exploring several ways to use CRISPR in cancer treatment. One approach is to directly edit cancer cells to disrupt the genes that promote tumor growth or to restore the function of genes that suppress tumors. For instance, CRISPR can be used to knock out oncogenes—genes that have the potential to cause cancer when mutated or overexpressed. By inactivating these oncogenes, CRISPR could potentially halt the progression of the disease.

Another promising application is using CRISPR to make cancer cells more susceptible to existing treatments. For example, some cancers develop resistance to chemotherapy by acquiring additional mutations. CRISPR could be employed to reverse these mutations or sensitize cancer cells to drugs, enhancing the effectiveness of treatment.

CRISPR and Immunotherapy: A Powerful Toolbox

Immunotherapy, which harnesses the body's immune system to fight cancer, has emerged as a groundbreaking approach in oncology. While traditional therapies like chemotherapy and radiation often target cancer cells directly, immunotherapy aims to boost or modify the immune system to recognize and destroy cancer cells more effectively. Among the various forms of immunotherapy, CAR-T cell therapy and T-cell receptor (TCR) therapy have shown remarkable success, particularly in treating blood cancers like leukemia and lymphoma. CRISPR is now being integrated with these therapies to further enhance their efficacy and broaden their applicability.

Figure 2. CAR-T  versus TCR molecular mechanisms. (Source: BioRender)

Chimeric Antigen Receptor T-cell (CAR-T) therapy involves extracting T-cells from a patient's blood, genetically engineering them to express a receptor that recognizes a specific protein on the surface of cancer cells, and then infusing these modified cells back into the patient. The engineered T-cells can then seek out and destroy the cancer cells.

CRISPR is being used to improve CAR-T therapy in several ways. One approach is to enhance the specificity and persistence of CAR-T cells by editing genes that regulate T-cell function and survival. For example, researchers are using CRISPR to knock out the PD-1 gene in CAR-T cells, which is responsible for immune checkpoint inhibition. By preventing PD-1 expression, the engineered T-cells are less likely to be "turned off" by the tumor's immune evasion mechanisms, potentially improving the therapy's effectiveness.

Another innovative application of CRISPR in CAR-T therapy is the development of "universal" CAR-T cells. These are T-cells derived from healthy donors that are genetically modified to prevent rejection by the recipient's immune system. By knocking out genes that contribute to immune rejection, such as the T-cell receptor (TCR) gene, researchers hope to create off-the-shelf CAR-T therapies that are more accessible and cost-effective.

Figure 3. How CRISPR is changing cancer research and treatment. (Credit National Cancer Institute)

TCR Therapy

T-cell receptor (TCR) therapy is another form of immunotherapy that, like CAR-T therapy, involves genetically engineering T-cells to target cancer cells. However, while CAR-T cells recognize antigens on the surface of cancer cells, TCR therapy targets intracellular proteins presented on the surface by molecules called human leukocyte antigens (HLAs). This allows TCR therapy to target a broader range of cancers, including solid tumors, which have been more challenging to treat with CAR-T therapy.

CRISPR is being employed in TCR therapy to improve the precision and efficacy of these engineered T-cells. For instance, CRISPR can be used to knock out endogenous TCR genes in T-cells before introducing the engineered TCR, which reduces the risk of mispairing between the natural and introduced receptors. This mispairing can lead to off-target effects and reduce the effectiveness of the therapy.

Moreover, CRISPR can be used to enhance the ability of TCR-engineered T-cells to survive and function in the tumor microenvironment, which is often immunosuppressive. By knocking out genes that inhibit T-cell activity or by inserting genes that enhance T-cell function, researchers are working to create TCR therapies that are more potent and durable.