Acıbadem Labcell Cellular Therapy Center

Derya DİLEK KANÇAĞI

Cancer disease, which is increasing in society today, is a great concern. Therefore, finding safe and effective alternative treatments has become one of the main goals of researchers around the world. One of these alternative approaches, called immunotherapy, uses and activates components of the immune system such as antibodies, dendritic cells and T lymphocytes to fight cancer. In particular, T lymphocytes have a critical role in the identification of tumor-specific antigens. For this reason, using the power of the patient's own immune system to destroy cancerous cells is discussed within the scope of immunotherapy.

Immunotherapy methods have fewer side effects than traditional chemotherapies, but it cannot be said that they are completely without side effects. Side effects may be observed due to over activation of the immunesystem, which may sometimes required is continuation of treatment or it can make the tumor appear larger than it is, causing confusion. Despite all its success, immunotherapy still works for a certain period of time in a certain group of patients; that is, the response to treatment varies from person to person. Of course, it is important to do something to increase the effect of the treatments given; first of all, whatever is done to make the immune system strong -normally- should be continued.

Current cellular immunotherapeutic products for cancer are not effective for achieving complete remission, although they do improve survival to some extent. This is mainly because immune cells are stimulated against cancer cells, but they have low-affinity receptors for cancerous cells. Immunotherapy started with Coley's toxin and continued with adoptive immunotherapy, and today CAR technology has entered the field of modern medicine. By using this technology, it is aimed to produce T cells with higher receptor affinity with more effective results.

Chimeric antigen receptor-T (CAR-T) cell therapy is a promising new T-cell immunotherapy in cancer therapies. Chimeric antigen receptor T cells are T cells that have been genetically engineered to produce an artificial T cell receptor for use in immunotherapy. Chimeric antigen receptors are receptor proteins designed to give T cells the new ability to target a particular protein. CAR-T cell therapy has been used in the treatment of hematological cancers predominantly, including acute lymphoblastic leukemia (ALL), chroniclymphocytic leukemia (CLL), lymphoma (Lymphcancer), multiple myeloma (bone marrow cancer). On the other hand, it shows great promise in the treatment of solid tumors such as melanoma (skin cancer), breast cancer and sarcoma (tumor formed in the connective tissue).

Therapy is started with drawing blood from patients and isolating T cells. Next, the T cells are genetically engineered in a lab using lentivirus/retrovirus or sleeping beauty to produce receptors called chimeric antigen receptors or CARs on their surface. As a final step, CAR T cells are infused back to the patient. After infusion, the number of CAR T cells in the patient's body is expected to increase further and with the help of designed receptors, they are expected to recognize and kill cancerous cells targeting the antigen on their surface.

“Is remission possible with CAR T cell therapy?”

Clinical trials of CAR T cell therapy began in the late nineties. As of 2009, this technology has reached its maximum level and CAR positive T cells have been included in clinical studies. Phase I and II trials are still evaluating the efficacy and safety of CAR T cells in hematological and solid cancers. CAR-T immunotherapy has also achieved remarkable results in the treatment of hematological malignancies and has led to the commercialization of CAR-T cells as pharmaceutical products. Despite the positive results, side effects such as loss of expression of the target antigen and cytokine release syndrome (CRS) need to be improved. In solid tumors, additional complications arising from intratumoral cell heterogeneity cause low responses and high toxicities.

In Turkey, meeting the production efficiency and quality control criteria in the CAR T cell clinical study conducted by our team in leukemia and lymphoma patients was found to be satisfying for academic production. Response rates and toxicity profiles were agreeable for the previously heavily treated/refractory patient group. In the light of the results obtained, CAR T cells seem to be a safe and effective treatment option for CD19 expressing cancers. However, studies are underway to improve CAR technology to increase safety and efficacy, reduce production costs, and make it applicable beyond hematological cancers, and the number of clinical trials continues to increase exponentially.

Advances in the field of CAR-T cell therapy have been exciting, to say the least…

Clearly, there are challenges ahead that need to be adequately addressed. One of these challenges is a better understanding of the host tumor micro environment, particularly the immune response. Another challenge is making the therapy available for the treatment of many different human cancers, which will include testing new antigens and optimizing CARs to target specific cancers. Since CAR-T treatment is expensive and costly, it requires improvements in terms of pricing and affordability. But given the progress this therapy has made in recent years, we should be optimistic about its future development and utility.

In summary…

In the next decade, it is expected to enter a new era of cellular therapy in both hematological and solid cancer patients as a result of advances in genomic editing and production processes, as well as the development of additional strategies to manipulate the immune system.