Adoptive T cells – pathbreaking immunotherapies

14/08/19

Immunotherapies treat diseases by activating, modulating or suppressing the body’s own immune system. The success story of such therapies began about 130 years ago, when an American physician, Dr. William Coley, brewed a mix of bacteria with which he could curb sarcoma cancer. After injecting the mixture into a patient's tumor, the bacteria’s endotoxins led to erysipelas, a skin infection. That in turn caused an immune reaction, which decreased the size of the tumor. Since then, our growing knowledge of the functionality of the human immune system and all its components has been used to develop and continuously improve immunotherapies. Today, immunotherapies are used to treat autoimmune diseases, allergies, and cancer, and to prevent rejection reactions in organ transplant patients.

Since the 1980s, after discovery of the T cell growth factor interleukin-2, it has been possible to grow and expand T cell lymphocytes ex-vivo, meaning outside a living being. Intensive further research has paved the way for adoptive T cell therapy, a new area of transfusion medicine involving the infusion of lymphocytes to mediate anti-tumor, anti-viral, or anti-inflammatory effects. Especially in fighting cancer, this method is currently one of the most promising and powerful options. Let’s have a closer look…

High potential therapy for cancer
Exploiting inherent mechanisms of the immune system to locate, target, and attack tumor cells is the key working principle of anti-cancer immunotherapy. In adoptive T cell therapies, tumor-specific cytotoxic T cells are infused into patients to recognize and destroy targeted tumor cells. In general, the therapy involves three steps: the isolation of T cells from the patient or other individuals, their cultivation, treatment or genetic modification, and finally the transfer into the patient. But what makes this therapy as powerful as it is and why is it necessary to process the cells ex-vivo? There is more than one reason: First, expanding T cells in cell culture allows for huge cell numbers, which exceed the number of active T cells that can be recruited naturally by our immune system. And, it’s obvious that the more cells that are affecting the tumor, the better the therapeutic effect. Another benefit is the possibility to treat cells in a culture with agents that cannot be used within the body. It might happen that a compound is not properly released in the organism or degraded too early to be effective. Other agents might be toxic under physiological conditions and would harm the patient’s healthy cells as well. Finally, ex-vivo cell culture allows us to genetically modify the T cells to improve their tumor specificity and overall effectiveness, and to influence their mode of action. Actually, three different methods are used for adoptive T cell therapy.

TILs - Culturing tumor-infiltrating lymphocytes
Lymphocytes isolated from a tumor are referred to as tumor-infiltrating lymphocytes, or TILs. These white blood cells are part of the natural immune response aiming to kill cancerous cells. TILs are transferred from the bloodstream directly into the tumor tissue, where they recognize and mark tumor antigens and mediate the destruction of the tumor cells. However, in advanced cancer the infiltrating lymphocytes are often suppressed. Adoptive T cell therapies with TILs can overcome this problem. To utilize TILs, they are extracted from tumor tissue, grown in interleukin cell culture, and then massively expanded in number. After infusion back into the patient, the high number of TILs re-infiltrate the tumor and reactivate the anti-tumor immune response of the body. Adoptive T cell therapy via TILs works best in malignant melanoma and pancreas carcinoma. TILs can trace tumor metastases and even cross the blood-brain barrier, which makes them a promising solution to treat brain cancers.

Isolating and expanding one particular T cell clone
Not all types of cancer show tumor-infiltrating lymphocytes. For patients from whom no TILs can be isolated, tumor-specific responses can be derived by antigen-specific expansion. The patient initially receives a cancer vaccine. This active immunization to tumor-specific antigens leads to an increase of the naturally rare tumor antigen specific T cells, which can be afterwards isolated from the patient’s blood. After identifying and sorting out tumor-specific clones via flow cytometry, the very pure tumor-reactive T cells can be expanded in culture, and transferred back into the patient.

Using engineered T cells
The latest approach in adoptive T cell therapy uses tailor-made, genetically engineered T cells. To receive a highly tumor-specific T cell culture, common T cells from a patient are modified in a way that they express tumor-specific receptors on their surface. These “designer T cells” can detect and destroy cancer cells in one step. The genes for such specific T-cell receptors can be isolated from tumor reactive T cells received from cancer patients, or by immunization of mice with specific antigens.

Another very smart and quite new method is to create CAR-T cells. These are T cells expressing a synthetic gene that codes for a chimeric antigen receptor. Such a CAR molecule includes three components: an extracellular, tumor-antigen-binding antibody fragment, a transmembrane anchor, and an intracellular part for cell signaling. The main challenge is to identify the best target structure. Some issues still have to be overcome. Researchers currently try to get the cytokine-release syndrome under control, a potential severe side effect of CAR-T cell-based therapies. However, because of their high specificity and selectivity, CAR-T cells are currently one of the most promising methods to create novel, high-potential cancer treatments—they may revolutionize the fight against cancer.

Cancer first, now other diseases
Even though adoptive T cell immunotherapies are mainly applied to cancer today, they have much broader scope. Scientists are at work on applying the knowledge on anti-cancer T cell therapies to other diseases, including viral infections such as HIV, and autoimmune diseases. The results of the first clinical trials for progressive multiple sclerosis are being reported, for example. Much more is expected in the coming years.

Literature:
Carl H. June et al. (2018): CAR T cell immunotherapy for human cancer. Science,
359(6382):1361-1365; DOI: 10.1126/science.aar6711
Perica K. et al. (2015): Adoptive T Cell Immunotherapy for Cancer. Rambam Maimonides Med J, 6(1):e0004; DOI: 10.5041/RMMJ.10179
Shelley F. Stoakes (2018): Adoptive T Cell Therapy Methodology. Online: news-medical.net
Michael Pender & Rajiv Khanna (2018): Adoptive transfer of EBV-specific T cells in patients with multiple sclerosis. YouTube video: https://www.youtube.com/watch?time_continue=127&v=JNIKMiH-GR8