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We Need CARs More and More
In the era of movement and transport, the name CAR does not mean a moving engine on a road only. It stands for Chimeric Antigen Receptor too, also known as chimeric antigen T cell receptors or briefly, CAR-T. These cells are, and promise to become, one of the most powerfull modalities to cure cancer cells by immunologic therapy (1-3).
CAR-T cells belong to a larger family of immunological therapies of cancer called Adoptive T Cell Therapy (ATC), which includes different models of engineering T cells in order to attack and kill cancer cells (4). Examples of such therapies include TIL (Tumor Inflitrating Lymphocytes), TCR (T-cell receptor Redirected cells), Armoured T-cells and others. However, the most developed technology of ATC is that of CAR-T cells. This was most often used in clinical trials, and in some very difficult conditions it had excelent results in lymphocytic leukemias and different types of Hodgkin disease. The other techniques, as well as CAR-T itself, constitute today a great hope to attack solid tumors (1-4).
The name of CAR-T cells comes from the idea that they are „chimeric”, meaning that they have compounds of different origins. Indeed, the main way to produce a CAR-T cell is to transfer to it a monoclonal antibody directed towards a specific cancer antigen. This is generally obtained by retroviral vectors (1-4). Today, genetic engineers are working with the fourth generation of CAR-T, which constitute a real „living drug” against cancer.
The most remarkable results were obtained in difficult cases of Acute Lymphoblastic Leukemia (ALL) and Chronic Lymphoblastic Leukemia (CLL) in children and adolescents and in Hodgkin Lymphoma in adults. In these cases, the T-cell antibody is directed towards the CD-19 antigen, which is present on the surface of the lymphocyte B-cells and only there. Cancers linked to B-cells, like those mentioned above, present the CD-19 antigen, which is attacked with high efficacy by CAR-T prepared against this antigen.
Eighty percent of children with ALL respond to standard therapies, but those who do not have no other therapeutic alternative and are condemned. In 2014, a team from Philadelphia treated 30 such children with ALL refractory to any other therapy with CAR-T cells, and complete remission at two years was obtained in 27 out of 30 (5). Some other simmilar successes were reported.
Given these achievements, FDA gave two approvals for CAR-T cell therapies in humans in 2017: the first one, in August 2017, was for the so-called tisagenlecleucel (Kymriah™) to treat children and adolescents with ALL, and the second for axicabtagene ciloleucel (Yescarta™) to treat adult solid lymphoma. Both products are based on CAR-T cells directed against the CD-19 lymphocytic B-cell antigen.
The great challenge of ACT therapies, including mainly CAR-T, is to treat solid tumors. The challenge is to find, on the surface of such different solid tumor cells, specific antigens found only there, which can be attacked. Once the antigen is identified, the way of constructing the appropriate antibody seems not to be too complicate.
In the excellent review of D’Alloia et al. regarding this subject, 17 such antigens are described in very different solid tumors against which experimental and clinical trials are already taking place (2). Small clinical trials on mesothelioma (pleural), melanoma, ovarian cancer, brain glioblastoma, hepatic colorectal glioblastoma, peritoneal carcinomatosis, pancreatic cancer and lung cancer are already reported (6). Most of these examples have today no therapeutic alternative. Besides the difficulty to find the appropriate antigen target, there is another common difficulty: around solid tumor cells there is often a liquid micro-ambient which abruptly lowers the power of action of antibodies fixed on the CAR-T (2-4). Using Armored T-cells could be one solution for this obstacle.
Another very important problem is the side effects, sometimes so strong that they kill by themselves. Some examples include: Cytokine release syndrome (CLS), neurological toxicity, On-Target, Off-Tumor Toxicity, Insertional Mutagenesis or anaphylaxis (1, 2).
The professional and financial investment in this domain is huge. Some obstacles and future directions are mentioned below (3):
- in the domain of Recognition, it is to overcome resistance (antigen loss) and tumor heterogeneity, and to identify combination signatures;
- in the domain of Proliferation/Persistence, better control is needed;
- in the domain of microenvironment of solid tumors, it is to identify and block the modalities by which tumors defend themselves against immunologic attack;
- precision medicine, including profound identification and use of genetic information, is another point where Immunologic Therapy of Cancer may interfere with tumor and host genetics to become more and more specific, more and more precise.