With the rapid development of new therapeutic options in oncology, immunotherapy has a high priority. Thus, CAR T cells are also a promising approach to treat advanced cancers. In particular, they are already used in the therapy of lymphomas and ALL. However, treatment with the patient’s own armed immune cell is also raising hopes in various other areas of application, even if there are still some hurdles to overcome before it becomes widely available.
In the context of immunotherapy, chimeric antigen receptor T cells, so-called CAR T cells, are becoming increasingly important. These are manipulated patient’s own T cells, which are obtained by T cell leukapheresis similar to autologous stem cell transplantation. These cells are primed by implanting a receptor that can be directed against various tumor cell surface antigens, expanded in vitro, and then infused into the patient. Further expansion of CAR T cells then takes place in the body, on which the response to therapy depends to a large extent. In other words, the patient’s own T cells are reprogrammed in such a way that they can recognize tumor cells and subsequently destroy them efficiently.
The chimeric T cell receptor, the key genetic element of the CAR T cell, is an artificial product consisting of three parts. The superficial part acts as an antibody and mediates binding to a specific surface protein. It thus conditions the specificity of the T cell. In addition, there is a regulatory domain that plays an important role in the activity and survival of the cell, and the so-called T-cell receptor complex, via which the destruction of the target cell is triggered. CAR T cell therapy is based on the presence of targetable surface antigens such as CD19 in aggressive lymphomas or BCMA (B-Cell Maturation Antigen) in multiple myeloma.
Course of treatment with CAR T cells
The production of CAR T cells as living and individual drugs is extremely complex and requires good collaboration between hospitals and the pharmaceutical industry. After lymphocytes are collected, usually on an outpatient basis, they are reprogrammed in the laboratory. In this process, the T cell receptor is introduced into the genome by means of a viral vector and the cells are propagated in vitro. This step takes about three weeks. Before the cells are returned, the patient undergoes preparatory chemotherapy with the aim of destroying lymphocytes to ensure the most efficient spread of the CAR T cells infused afterwards. These reach the lymph nodes on the first day after infusion and begin to divide on day 7. For this reason, effects and also side effects can be expected from the 7th day. A hospital stay of two to three weeks is usually required for the preparatory chemotherapy, infusion of CAR T cells and follow-up. In the USA, these steps are already performed on an outpatient basis, which could also be a possibility in Switzerland in the future. The activity of CAR T cells can be measured in the blood. This is important to counteract premature imaging diagnostics.
Experience in recent years shows that sometimes several aphereses may be necessary to obtain lymphocytes. This is due to the complex production process, which can fail, among other things, due to the selection of T cells. In order for the patient to receive the product, certain quality characteristics, such as a certain viability of the cells, must be ensured. The applicable cut-off values are the subject of current investigations and influence the chances of success and safety on the one hand, but also the accessibility of the therapy on the other.
Different chimeric T cell receptors and their introduction.
Currently, the three companies Novartis, Gilead and Celgene offer CAR T cells. The different products differ in the regulatory domain, as well as in the mode of gene transfer. Depending on the co-stimulatory, i.e. regulatory, domain of the T cell receptor, the function, differentiation, metabolism and survival of the CAR T cell vary [1]. Tolerability and side effects also seem to depend strongly on the co-stimulation domain. Depending on the company, the apheresate must be sent in frozen or warm. Similarly, target volumes of apheresis and the number of vital cells infused differ. This product diversity results in the need to establish different processes in the hospital, which contributes to the complexity of the therapy.
Currently, two products, both directed against the CD19 surface antigen, are approved in Switzerland for use outside of trials. Indications include diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, and B-cell ALL, all in relapsed or refractory stage [2]. For DLBCL, estimates suggest that 80 to 90 patients will qualify for CAR T cell therapy in Switzerland in 2020. In ALL, there are likely to be significantly fewer, in the order of 5 patients. Studies on the use outside these diseases, in other patient groups and in various combinations, for example with pembrolizumab, are in full swing. These include use in acute myeloid leukemia, multiple myeloma and also solid tumors. For example, the B-cell maturation antigen BCMA, which is expressed on myeloma cells, appears to be a promising target for new therapies.
Treatment with CAR T cells is expensive and the cost, which is about $275,000 in the U.S., is secret in Switzerland. This raises several issues when introducing products to the market. While some countries, such as Austria, rely on clear guidelines to ensure distributional equity, access in Switzerland has so far been little regulated and is handled differently by the various centers and health insurers.
Efficacy and side effects of CAR T cells
The pivotal studies in pretreated patients with aggressive lymphomas have shown remission rates of 50-80%. These data on effectiveness are consistent with previous observations from the field. Preliminary clinical experience indicates that efficacy appears to be higher at lower tumor burden, which would argue for the use of CAR T cells earlier in the disease course. Up to 33% of the included patients died during the production of CAR T cells, which was often delayed by production errors. In DLBCL, response at month 3 after infusion was shown to have prognostic significance. Patients who responded to therapy at this time had a high probability that the effect persisted. In a subgroup analysis, it became clear that the therapy was just as efficient in patients over 65 years of age as in younger patients and that progression-free survival was even longer.
Known side effects of CAR T-cell therapy include cytokine release syndrome (CRS), CAR T-cell-related encephalopathy syndrome (CRES), neurotoxicity, lymphoma, and cytopenias. CRS usually occurs 5-14 days after infusion and can be mild to fulminant. Treatment is primarily symptomatic with fever reduction and hydration. In severe cases, tocilizumab and possibly steroids are used. In some cases, vasopressors and ventilation are also necessary.
Despite legitimate concerns, these therapies have been shown not to interfere with CAR T cell efficacy. In CRES, the mechanism of which is still unclear, cognitive impairment, convulsions, papilledema and cerebral edema occur. This specific side effect of CAR T-cell therapy can either occur along with CRS or occur afterward and last for hours to weeks. CRES is reversible in most cases and is also treated with corticosteroids. CAR-T cells are detectable in the blood for up to five years. Thus, there is a risk of uncontrolled multiplication, which is why all patients must be reported and recorded in the EBMT registry.
A look into the future
The question arises whether exogenous lymphocytes can also be used to produce CAR T cells. This would allow access to therapy for a larger number of patients, simplify repeat therapy and speed up the manufacturing process. Furthermore, it could be ensured that the cells used are healthy lymphocytes. However, the production of such allogeneic CAR T cells is extremely complex, as graft-versus-host disease must be prevented, which requires, among other things, the removal of the cell’s own T cell receptor.
Another option for the future is the production of dual CAR T cells, i.e. T cells with multiple specificities. Such cells could play an important role in the case of resistance. In addition to different manufacturing options, localization of production will also be an issue in the future. Geographical proximity could shorten production time and simplify logistics in manufacturing. The question of costs remains open, for which a uniform, transparent solution is desirable. Direct comparisons between the different products are also still lacking at the moment.
Source: Forum for Continuing Medical Education (FOMF), Refresher, Immunoncologics and Targeted Therapies – Presentation on CAR T-cells Update, Livestream 20.06.2020, PD Dr. med. U. Novak, Senior Physician Medical Oncology at Inselspital Bern.
Literature:
- van der Stegen SJ, Hamieh M, Sadelain M: The pharmacology of second-generation chimeric antigen receptors. Nat Rev Drug Discov. 2015;14(7): 499-509.
- swissmedic Swiss Agency for Therapeutic Products [Available from: www.swissmedic.ch/swissmedic/de/home/humanarzneimittel/authorisations/new-medicines
InFo ONCOLOGY & HEMATOLOGY 2020; 8(4): 34-35 (published 9/21/20, ahead of print).
