New advances in cancer immunotherapy
Researchers at the University of Pennsylvania, working under the guidance of Professor Carl H. June, published data according to which immune cells modified with the method they developed demonstrated pronounced antitumor activity in the treatment of two patients with late-stage cancer who did not respond to traditional therapy. Modified T-lymphocytes, called CARTmeso, selectively destroy tumor cells expressing the mesothelin protein.
The approach used by the authors is known as chimeric antigen receptor (CAR) technology and is a variant of personalized cell therapy based on the use of the patient's own T-lymphocytes. The cells isolated from the patient are modified in such a way that a receptor is expressed on their surface that selectively interacts with a certain protein contained in the cells of his tumor. The use of CAR technology has already demonstrated promising preliminary results in the treatment of patients with certain types of leukemia and lymphoma, but has not yet brought tangible success in the treatment of solid tumors. The main problem in this case is cytotoxicity – the death of healthy cells expressing a target protein in small quantities, to which CAR lymphocytes are specific.
The principle of operation of modified T-lymphocytesChimeric antigen receptors (CARs) embedded in the shells of T-killers are modified to increase the ability to find and destroy the target cell.
This is achieved by increasing the affinity (binding strength) of antibody fragments (scFv) with surface markers of tumor cells, changing the length of the spacer (insertion element) of the receptor protein or the structure of the signaling sites of receptors located inside T cells that activate the work of killer mechanisms. Scheme based on the article Turtle et al. Engineered T cells for anti-cancer therapy (Current Opinion Immunology, 2012).The secret of the approach proposed by the authors lies in the fact that T-lymphocytes modified with the help of informational RNAs (mRNAs) express CAR for about three days, after which the mRNAs introduced into them are split and the cells return to their original state.
The modified cells recognize the mesothelin protein expressed by many tumors, including mesothelioma and pancreatic cancer, which is why they are called CARTmeso. The strategy of using these cells implies their repeated administration to the patient and discontinuation of therapy in case of adverse reactions.
To date, two patients aged 75 and 81 have participated in the phase I clinical trial of the method. One of them was diagnosed with late–stage mesothelioma, and the second had metastatic pancreatic cancer, which progressed after an unsuccessful treatment attempt. The aim of the study was to evaluate the possibility of creating modified cells in practice and to verify the safety of their use. To do this, the researchers isolated T-lymphocytes from patients, multiplied them in the laboratory and modified them with the help of mRNA. After checking the viability and specificity, the cells were injected into the patients.
After three CARTmeso injections, the patient with mesothelioma stabilized the tumor, which was confirmed by imaging methods. A patient with pancreatic cancer received 8 injections of cells, after which an analysis of the intraperitoneal fluid showed that the content of mesothelin-expressing cells in it decreased by 40%. Assessment of the levels of additional tumor markers confirmed the antitumor activity of therapy.
According to Jun, CARTmeso not only inhibits tumor growth, but also acts as a kind of vaccine that triggers the formation of antibodies against the tumor by the patient's own immune system.
The most significant side effects of therapy observed during the clinical trial were anaphylactic reaction and intestinal obstruction. At the same time, no manifestations of cytotoxicity were registered.
Article by Gregory L. Beatty et al. Mesothelin-Specific Chimeric Antigen Receptor mRNA-Engineered T Cells Induce Antitumor Activity in Solid Malignancies is published in the journal Cancer Immunology Research.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on Medical Xpress materials:
New data for engineering immune cells shows early promise in solid tumors.
25.12.2013