Radiotherapy is one of the standard procedures for cancer treatment; in combination with chemotherapy most of primary tumors can be controlled. Nevertheless, a major problem remains selection of radioresistant cancer cell clones responsible for the relapse of the disease. This clearly emphasizes the clinical need for adjuvant treatment options able to overcome tumor radioresistance.
Recently developed strategy for prevention of cancer relapse due to acquired radioresistance may be based on immunotherapies. One promising approach is based on genetically modified T cells expressing chimeric antigen receptors (CAR) (1). Two such immunotherapeutics, namely axicabtagene ciloleucel and tisagenlecleucel (based on CD19-specific CAR T cells) were approved by the FDA already three years ago for treatment of B cell malignancies. CARs consist of an extracellular domain specifically binding a tumor-associated antigen (such as CD19) linked to transmembrane and intracellular signaling domains from immunoreceptors such as CD28, CD3-zeta, CD137 (4-1BB). Such genetically modified T cells bind tumor cells via their CAR regardless of their original TCR specificity, become activated and kill the tumor cells.
However, the use of CAR T cells may be accompanied by serious side effects, because conventional CAR T cells do not have sufficient self-limiting control mechanisms. One of possible solutions of this problem is the use of the switchable UniCAR system (2).
A recent paper examined whether the regulated UniCAR T cells can be used against highly radioresistant head and neck squamous cell carcinoma (3). The authors selected epidermal growth factor receptor (EGFR; an important regulator of cell growth) and CD98 (an amino acid transporter) as the targeted tumor associated targets, as these molecules are known to be overexpressed in the carcinoma cells and their high expression levels correlate with a poor prognosis. In addition, CD98 was identified as a marker and regulator of cancer stem cells. Moreover, ionizing radiation is known to stimulate both EGFR and CD98 expression.
The study demonstrated that following contact of the UniCAR T cell with target carcinoma cells the genetically modified T cells proliferated, secreted inflammatory cytokines and up-regulated cytolytic granzyme B and perforin. Importantly, the CD98- or EGFR-redirected UniCAR T cells efficiently lysed radioresistant tumor cells and significantly inhibited the growth of radioresistant cancer cells in immunodeficient mice. These exciting data indicate that the use of the UniCAR system (in combination with other treatments) may be able to solve the radioresistance problem of patients with metastatic radioresistant tumor diseases.
Prof. Václav Hořejší, PhD
Inst. of Molecular Genetics AS CR
VH Profile here...
EXBIO PRODUCTS RELATED TO EGFR AND CD98:
Anti-Hu CD98 antibody (clone MEM-108), multiple formats available - anti-CD98 CAR mantioned above was already developed by V. Hořejší and collaborating team from genes coding CD98 MAb clone MEM-108)
Anti-EGFR antibody (clone EGFR1), multiple formats available
Anti-Hu EGFR (pY1173) antibody (clone EM-13)
Anti-Hu EGFR (pY992) antibody (clone EM-12)
1. Gill S, Maus MV, Porter DL. Chimeric antigen receptor T cell therapy: 25years in the making. Blood Rev. 2016 May;30(3):157–167.
2. Feldmann A, Arndt C, Koristka S, Berndt N, Bergmann R, Bachmann M. Conventional CARs versus modular CARs. Cancer Immunol Immunother. 2019 Oct;68(10):1713–1719.
3. Arndt C, Loureiro LR, Feldmann A, Jureczek J, Bergmann R, Máthé D, Hegedüs N, Berndt N, Koristka S, Mitwasi N, Fasslrinner F, Lamprecht C, Kegler A, Hoffmann A, Bartsch T, Köseer AS, Egan G, Schmitz M, Hořejší V, Krause M, Dubrovska A, Bachmann M. UniCAR T cell immunotherapy enables efficient elimination of radioresistant cancer cells. Oncoimmunology. 2020 Apr 5;9(1):1743036
Trop-2 is thought to be associated with the epithelial phenotype of cancer cells and many studies have reported that epithelial markers positively correlate with its expression, whereas mesenchymal markers typically exert negative correlation.
Cytokeratins are a subfamily of intermediate filaments and are characterized by remarkable biochemical diversity. Among other applications, they also can be used as markers for detection and characterization of circulating tumor cells.