Article
Characterisation of RNA expression of eight antigens relevant for immunotherapy of glioblastoma by qPCR
Charakterisierung der RNA Expression von acht für die Immuntherapie von Glioblastomen relevanten Antigenen durch qPCR
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Published: | May 25, 2022 |
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Objective: Immunotherapy leads to promising results in the treatment of glioblastoma (GBM) patients. Recent clinical trials revealed a survival benefit of patients treated with monospecific CAR T-cells. However, antigen escape mechanisms due to heterogeneous antigen-expression still constitute a critical hurdle for immunotherapeutic treatment of GBM and are a major reason for non-response or relapse. Therefore, a target has to be identified that is stably expressed in the tumor while having low expression in healthy tissue to avoid on-target off-tumor toxicity.
Methods: Eight in vitro and in vivo most interesting targets for CAR-T-cell therapy (B7H3, CD70, CSPG4, EphA2, HER2, IL-13Rα2, Podoplanine (PDPN) and ROR2) were analyzed by qPCR in primary as well as recurrent GBM of 29 patients. The median expression in brain samples of three healthy specimens served as controls and interpersonal heterogeneity of the tumor samples was addressed by comparing the median target expression. Expression of the most promising target was also analyzed in a pooled panel of healthy tissue. For survival analysis Kaplan-Meier analysis was performed.
Results: PDPN showed the highest expression (median: 4.73), followed by CSPG4 (median: 2.73) and B7H3 (median: 2.37). HER2 (median: 1.25), EphA2 (median: 0.866) and IL-13Rα2 (median: 0.512) displayed medium expression. The expression of CD70 (median: 0.009) and ROR2 (median: 0.038) was rather low. All investigated targets had high interpersonal heterogeneity but low expression in normal brain tissue. None of them had any significant impact on overall or progression-free survival. Since PDPN showed the highest expression, it was additionally investigated in pooled tissue samples of healthy donors. Despite being lower compared to GBM samples, it was moderately expressed in placenta, ovary and lung.
Conclusion: Interpersonal heterogeneity constitutes a major obstacle for the implementation of GBM immune therapies. PDPN shows high expression in a distinct patient collective whilst low expression in pooled healthy tissue. Therefore, it could be suitable as potential target for CAR-T cell therapy.