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Impact of concomitant medications on efficacy of CLDN18.2-specific CAR-T cell therapy in advanced gastric cancer
Jiarui Li1, Lian Liu1, Min Tao1
1Beijing Key Laboratory of Cell & Gene Therapy for Solid Tumors, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.
Background:
Claudin18.2 (CLDN18.2)-specific CAR-T cell therapy has demonstrated promise in advanced gastric cancer (GC). However, the impact of concomitant medications on the efficacy outcomes remains unclear.
Methods:
We retrospectively analyzed advanced GC patients receiving CLDN18.2-specific CAR-T cell therapy from a phase I trial. Concomitant medications were defined as any drugs administered within 30 days before and after CAR-T cell infusion, including corticosteroids, antibiotics, tocilizumab, granulocyte colony-stimulating factor (G-CSF), thrombopoietin (TPO), and erythropoietin. Metagenomic sequencing was employed to elucidate the differences in gut microbiome signatures between responders and non-responders.
Results:
Of 72 patients included in the study, 6 (8.3%) received corticosteroids, 49 (68.1%) received tocilizumab, and 22 (30.6%) received antibiotics, 15 (20.8%) received G-CSF, 5 (6.9%) received thrombopoietin, and no patient received erythropoietin. The median progression-free survival (PFS) (2.6 vs. 5.8 months; P < 0.001) and overall survival (OS) (3.9 vs. 9.5 months; P < 0.001) were significantly shorter for patients who received antibiotics for infection compared to those who did not. No significant differences were observed in objective response rate (ORR), PFS, and OS between patients who received corticosteroids, tocilizumab, antibiotics for prophylaxis, G-CSF, or TPO and those who did not. A higher abundance of Fusobacterium nucleatum, Lactobacillus mucosae, Prevotella pallens, and Streptococcus pseudopneumoniae in gut microbiome was associated with a superior treatment response.
Conclusions:
The study indicates that the use of antibiotics for infection reduces the efficacy outcomes of CLDN18.2-specific CAR-T cell therapy for advanced GC, while other concomitant medications do not affect the outcomes. Further research is needed to clarify the optimal administration of these medications and the underlying mechanisms of the gut microbiome in impacting CAR-T treatment response.
Trial Registration:
NCT03874897.
Insights
Antibiotics for infection significantly reduce the effectiveness of Claudin18.2-specific CAR-T cell therapy in advanced gastric cancer. Other common medications did not impact outcomes, but gut microbiome composition may influence treatment response.
Area of Science:
- Immunotherapy
- Oncology
- Gastroenterology
Background:
- Claudin18.2 (CLDN18.2)-specific CAR-T cell therapy shows promise for advanced gastric cancer (GC).
- The influence of concurrent medications on CAR-T therapy efficacy in GC is not well understood.
Purpose of the Study:
- To investigate the impact of concomitant medications on the efficacy of CLDN18.2-specific CAR-T cell therapy in advanced GC patients.
- To explore the role of gut microbiome signatures in predicting treatment response.
Main Methods:
- Retrospective analysis of 72 advanced GC patients undergoing CLDN18.2-specific CAR-T cell therapy.
- Evaluation of concomitant medications (corticosteroids, antibiotics, tocilizumab, G-CSF, TPO, erythropoietin) administered within 30 days of infusion.
- Metagenomic sequencing to analyze gut microbiome composition in responders versus non-responders.
Main Results:
- Antibiotic use for infection was associated with significantly shorter progression-free survival (PFS) and overall survival (OS).
- No significant differences in objective response rate (ORR), PFS, or OS were observed for corticosteroids, tocilizumab, prophylactic antibiotics, G-CSF, or TPO.
- Higher abundance of specific bacteria (Fusobacterium nucleatum, Lactobacillus mucosae, Prevotella pallens, Streptococcus pseudopneumoniae) correlated with superior treatment response.
Conclusions:
- Antibiotics administered for infection negatively impact the efficacy of CLDN18.2-specific CAR-T cell therapy in advanced GC.
- Other concomitant medications studied do not appear to affect treatment outcomes.
- Gut microbiome composition plays a role in CAR-T treatment response, warranting further investigation for optimal therapeutic strategies.
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