Lymphodepleting chemotherapy practices and effect on safety and efficacy outcomes in patients with solid tumours undergoing T cell receptor-engineered T cell (TCR-T) Therapy: a systematic review and meta-analysis

Abstract

Background T cell receptor-engineered T cell (TCR-T) therapy has shown promising efficacy in advanced solid tumours. Lymphodepleting (LD) chemotherapy improves TCR-T cell therapy efficacy but is associated with significant toxicities. Evidence is sparse regarding the optimum LD regimen for TCR-T cell therapy in solid tumours. Methods A systematic review was conducted of interventional, prospective clinical trials describing LD practices prior to TCR-T cell therapy in patients with advanced solid tumours. The objective was to define LD regimens administered prior to TCR-T cell therapy and their effects on specific safety and efficacy outcomes in this patient population. Results Searches returned 484 studies, 19 (231 patients) met the eligibility criteria. Cyclophosphamide (cyclo) 60 mg/kg daily (2 days), plus fludarabine (fludara) 25 mg/m2 daily (5 days) was the most common LD regimen (38% of studies). Higher dose LD regimens were associated with increased pooled incidence rates of febrile neutropaenia compared to low dose (0.64, [95% Confidence interval (CI): 0.50–0.78], vs. 0.39 [95% CI: 0.25–0.53], respectively) but were not significantly associated with higher objective responses (odds ratio: 1.05, 95%CI: 0.60–1.82, p = 0.86). A major shortfall in safety data reporting was identified; determination of LD regimen effects on many safety outcomes was not possible. Conclusion Standard consensus guidelines for the design and reporting of adoptive cell therapy (ACT) studies would facilitate accurate risk–benefit analysis for optimising LD regimens in patients with advanced solid tumours.

Safety and Clinical Response to Combined Immunotherapy with Autologous iNKT Cells and PD-1+CD8+ T Cells in Patients Failing First-line Chemotherapy in Stage IV Pancreatic Cancer

“…Hence, compared with those at the baseline, PD-1 + CD8 + T cells isolated after each cycle could differ a lot in TCR repertoire and be more efficient with better tumor specificity. Lymphodepleting chemotherapy preconditioning is regarded to be pivotal to improve ACT therapy efficacy by eliminating endogenous lymphocytes that compete for homeostatic cytokines, including IL2 and IL7, which are require for the engraftment and persistence of infused cells ( 53 ), and reducing regulatory T cells (Treg) which in turn strengthen the antitumor efficiency of infused cells ( 54 ), but is associated with significant toxicities of febrile neutropenia ( 55 ). Higher dose of lymphodepleting chemotherapy was reported to be associated with increased incidence rate of febrile neutropenia compared with low dose, but were not significantly associated with higher objective responses ( 55 ).…”

“…Lymphodepleting chemotherapy preconditioning is regarded to be pivotal to improve ACT therapy efficacy by eliminating endogenous lymphocytes that compete for homeostatic cytokines, including IL2 and IL7, which are require for the engraftment and persistence of infused cells ( 53 ), and reducing regulatory T cells (Treg) which in turn strengthen the antitumor efficiency of infused cells ( 54 ), but is associated with significant toxicities of febrile neutropenia ( 55 ). Higher dose of lymphodepleting chemotherapy was reported to be associated with increased incidence rate of febrile neutropenia compared with low dose, but were not significantly associated with higher objective responses ( 55 ). In our clinical trial, according to the fact that all 9 patients received chemotherapy prior to the study entry, of whom peripheral cytopenia was noted, lymphodepleting chemotherapy was not performed so as to avoid potential severe toxicity.…”

CAR-T-Cell-Based Cancer Immunotherapies: Potentials, Limitations, and Future Prospects

“…Lymphodepletion can help to lessen the severity of CRS by decreasing the quantity of lymphocytes that can contribute to the release of cytokines. Lymphodepletion can improve the engraftment, expansion, and function of the CAR-T cells and reduce the immunosuppression and competition from the own T cells of patients [ 90 , 91 ].…”

The screening, identification, design and clinical application of tumor-specific neoantigens for TCR-T cells

“…Safety is an issue that must be addressed before TCR-T cells can be used in clinical therapy [ 498 , 499 ]. There have been cases of death in clinical trials of TCR-T cells.…”