Dataset Information

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.

SUBMITTER: Owen K

PROVIDER: S-EPMC9628360 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

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.

Owen Kathryn K Ghaly Ramy R Shohdy Kyrillus S KS Thistlethwaite Fiona F

Cancer immunology, immunotherapy : CII 20221031 4

<h4>Background</h4>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.<h4>Methods</h4>A systematic review was conducted of interventional, prospective clinical trials describing LD practices prior to TCR-T cell therapy in patients with ...[more]

PMID: 36315268

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Project description:Adoptive cell therapy with T cells genetically engineered to express a chimeric antigen receptor (CAR-T) or tumor-infiltrating T lymphocytes (TIL) demonstrates impressive clinical results in patients with cancer. Lymphodepleting preconditioning prior to cell infusion is an integral part of all adoptive T cell therapies. However, to date, there is no standardization and no data comparing different non-myeloablative (NMA) regimens. In this study, we compared NMA therapies with different doses of cyclophosphamide or total body irradiation (TBI) in combination with fludarabine and evaluated bone marrow suppression and recovery, cytokine serum levels, clinical response and adverse events. We demonstrate that a cumulative dose of 120 mg/kg cyclophosphamide and 125 mg/m2 fludarabine (120Cy/125Flu) and 60Cy/125Flu preconditioning were equally efficient in achieving deep lymphopenia and neutropenia in patients with metastatic melanoma, whereas absolute lymphocyte counts (ALCs) and absolute neutrophil counts were significantly higher following 200 cGyTBI/75Flu-induced NMA. Thrombocytopenia was most profound in 120Cy/125Flu patients. 30Cy/75Flu-induced preconditioning in patients with acute lymphoblastic leukemia resulted in a minor ALC decrease, had no impact on platelet counts and did not yield deep neutropenia. Following cell infusion, 120Cy/125Flu patients with objective tumor response had significantly higher ALC and significant lower inflammatory indexes, such as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Receiver-operating characteristics curve analysis 7 days after cell infusion was performed to determine the cut-offs, which distinguish between responding and non-responding patients in the 120Cy/125Flu cohort. NLR≤1.79 and PLR≤32.7 were associated with clinical response and overall survival. Cytokine serum levels did not associate with clinical response in patients with TIL. Patients in the 120Cy/125Flu cohort developed significantly more acute NMA-related adverse events, including thrombocytopenia, febrile neutropenia and cardiotoxicity, and stayed significantly longer in hospital compared with the 60Cy/125Flu and TBI/75Flu cohorts. Bone marrow depletion and recovery were equally affected by 120Cy/125Flu and 60Cy/125Flu preconditioning; however, toxicity and consequently duration of hospitalization were significantly lower in the 60Cy/125Flu cohort. Patients in the 30Cy/75Flu and TBI/75Flu groups rarely developed NMA-induced adverse events; however, both regimens were not efficient in achieving deep bone marrow suppression. Among the regimens, 60Cy/125Flu preconditioning seems to achieve maximum effect with minimum toxicity.

Dataset Information

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.

Background

Methods

Results

Conclusion

Publications

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.

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