Influence of Adipose Tissue Distribution, Sarcopenia, and Nutritional Status on Clinical Outcomes After CD19 CAR T-cell Therapy.

Although CD19-directed chimeric antigen receptor T-cell therapy (CD19.CAR-T) has proven clinical efficacy for multiple refractory B-cell malignancies, over 50% of patients ultimately relapse. Recent evidence has underlined the critical role of the host in determining treatment responses. In this retrospective observational study of 106 patients with relapsed/refractory large B-cell lymphoma receiving standard-of-care CD19.CAR-T, we analyzed the impact of immunometabolic host features and detailed body composition measurements on post-CAR T clinical outcomes. We extracted muscle and adipose tissue distributions from prelymphodepletion CT images and assessed laboratory-based immuno-nutritional scores. Early responders displayed increased total abdominal adipose tissue deposits (TAT: 336 mm3 vs. 266 mm3, P = 0.008) and favorable immuno-nutritional scores compared to nonresponding patients. On univariate Cox regression analysis, visceral fat distribution, sarcopenia, and nutritional indices significantly impacted both progression-free (PFS) and overall survival (OS). Patients with a low skeletal muscle index (SMI; e.g.<34.5), a sarcopenia indicator, exhibited poor clinical outcomes (mOS 3.0 months vs. 17.6 months, log-rank P = 0.0026). Prognostically adverse immuno-nutritional scores were linked to inferior survival [low PNI: HROS, 6.31; 95% confidence interval (CI), 3.35-11.90; P < 0.001]. In a multivariable analysis adjusting for baseline Eastern Cooperative Oncology Group performance status, C-reactive protein, and lactate dehydrogenase, increased TAT was independently associated with improved clinical outcomes (adjusted HROS, 0.27; 95% CI, 0.08-0.90; P = 0.03). We noted particularly favorable treatment outcomes in patients with both increased abdominal fat and muscle mass (TAThigh/SMIhigh: 1-year PFS 50%, 1-year OS 83%). These real-world data provide evidence for a role of body composition and immuno-nutritional status in the context of CD19.CAR-T and suggest that the obesity paradox may extend to modern T cell-based immunotherapies. See related Spotlight by Nawas and Scordo, p. 704.

Survival and immunotoxicities in association with sex-specific body composition patterns of cancer patients undergoing immune-checkpoint inhibitor therapy - A systematic review and meta-analysis.

BACKGROUND: Imbalanced body composition is mechanistically connected to dysregulated immune activities. Whether overweight/obesity or sarcopenia has an impact on treatment results in cancer patients undergoing immune checkpoint inhibitor (ICI) therapy is currently under debate. We aimed to answer if survival rates and occurrence of immune-related adverse events (irAEs) were different in obese or sarcopenic patients. METHODS: A systematic search was conducted in PubMed, Embase and CENTRAL for all records published until July 2022 using specific search terms for body composition in combination with terms for ICI regimens. Two authors screened independently. All studies that reported on body mass index or sarcopenia measures were selected for further analysis. RESULTS: 48 studies reporting on overweight/obesity comprising of 19,767 patients, and 32 studies reporting on sarcopenia comprising of 3193 patients fulfilled the inclusion criteria. In the entire cohort, overweight/obesity was significantly associated with better progression-free survival (PFS; p = 0.009) and overall survival (OS; p <0.00001). Subgroup analyses stratified by sex revealed that overweight/obese males had the strongest survival benefit (PFS: p = 0.05; OS: p = 0.0005), and overweight/obese female patients did not show any. However, overweight/obese patients of both sexes had a higher risk to develop irAEs grade ≥3 (p = 0.0009). Sarcopenic patients showed significantly shorter PFS (p <0.0001) and OS (p <0.0001). The frequency of irAEs did not differ between sarcopenic and non-sarcopenic patients. CONCLUSION: This meta-analysis suggests that body composition is associated in a sex-specific manner with survival and irAEs in cancer patients undergoing ICI treatment.

Increased visceral fat distribution and body composition impact cytokine release syndrome onset and severity after CD19 chimeric antigen receptor T-cell therapy in advanced B-cell malignancies.

Chimeric antigen receptor T-cell (CAR-T) therapy is associated with a distinct toxicity profile that includes cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS is characterized by the release of pro-inflammatory cytokines such as interleukin 6 (IL-6) and is closely linked to CAR-T expansion and bystander cells like monocytes/macrophages. In other hyperinflammatory states, obesity contributes to inflammatory cascades and acts as a risk factor for disease severity. We aimed to study the influence of anthropometric and body composition (BC) measurements on CAR-T-related immunotoxicity in 64 patients receiving CD19-directed CAR-T for relapsed/refractory Bcell malignancies. Patients with grade ≥2 CRS presented with a significantly higher median body mass index (BMI), waist circumference, waist-to-height ratio (WtHR) and visceral adipose tissue (VAT). These parameters were also found to be associated with an earlier CRS onset. Other adipose deposits and muscle mass did not differ between patients with grade 0-1 CRS versus grade ≥2 CRS. Moreover, BC parameters did not influence ICANS severity or onset. In a multivariate binary logistic regression incorporating known risk factors of immunotoxicity, the factors BMI, waist circumference, WtHR and VAT increased the probability of grade ≥2 CRS. Receiver operating characteristic analyses were utilized to determine optimal discriminatory thresholds for these parameters. Patients above these thresholds displayed markedly increased peak IL-6 levels. Our data imply that increased body composition and VAT in particular represent an additional risk factor for severe and early CRS. These findings carry implications for risk-stratification prior to CD19 CAR-T and may be integrated into established risk models.