Neutrophil:lymphocyte ratios and serum cytokine changes after hepatic artery chimeric antigen receptor-modified T-cell infusions for liver metastases

Abstract

Our phase I Hepatic Immunotherapy for Metastases (HITM) trial tested the safety of chimeric antigen receptor-modified T-cell (CAR-T) hepatic artery infusions (HAI) for unresectable carcinoembryonic antigen (CEA)+ liver metastases (LM). High neutrophil:lymphocyte ratios (NLR) predict poor outcome in cancer patients and we hypothesized that NLR changes would correlate with early responses to CAR-T HAI. Six patients completed the protocol. Three patients received CAR-T HAI in dose escalation (1 × 10(8), 1 × 10(9) and 1 × 10(10) cells) and the remainder received three doses (1 × 10(10) cells) with interleukin (IL)2 support. Serum cytokines and NLR were measured at multiple time points. The mean NLR for all patients was 13.9 (range 4.8-38.1). NLR increased in four patients following treatment with a mean fold change of 1.9. Serum IL6 levels and NLR fold changes demonstrated a trend towards a positive correlation (r=0.77, P=0.10). Patients with poor CEA responses were significantly more likely to have higher NLR level increases (P=0.048). Increased NLR levels were associated with poor responses following CAR-T HAI. NLR variations and associated cytokine changes may be useful surrogates of response to CAR-T HAI.

Conflict of interest statement

Conflict of Interest: The authors declare no conflict of interest.

Figures

Figure 1. Neutrophil:lymphocyte ratio changes in response to CAR-T hepatic artery infusions

(A) NLR serum levels for patients in the HITM trial who did or did not receive continuous low-dose systemic IL2 infusions. (B) Fold-changes in the NLR for each patient. NLR values were calculated from complete blood counts taken at multiple time points in relation to each CAR-T infusion.

Figure 2. Serum IL6 and IL17 responses to CAR-T hepatic artery infusions

(A) IL6 peripheral blood concentrations for each patient are illustrated, along with fold-changes (B). (C) IL6 absolute values throughout CAR-T HAI treatments in IL2 - and IL2 + groups. (D) IL17 peripheral blood concentrations for each patient are illustrated, along with fold-changes (E). Fold-changes were calculated as the ratio of final to pre-treatment levels. Patient 7 had IL17 detected in only one sample, while patient 8 did not have detectable IL17 at any point.

Figure 3. Correlation of HITM patient neutrophil:lymphocyte ratios with serum IL6 and IL17 levels

ROC plots illustrate the correlations between mean NLR values and mean serum IL6 (A) and IL17(B). (C) IL6 mean serum concentrations stratified and compared based on the mean NLR values.

Figure 4. Neutrophil:lymphocyte ratio changes following CAR-T HAI correlates with serologic response to treatment

(A) ROC plot to demonstrate the NLR fold-change and percentage change in serum CEA for each patient following completion CAR-T HAI. Percentage CEA change from baseline is presented on the x-axis while NLR fold change is illustrated in the Y-axis. (B) NLR fold-change stratification by level of serum CEA following treatment, a decrease of at least 10% in CEA levels was considered a positive response.