Anti-CCR7 Monoclonal antibody, clone 4E23 [Biotin]

Background Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade. Patients and methods We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8(+) T lymphocytes was conducted to explore the potential predictive biomarkers of HPD. Results A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival [hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868-7.440] and overall survival (HR, 5.079; 95% CI, 3.136-8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8(+) T lymphocytes, a lower frequency of effector/memory subsets (CCR7(-)CD45RA(-) T cells among the total CD8(+) T cells) and a higher frequency of severely exhausted populations (TIGIT(+) T cells among PD-1(+)CD8(+) T cells) were associated with HPD and inferior survival rate. Conclusion HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.

Lymphocyte recirculation within the human body is essential for efficient pathogen detection and immune responses. So far, immune cell migration has been investigated largely using ovine and murine models, with little evidence in humans. Here, we analyzed peripheral blood of healthy individuals following primary vaccination with the Yellow Fever vaccine YF-17D. We found that the number of leukocytes was transiently and sharply reduced in blood as detected on day 7 after vaccine administration. The T cell drop was restricted to cells expressing the lymph node-homing chemokine receptor CCR7. Interestingly, the vaccine-induced drop positively correlated with the expression of CD69 by the T cells before vaccination. This suggests that CCR7(+) T cells are being trapped within the lymph nodes through CD69-induced suppression of egress. Strikingly, we further found that the T cell drop negatively correlated with CD8 T cell activation and with production of neutralizing antibodies. In conclusion, early and transient T cell depletion in blood negatively correlated with protective immune response events induced by YF-17D vaccination. Our data highlight baseline CD69 expression and early drop in T cells as potential biomarkers of the Yellow Fever vaccine response.