The implications of clinical risk factors, CAR index, and compositional changes of immune cells on hyperprogressive disease in non-small cell lung cancer patients receiving immunotherapy

Abstract

Background: Immune checkpoint blockades (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor clinical outcomes. This study aimed to investigate implications of clinical factors and immune cell composition on different tumor responses to immunotherapy in patients with non-small cell lung cancer (NSCLC).Methods: This study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a >2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤ 2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry.Results: Of 231 NSCLC patients, PR/CR and SD were observed in 50 (21.6%) and 79 (34.2%) patients, respectively and 26 (11.3%) patients met the criteria for HPD. Median overall survival in poor response groups (HPD and non-HPD PD) was extremely shorter than region disease-controlled group (SD and PR/CR) (5.5 and 6.1 months vs. 16.2 and 18.3 months, respectively, P= 0.000). In multivariate analysis, HPD were significantly associated with heavy smoker (p=0.0072), PD-L1 expression ≤1% (0.0355), and number of metastatic site ≥3 (0.0297). Among the serologic indexes including NLR, PLR, CAR, and LDH, only CAR had constantly significant correlations with HPD at the beginning of prior treatment, immunotherapy, and at the 1st tumor assessment. The number of CD4+ effector T cells and CD8+ cytotoxic T cells, and CD8+/PD-1+ tumor-infiltrating lymphocytes (TIL) tended to be smaller, especially in stromata of HPD group. More M2-type macrophages expressing CD14, CD68 and CD163 in the stromal area and markedly fewer CD56+ NK cells in the intratumoral area were observed in HPD group.Conclusions: Our study suggests that not only clinical factors including heavy smoker, very low PD-L1 expression, multiple metastases, and CAR index, but also fewer CD8+/PD-1+ TIL and more M2 macrophages in the tumor microenvironment are significantly associated with the occurrence of HPD in the patients with advanced/metastatic NSCLC receiving immunotherapy.

Diffuse goitre enlargement after immunotherapy for non‐small cell lung cancer

“…Recently, increasing evidence shows that immunotherapy with anti‐PD‐(L)1 antibodies is associated with HPD 1 . Previous study shows that heavy smoking, very low PD‐L1 expression and multiple metastases are risk factors for the development of HPD 2 . The present case exhibits these risk factors.…”

“…1 Previous study shows that heavy smoking, very low PD-L1 expression and multiple metastases are risk factors for the development of HPD. 2 The present case exhibits these risk factors. Clinicians must keep in mind that, during immunotherapy, HPD can occur even in potential new metastatic sites.…”

Hyperprogressive disease in patients with unresectable hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy

“…Regarding the association between tumor characteristics at baseline and the risk of HPD, a high number of metastatic sites has been reported to be associated with HPD in patients with non-small cell lung cancer treated with ICIs, which is similar to what we observed. 6,34 A few studies showed the efficacy and safety of early atezolizumab plus bevacizumab therapy in the real-world settings in patients with HCC. [35][36][37] The ORR and DCR were 10.0%-25.4% and 79.6%-86.3%, respectively, in these studies, which were similar to those in the present study.…”

Neoadjuvant chemo-free combination of camrelizumab and apatinib for locally advanced resectable oral squamous cell carcinoma – A pilot study

“…In addition, an abnormal increase of CD163+ in ltration was observed in HPD tumors. Because higher levels of CD4+ and CD8+/FoxP3+ ratios were associated with better outcomes of neoadjuvant therapy, and M2 macrophages in the tumor microenvironment have been reported to be associated with the occurrence of HPD [40][41][42] , further analyses of our tumor samples are urgently needed to explore the underlying mechanisms. Angiogenesis markers for apatinib treatment, including CD31 and -SMA, were inhibited by neoadjuvant therapy in this trial, similarly to previously reported preclinical results 43,44 .…”