Transarterial Chemoembolization Combined With Immune Checkpoint Inhibitors and Tyrosine Kinase Inhibitors for Unresectable Hepatocellular Carcinoma: Efficacy and Systemic Immune Response

Abstract

BackgroundLocoregional therapy combined with systemic therapy can further improve the prognoses for HCC. However, the efficacy of TACE combined with ICIs and TKIs for HCC and whether this triple therapy can activate systemic immune response are still unknown.PurposeTo identify the efficacy of TACE+ICIs+TKIs for unresectable hepatocellular carcinoma (uHCC) and its effect on systemic immunity.Materials and MethodsThis single-center retrospective study was approved by the Institutional Review Board. From August 1, 2019, to March 30, 2021, patients with uHCC who received the combination therapy of TACE+ICIs+TKIs were included. Peripheral blood samples were collected at baseline and once a month for 4 months after treatment. Lymphocyte subsets were measured by flow cytometry. Immunoglobulins were measured using the immune turbidimetric method. The dynamic change trend of circulating parameters was tested using simple linear regression.ResultsFifty-three patients with a mean age of 59 ± 10.6 years were included. TTP was 8.0 months (95% CI, 5.5–10.5) and PFS was 8.5 months (95% CI, 5.4–11.5). ORR was 52.8% and DCR was 81.1%. Twenty patients had completed analysis of biomarkers in peripheral blood. For cellular immune response, the level of circulating CD8+, CD3+ T cells and NK cells increased, the frequency of CD4+T cells and the CD4+/CD8+ ratio decreased, and among them, CD8+ T cells increased significantly. For humoral immune response, there was a significant decrease in B cells and a significant increase in Ig G, Ig κ, and Ig λ. Moreover, Ig G, Ig κ, and Ig λ were related to tumor response.ConclusionTACE+ICIs+TKIs showed considerable efficacy in patients with uHCC. This triple therapy activated not only cell immune but also humoral immune activation. Circulating Ig G, Ig λ, and Ig κ can serve as potential biomarkers.

The Significance of Transarterial Chemo(Embolization) Combined With Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors for Unresectable Hepatocellular Carcinoma in the Era of Systemic Therapy: A Systematic Review

“…On the other hand, systemic therapy is the key to improve the long-term prognosis, but unsatisfactory LC will impair the long-term survival advantage. Preclinical studies have identified the synergistic effect of TACE/HAIC and systemic therapy ( 20 , 21 ), which was also confirmed in practice of the combination of TACE and sorafenib ( 22 ), TACE and lenvatinib ( 23 ), HAIC and sorafenib ( 24 ), and HAIC plus lenvatinib and toripalimab ( 25 ), but it is not the end.…”

“…Yang et al. ( 20 ) firstly identified that the triple therapy could not only activate cell immunity but also stimulate humoral immunity, and circulating Ig G, Ig λ, and Ig κ could serve as potential biomarkers of triple therapy. In the future, more attention should be paid on the triple combination modality for uHCC, especially for those with a strong willingness to receive radical resection.…”

“…The most common AEs are impaired liver function, fever, and abdominal pain related to TACE/HAIC ( 9 – 11 ); hypertension; diarrhea; and hand–foot syndrome to TKIs ( 52 , 53 ) and rash, fatigue, and pruritus to ICIs ( 14 , 19 ), respectively. A combination of TACE/HAIC and TKIs often increases the AEs of hypertension, hand–foot syndrome, and diarrhea, and a combination of TKIs and ICIs increases the risk of fatigue, rash, and hypothyroidism ( 20 , 25 , 31 ). As for the triple combination modality, safety can never be overemphasized.…”

“…Furthermore, the current strategy is far from enough to satisfy the increasing demands of “conversion therapy” for uHCC. In the past 2 years, the triple therapy of TACE/HAIC, TKIs, and ICIs has been tried with encouraging results ( 20 , 25 , 26 ), but most of the studies were retrospective with a small sample size. Therefore, in this study, we comprehensively reviewed all the literature on the triple therapy of TACE/HAIC, TKIs, and ICIs and aimed to provide substantial clues for the subsequent studies.…”

Hepatic artery intervention combined with immune-targeted therapy is superior to sequential therapy in BCLC-C hepatocellular carcinoma

“…Immunotarget therapy with a median PFS of 4.6-6.8 months and ORR of 20-30% still failed to meet clinical needs 17 . In recent years, encouraging results have been made regarding the e cacy of the triple combination, and the ORR and DCR were approximately 50%-70% and 80%-100%, respectively 18,19 . Unfortunately, these results were from studies on small sample populations with fewer than 50 participants.…”