Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Perla Chami
 -- 1580 2023-12-05 17:16:54 |
2 format correct
Catherine Yang
 Meta information modification 1580 2023-12-06 01:48:34 |

Video Upload Options

We provide professional Video Production Services to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Chami, P.; Diab, Y.; Khalil, D.N.; Azhari, H.; Jarnagin, W.R.; Abou-Alfa, G.K.; Harding, J.J.; Hajj, J.; Ma, J.; El Homsi, M.; et al. Immunotherapies for Hepatocellular Carcinoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/52398 (accessed on 26 December 2024).
Chami P, Diab Y, Khalil DN, Azhari H, Jarnagin WR, Abou-Alfa GK, et al. Immunotherapies for Hepatocellular Carcinoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/52398. Accessed December 26, 2024.
Chami, Perla, Youssef Diab, Danny N. Khalil, Hassan Azhari, William R. Jarnagin, Ghassan K. Abou-Alfa, James J. Harding, Joseph Hajj, Jennifer Ma, Maria El Homsi, et al. "Immunotherapies for Hepatocellular Carcinoma" Encyclopedia, https://encyclopedia.pub/entry/52398 (accessed December 26, 2024).
Chami, P., Diab, Y., Khalil, D.N., Azhari, H., Jarnagin, W.R., Abou-Alfa, G.K., Harding, J.J., Hajj, J., Ma, J., El Homsi, M., Reyngold, M., Crane, C., & Hajj, C. (2023, December 05). Immunotherapies for Hepatocellular Carcinoma. In Encyclopedia. https://encyclopedia.pub/entry/52398
Chami, Perla, et al. "Immunotherapies for Hepatocellular Carcinoma." Encyclopedia. Web. 05 December, 2023.
Immunotherapies for Hepatocellular Carcinoma
Edit
This entry is adapted from the peer-reviewed paper 10.3390/ijms242316773

Hepatocellular carcinoma (HCC) is a prominent health issue with an increasing rate of worldwide occurrence. In 2020, HCC accounted for 906,000 new cases and 830,000 new deaths, making it the third greatest cause of cancer death. Liver diseases, such as cirrhosis and chronic viral hepatitis, often result in the development of inflammation, fibrosis, necrosis, and subsequent regeneration, which will injure and alter the organization of the liver tissues, contributing to HCC prognosis. The main risk factors include hepatitis C virus (HCV), hepatitis B virus (HBV), alcohol use disorder, and non-alcoholic steatohepatitis (NASH).

hepatocellular carcinoma immunotherapy immune checkpoint inhibitors radiation therapy

1. Immunotherapies Available for HCC

Following the approval of atezolizumab (anti-PD-L1) plus bevacizumab, an anti-vascular endothelial growth factor A (anti-VEGF-A), as first-line therapy for unresectable HCC in 2020, treatment with ICIs has generated growing interest for the treatment of HCC. The combination of atezolizumab plus bevacizumab in IMbrave150, a global, multicenter, open-label, phase 3 randomized trial, resulted in superior outcomes in terms of overall survival (OS) and progression-free survival (PFS) over the tyrosine kinase inhibitor sorafenib, which had previously been the standard of systemic therapy for patients with advanced HCC (OS at 12 months: 67.2% vs. 54.6%; median PFS: 6.8 months vs. 4.3 months; p < 0.001) [1]. Another phase 2/3 randomized trial investigating the combination of sintilimab (anti-PD-1) plus IBI305 (a bevacizumab biosimilar) as first-line therapy revealed increased OS and PFS over sorafenib (median OS: NA vs. 10.4 months; median PFS: 4.6 months vs. 2.8 months; p < 0.0001) in patients with unresectable HBV-related HCC [2]. In the more recent randomized, open-label, sponsor-blind, multicenter, global, phase 3 HIMALAYA trial, durvalumab (anti-PD-L1) monotherapy was found to be non-inferior to sorafenib (16.56 months vs. 13.77 months, respectively; p = 0.0035) and the combination of durvalumab plus tremelimumab (anti-CTLA-4) was shown to improve median OS over sorafenib (16.43 months vs. 13.77 months, respectively; p = 0.0035) in patients with unresectable HCC [3]. Updated findings were recently reported by the European Society for Medical Oncology (ESMO), in which the combination of durvalumab plus tremelimumab was found to yield a higher 4-year OS rate compared to sorafenib (25.2% vs. 15.1%, respectively) [4]. Currently, nivolumab (anti-PD-1) monotherapy, nivolumab plus ipilimumab (anti-CTLA-4), pembrolizumab (anti-PD-1), ramucirumab (anti-VEGF-R2), cabozantinib (mTKI), and regorafenib (mTKI) monotherapy are approved by the FDA as second-line therapy for unresectable HCC following the results of several clinical trials [5][6][7][8][9][10]. Results from a phase II study evaluating treatment with tislelizumab (anti-PD-1) as second-line therapy in patients with unresectable HCC have demonstrated an acceptable safety and tolerability profile with an overall response rate (ORR) of 12.4%, a median PFS of 2.7 months, and median OS of 12.4 months [11]. Tislelizumab is currently under study in comparison with sorafenib as first-line therapy in a phase 3 trial in patients with unresectable HCC (NCT03412773). Similarly, camrelizumab (anti-PD-1) was investigated as second-line treatment in a phase 2 trial for patients with advanced HCC and demonstrated anti-tumor activity with an ORR of 14.7%, median PFS of 2.1 months, and a median OS of 13.8 months [12]. A phase 3 trial looking to compare camrelizumab plus apatinib (a VEGF-R2 inhibitor) versus sorafenib as first-line therapy for patients with advanced HCC reported significantly improved outcomes in the combination group over sorafenib (median OS: 22.1 vs. 15.2 months; median PFS: 5.6 vs. 3.7 months, respectively; p < 0.0001) [13]. Moreover, toripalimab (anti-PD-1) plus anlotinib (a VEGF-R2 inhibitor) showed promising results as first-line therapy for patients with unresectable HCC with an ORR of 29%, median PFS of 11 months, and median OS of 18.2 months [14].

2. Mechanism of Action of Immune Checkpoint Inhibitors

Immune checkpoint molecules correspond to ligand–receptor pairs expressed on immune cells, APCs, and tumor cells possessing inhibitory or stimulatory functions, which serve to mediate the innate and adaptive immune responses. The presence of these molecules on tumor cells does not only facilitate escape from the immune system but is also involved in maintaining tumor activities, such as epithelial–mesenchymal transition, self-renewal, metastasis, resistance to anti-tumor drugs, angiogenesis, and anti-apoptosis, among others [15]. Examples of inhibitory immune checkpoint receptors include CTLA-4, PD-1, T cell immunoglobulin and mucin domain 3 (TIM-3), lymphocyte activation gene 3 (LAG-3), and killer immunoglobulin-like receptors (KIRs) [16].
The activation or inhibition of the immune response begins with the binding of the MHC receptors on T cells to the tumor-associated antigens (TAMs) on APCs. This process also requires additional costimulatory or coinhibitory binding associations, which constitute the basis of the immune checkpoint. For instance, the costimulatory marker CD28 on T cells binds to CD80 (B7-1) and CD86 (B7-2) on APCs. The result of both signals is the activation of the immune response as T cells proliferate and cytokines are released [17]. CTLA-4, which is expressed on active CD4+, CD8+, and regulatory T cells, is upregulated following T cell activation and acts as a competitive inhibitor of CD28 and binds to its receptors with higher affinity, thus diminishing T cell costimulation and curtailing the T cell response [17][18][19]. While its role under healthy conditions is to modulate T cell activity by inhibiting excessive T cell activation, CTLA-4, in the context of cancer, prevents the proliferation and activation of tumor-specific T cells [20]. Anti-CTLA-4 ICIs, such as ipilimumab and tremelimumab, bind to the CTLA-4 receptor in order to lift the inhibitory signal and favor the activation and proliferation of T cells and, therefore, the enhancement the immune response [17][21]. Similarly, anti-PD-1 and anti-PD-L1 ICIs serve to block binding at the PD-1/PD-L1 or PD-1/PD-L2 checkpoints and prevent the interaction between T cells and other immune cells (e.g., B cells, myeloid cells) expressing PD-1 and tumor cells, APCs, and other immune cells expressing PD-1 ligands [22]. In the absence of these ICIs, the binding between PD-1 and PD-L1 allows tumor cells to evade immune detection by the inactivation of T cells through the dephosphorylation of T cell-activating kinases [23]. In addition, the prevention of interleukin-2 (IL-2), interferon-𝛾 (IFN-𝛾), and tumor necrosis factor-𝛼 (TNF-𝛼) release and the decrease in T cell survival are characteristic of both CTLA-4 and PD-1 signaling. However, these pathways differ in the timing and location of their inhibitory functions as CTLA-4 acts in the lymph nodes early in the immune response during T cell priming while PD-1 generally acts later in the immune response during the T cell effector phase in peripheral tissues [22].
Table 1 summarizes the timing, location, and mechanisms of action of several ICIs that have been administered to patients with HCC.
Table 1. Role of several immune checkpoint inhibitors used to treat hepatocellular carcinoma.
Immune Checkpoint Inhibitors Target Timing and Location in Immunity Cycle [22] Mechanism of Action [18][22]
Ipilimumab CTLA-4 T cell priming phase in lymph nodes Anti-CTLA-4 binds to the CTLA-4 receptor on CD4+, CD8+, and regulatory T cells allowing T cell costimulation and activation
Tremelimumab
Nivolumab PD-1 T cell effector phase in peripheral tissues Anti-PD-1 binds to the PD-1 receptor on T cells, B cells, and myeloid cells, allowing immune detection of tumor cells
Pembrolizumab
Sintilimab
Tislelizumab
Camrelizumab
Toripalimab
Atezolizumab PD-L1 T cell effector phase in peripheral tissues Anti-PD-L1 binds to PD-L1 on APCs, tumor, and other immune cells, allowing immune detection of tumor cells
Durvalumab
CTLA-4: Cytotoxic T lymphocyte-associated protein 4; PD-1: programmed cell death receptor 1; PD-L1: programmed cell death ligand 1; APCs: antigen-presenting cells.

3. Combination of Immune Checkpoint Inhibitors

Combinations of ICIs, such as atezolizumab plus bevacizumab and tremelimumab plus durvalumab, have shown promising additive anti-tumor activity for patients with HCC [1][3]. In the HIMALAYA trial, a single dose of tremelimumab (anti-CTLA-4) was given as a priming dose and was followed by durvalumab (anti-PD-L1), which was given every 4 weeks to patients with unresectable HCC [3]. Similarly, the CheckMate 040 trial aimed to assess different dosing plans of nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) in HCC patients that had received sorafenib treatment and reported the highest ORR in the treatment arm that received nivolumab plus a higher dose of ipilimumab (4 doses/every 3 weeks) followed by nivolumab every 2 weeks [6]. The rationale behind administering a priming dose of an CTLA-4 inhibitor followed by a PD-L1 inhibitor is that anti-CTLA-4 drugs can restore cytotoxic T cell activation in lymphoid tissues, which would consequently result in increased CD8+ T cell infiltration at the tumor site. In the absence of CTLA-4 blockers, the inhibition of the PD-1/PD-L1 checkpoint would not lead to anti-tumor activity as T cells would have been inactivated in the priming phase, and since they have not yet reached the effector phase they would be absent from tumor tissues [20]. In addition, the combination of VEGF blockers (e.g., bevacizumab or ramucirumab) with PD-1/PD-L1 ICIs has displayed the ability to remodel the immunosuppressive microenvironment characteristic of tumor growth. In the case of solid tumors, such as HCC, VEGF is secreted by hypoxic tumor cells and vascular endothelial cells, and leads to the recruitment of regulatory T cells, TAMs, and MDSCs, which in turn release additional VEGF and immunosuppressive cytokines (e.g., IL-10, TGF-β). VEGF also affects both the priming and effector stages by suppressing the maturation of dendritic cells and the presentation of antigens and by inhibiting the infiltration of activated T cells into cancer tissues, respectively. Consequently, anti-VEGF drugs facilitate the restoration of an immunostimulatory microenvironment. This is carried out through (1) a decrease in the production and release of regulatory T cells, TAMs, MDSCs, IL-10, and TGF-β, (2) the enhancement of CD8+ T cell activation in the priming stage by promoting dendritic cell antigen presentation, and (3) the normalization of tumor vasculature to allow the migration of activated T cells to the cancer. The addition of PD-1/PD-L1 ICIs serves to promote the anti-tumor response by activated T cells [24]. Currently, the TRIPLET-HCC phase 2/3 trial (NCT05665348) is planned to assess the efficacy and safety of combining an anti-CTLA-4 with an anti-PD-L1 and an anti-VEGF agent in patients with HCC by comparing treatment with ipilimumab plus atezolizumab and bevacizumab to the atezolizumab plus bevacizumab combination [25].

References

  1. Finn, R.S.; Qin, S.; Ikeda, M.; Galle, P.R.; Ducreux, M.; Kim, T.-Y.; Kudo, M.; Breder, V.; Merle, P.; Kaseb, A.O. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 2020, 382, 1894–1905.
  2. Ren, Z.; Xu, J.; Bai, Y.; Xu, A.; Cang, S.; Du, C.; Li, Q.; Lu, Y.; Chen, Y.; Guo, Y.; et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): A randomised, open-label, phase 2–3 study. Lancet Oncol. 2021, 22, 977–990.
  3. Abou-Alfa, G.K.; Lau, G.; Kudo, M.; Chan, S.L.; Kelley, R.K.; Furuse, J.; Sukeepaisarnjaroen, W.; Kang, Y.-K.; Van Dao, T.; De Toni, E.N. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022, 1, EVIDoa2100070.
  4. Mode, D. AstraZeneca: Imfinzi Plus Imjudo Demonstrated Sustained Overall Survival Benefit in Advanced Liver Cancer with an Unprecedented One in Four Patients Alive at Four Years in HIMALAYA Phase III Trial. Available online: https://mfn.se/cis/a/astrazeneca/astrazeneca-imfinzi-plus-imjudo-demonstrated-sustained-overall-survival-benefit-in-advanced-liver-cancer-with-an-unprecedented-one-in-four-patients-alive-at-four-years-in-himalaya-phase-iii-trial-4799270e (accessed on 7 September 2023).
  5. Yau, T.; Park, J.W.; Finn, R.S.; Cheng, A.L.; Mathurin, P.; Edeline, J.; Kudo, M.; Harding, J.J.; Merle, P.; Rosmorduc, O.; et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): A randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022, 23, 77–90.
  6. Yau, T.; Kang, Y.K.; Kim, T.Y.; El-Khoueiry, A.B.; Santoro, A.; Sangro, B.; Melero, I.; Kudo, M.; Hou, M.M.; Matilla, A.; et al. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA Oncol. 2020, 6, e204564.
  7. Zhu, A.X.; Finn, R.S.; Edeline, J.; Cattan, S.; Ogasawara, S.; Palmer, D.; Verslype, C.; Zagonel, V.; Fartoux, L.; Vogel, A.; et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): A non-randomised, open-label phase 2 trial. Lancet Oncol. 2018, 19, 940–952.
  8. Zhu, A.X.; Kang, Y.K.; Yen, C.J.; Finn, R.S.; Galle, P.R.; Llovet, J.M.; Assenat, E.; Brandi, G.; Pracht, M.; Lim, H.Y.; et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019, 20, 282–296.
  9. Psilopatis, I.; Damaskos, C.; Garmpi, A.; Sarantis, P.; Koustas, E.; Antoniou, E.A.; Dimitroulis, D.; Kouraklis, G.; Karamouzis, M.V.; Vrettou, K.; et al. FDA-Approved Monoclonal Antibodies for Unresectable Hepatocellular Carcinoma: What Do We Know So Far? Int. J. Mol. Sci. 2023, 24, 2685.
  10. Kelley, R.K.; Mollon, P.; Blanc, J.F.; Daniele, B.; Yau, T.; Cheng, A.L.; Valcheva, V.; Marteau, F.; Guerra, I.; Abou-Alfa, G.K. Comparative Efficacy of Cabozantinib and Regorafenib for Advanced Hepatocellular Carcinoma. Adv. Ther. 2020, 37, 2678–2695.
  11. Ducreux, M.; Abou-Alfa, G.; Ren, Z.; Edeline, J.; Li, Z.; Assenat, E.; Rimassa, L.; Blanc, J.; Ross, P.; Fang, W. O-1 Results from a global phase 2 study of tislelizumab, an investigational PD-1 antibody, in patients with unresectable hepatocellular carcinoma. Ann. Oncol. 2021, 32, S217.
  12. Qin, S.; Ren, Z.; Meng, Z.; Chen, Z.; Chai, X.; Xiong, J.; Bai, Y.; Yang, L.; Zhu, H.; Fang, W. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: A multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol. 2020, 21, 571–580.
  13. Qin, S.; Chan, L.; Gu, S.; Bai, Y.; Ren, Z.; Lin, X.; Chen, Z.; Jia, W.; Jin, Y.; Guo, Y. LBA35 Camrelizumab (C) plus rivoceranib (R) vs. sorafenib (S) as first-line therapy for unresectable hepatocellular carcinoma (uHCC): A randomized, phase III trial. Ann. Oncol. 2022, 33, S1401–S1402.
  14. Zhang, C.S.; Zeng, Z.M.; Zhuo, M.Y.; Luo, J.R.; Zhuang, X.H.; Xu, J.N.; Zeng, J.; Ma, J.; Lin, H.F. Anlotinib Combined With Toripalimab as First-Line Therapy for Unresectable Hepatocellular Carcinoma: A Prospective, Multicenter, Phase II Study. Oncologist 2023, oyad169.
  15. Zhang, Y.; Zheng, J. Functions of Immune Checkpoint Molecules Beyond Immune Evasion. Adv. Exp. Med. Biol. 2020, 1248, 201–226.
  16. Pennock, G.K.; Chow, L.Q. The evolving role of immune checkpoint inhibitors in cancer treatment. Oncologist 2015, 20, 812–822.
  17. Saad, P.; Kasi, A. Ipilimumab; StatPearls Publishing: Treasure Island, FL, USA, 2020.
  18. Walker, L.S.; Sansom, D.M. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat. Rev. Immunol. 2011, 11, 852–863.
  19. Zhang, H.; Dai, Z.; Wu, W.; Wang, Z.; Zhang, N.; Zhang, L.; Zeng, W.J.; Liu, Z.; Cheng, Q. Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer. J. Exp. Clin. Cancer Res. 2021, 40, 184.
  20. Kudo, M. Scientific rationale for combination immunotherapy of hepatocellular carcinoma with anti-PD-1/PD-L1 and anti-CTLA-4 antibodies. Liver Cancer 2019, 8, 413–426.
  21. Keam, S.J. Tremelimumab: First Approval. Drugs 2023, 83, 93–102.
  22. Buchbinder, E.I.; Desai, A. CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. Am. J. Clin. Oncol. 2016, 39, 98–106.
  23. Yokosuka, T.; Takamatsu, M.; Kobayashi-Imanishi, W.; Hashimoto-Tane, A.; Azuma, M.; Saito, T. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J. Exp. Med. 2012, 209, 1201–1217.
  24. Kudo, M. Scientific Rationale for Combined Immunotherapy with PD-1/PD-L1 Antibodies and VEGF Inhibitors in Advanced Hepatocellular Carcinoma. Cancers 2020, 12, 1089.
  25. Merle, P.; Blanc, J.F.; Edeline, J.; Le Malicot, K.; Allaire, M.; Assenat, E.; Guarssifi, M.; Bouattour, M.; Péron, J.M.; Laurent-Puig, P.; et al. Ipilimumab with atezolizumab-bevacizumab in patients with advanced hepatocellular carcinoma: The PRODIGE 81-FFCD 2101-TRIPLET-HCC trial. Dig. Liver Dis. 2023, 55, 464–470.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Perla Chami
,
Youssef Diab
,
Danny N. Khalil
,
Hassan Azhari
,
William R. Jarnagin
,
Ghassan K. Abou-Alfa
,
James J. Harding
,
Joseph Hajj
,
Jennifer Ma
,
Maria El Homsi
,
Marsha Reyngold
,
Christopher Crane
,
Carla Hajj
View Times: 403
Revisions: 2 times (View History)
Update Date: 06 Dec 2023
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback