The Role Of Immunotherapy in

Hepatcellular Carcinoma (HCC)

dr. Lisa
 Outlines
• Definition and Risk Factors of HCC
• Pathophysiology of HCC
• surveillance and Diagnostic of HCC
• Treatments of HCC
• Rule of immunotherapy in HCC
⚬ To Understand what immunotherapy checkpoint inhibitors are and how they can help to fight
cancer
⚬ PD-1 inhibitors
⚬ ctla-4 inhibitors
⚬ combination immune therapy and side effects
 Hepatocellular Carcinoma (HCC)

is the most common primary liver malignancy and is a

leading cause of cancer-related death worldwide.

1. Bolagh J, Victor D, et all. Hepatocellular Carcinoma : a review. Journal Hepatocellular carcinoma.2016:3.41-53.http://dx.doi.org/10.2147.JHC.S61146

2. Noha E. Ibrahim, Wael M. Aboulthana, Ram Kumar Sahu. Hepatocellular Carcinoma: Causes and Prevention. PBJ [Internet]. 2018Oct.23 [cited
2021Nov.29];00:48-5. Available from: http://pharmabiosciencejournal.com/index.php/pbj/article/view/1928
 Rising New Case and Deaths from Liver Cancer in the Worldwide

• Worldwide 2020 ; estimated 905,667 new cases  830.180

deaths
– East asia ; 17.9/ 100.000 population
• Prognosis for survival is poor ;
– 5 year relative survival ; 18.4%
– Length of survival depends on largely on extent of cirrhosis in the
liver; cirrhotic patients have shorter survival times and more
limited therapeutic options.

Cicalese,L. Hepatocellular Carcinoma.[2021].cited on Nov 29 2021. 08.33. available from : https://emedicine.medscape.com/article/197319-overview#a10

 RISK FACTORS AND PROGRESSION TO HCC

1. Bolagh J, Victor D, et all. Hepatocellular Carcinoma : a review. Journal Hepatocellular carcinoma.2016:3.41-53.http://dx.doi.org/10.2147.JHC.S61146

2. Sudoyo A. W, et all. Buku Ajar Ilmu Penyakit Dalam ed.IV. Jakarta: Pusat Penerbitan Departemen Ilmu Penyakit Dalam FKUI. 2006. hal 457
 Pathophysiology of
HCC

1. Sudoyo,A.W, et all. Buku Ajar Ilmu Penyakit Dalam ed.IV. Jakarta: Pusat Penerbitan Departemen Ilmu Penyakit
Dalam FKUI. 2006. hal 457.
2. Dhabasekaran,R, Bandoh S, Roberts,L.R. Molecular Pathogenesis of hepatocellular carcinoma and impact of
therapeutic advances (version 1; referees: 4 approved). [2016]. https://doi.org/10.12688/f1000research.6946.1
 Surveillance and Diagnostic

• Benefit Surveillance is improves overall survival

• Every 6 months ; ultrasound and alfa feto protein test

1. Marrero, J.A, et all.(Ed). Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 practice guidance by the American
Association for the Study of Liver Disease. Practice Guidance Hepatology. 2018. Vol. 68, No.2.
 Diagnostic
The AASLD recommends diagnostic evaluation for HCC with either multiphase CT with contrast
or multiphase MRI, if the diagnosis still remains uncertain, a AFP serum level >400 ng/ml has a
high predictive value.

Figure of HCC shows arterial phase hypervascularity with washout

of contrast

1. Marrero, J.A, et all.(Ed). Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 practice guidance by the American Association for the Study of Liver
Disease. Practice Guidance Hepatology. 2018. Vol. 68, No.2.
2. Bolagh J, Victor D, et all. Hepatocellular Carcinoma : a review. Journal Hepatocellular carcinoma.2016:3.41-53.http://dx.doi.org/10.2147.JHC.S61146
1. Marrero, J.A, et all.(Ed). Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 practice guidance by the American
Association for the Study of Liver Disease. Practice Guidance Hepatology. 2018. Vol. 68, No.2.
1. Sudoyo,A.W, et all. Buku Ajar Ilmu Penyakit Dalam ed.IV. Jakarta: Pusat Penerbitan Departemen Ilmu Penyakit Dalam FKUI. 2006. hal 457.
 Multidisciplinary Team

1. Bolagh J, Victor D, et all. Hepatocellular Carcinoma : a review. Journal Hepatocellular carcinoma.2016:3.41-53.http://dx.doi.org/10.2147.JHC.S61146

2. Marrero, J.A, et all.(Ed). Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 practice guidance by the American Association for the Study of Liver
Disease. Practice Guidance Hepatology. 2018. Vol. 68, No.2.
 What are Immune Checkpoint inhibitors?
• Type of cancer treatment that utilizes the patient's immune system to fight cancer
• Immune systems checkpoints are proteins present on immune cells, needs to be inactivated to start an
immune response
• Checkpoint inhibitors : working as a ‘brakes’ off the immune system  helps recognize and attack
cancer cells.
• Types of inhibitors :
• PD-1/PD-L1
• CTLA-4 inhibitors

1. Eno, J. Immunotherapy Through the Years. J Adv Pract Oncol.[2017]. Vol 8;747-753. Https://doi.org/10.6004/jadpro.2017.8.7.8
2. Xu feng, et all. Immune Checkpoint Therapy in Liver cancer. Journal of Experimental & Clinical Cancer Center Research. [2018]. 37:110
Https://doi.org/10.1186/s13046-018-0777-4
 Figure illustration of stimulatory and inhibitory checkpoint beetwen T-cells ,
APCs, and cancer cells. Red: inhibitory immune checkpoint; Blue: Stimulatory
Immune Checkpoint.

1. Xu feng, et all. Immune Checkpoint Therapy in Liver cancer. Journal of Experimental & Clinical Cancer Center Research. [2018]. 37:110 Https://doi.org/10.1186/s13046-018-0777-4
 PD-1 and PD-L1 Immune checkpoints

• PD-1 is one of the checkpoints present on immune cells (T-cell)

• PD-1 act as a "switch off" that keep the T-cell from attacking other cells in the body

• PD-L1, a protein on some normal (and cancer) cells

• When PD-1 binds to PD-L1, it tells the T cell to leave the other cell alone. Some cancer
cells have large amounts of PD-L1, which helps them hide from an immune attack.

1. Abdin S.M, Zaher D.M, et all. Tackling cancer resistance by immunotherapy: Updated clinical impact and safety of PD-1/PD-L1 inhibitors [internet]. Sharjah. [2018].
[cited 2021 nov 28] Available from http://www.mdpi.com/journal/cancers.
2. Eno, J. Immunotherapy Through the Years. J Adv Pract Oncol.[2017]. Vol 8;747-753. Https://doi.org/10.6004/jadpro.2017.8.7.8
 How PD-1 and PD-L1 inhibitors fight cancer

PD-1 binds to PD-L1 and inhibits T-cell

killing of tumor cell

Blocking PD-1 or PD-L1 allows

T-cell killing of tumor cell

1. Abdin S.M, Zaher D.M, et all. Tackling cancer resistance by immunotherapy: Updated clinical impact and safety of PD-1/PD-L1 inhibitors [internet]. Sharjah. [2018].
[cited 2021 nov 28] Available from http://www.mdpi.com/journal/cancers.
When and How PD-1 and PD-L1 inhibitors might be used?
Approved checkpoint inhibitors

PD-1 and PD-L1 inhibitors are used :

• not eligible for transplant, surgery, and local treatment
• have a good liver function; generally good in health
• approved only after prior sorafenib use

1. Eno, J. Immunotherapy Through the Years. J Adv Pract Oncol.[2017]. Vol 8;747-753. Https://doi.org/10.6004/jadpro.2017.8.7.8
what is CTLA-4 inhibitor ?

CTLA-4 is another protein on some T-cell

that act as a type of "switch off"
to keep the immune system in check

1. Eno, J. Immunotherapy Through the Years. J Adv Pract Oncol.[2017]. Vol 8;747-753. Https://doi.org/10.6004/jadpro.2017.8.7.8
Approved checkpoint inhibitors

1. Eno, J. Immunotherapy Through the Years. J Adv Pract Oncol.[2017]. Vol 8;747-753. Https://doi.org/10.6004/jadpro.2017.8.7.8
 Nivolumab and Ipilimumab combination therapy for HCC

• Based on CheckMate-040 study 49 patients with advanced liver cancer

• Approved for liver cancer who have been previously treated with sorefenib
• Approved dosage : nivolumab 1 mg/kg i.v. plus ipilimumab 3 mg/kg i.v. every 3 weeks
for four cycles, followed by nivolumab 240 mg i.v. every 2 weeks.

Saung M.T, et all. FDA Approval Summary: Nivolumab Plus Ipilimumab for the Treatment of Patients with Hepatocellular Carcinoma Previously Treated with Sorafenib
[internet]. USA. The Oncologist. 2021 [ 2021Nov.28]. Available from https://www.theoncologist.com. https://dx.doi.org/10.1002/onco.13819
 Combination of atezolizumab and bevacizumab

336 patients with atezolizumab–bevacizumab group and 165 patients with sorafenib
group, shows that atezolizumab–bevacizumab group have better overall and
progression-free survival outcomes than sorafenib group.

Finn R.S, et all. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 2020 May 19; 382: 1824-905. DOI: 10.1056/NEJMoa1915745
Thank you…