Immuno Term Paper
Immuno Term Paper
Immuno Term Paper
UNIVERSITY OF
PUNJAB
TERM PAPER
ESSENTIALS OF
IMMUNOLOGY
“IMMUNOTHERAPIES FOR
HEPATOCELLULAR
CARCINOMA”
Submitted by – Divya
Regd No.-22MSLSMM34
Submitted to – Dr. Ujjawal Sharma
Introduction:
Hepatocellular carcinoma (HCC) is a formidable adversary, accounting for a significant burden of cancer-related
deaths worldwide. Traditional treatment options, such as surgery and chemotherapy, have limitations, particularly in
advanced-stage HCC. However, a ray of hope has emerged in the form of immunotherapy, which harnesses the
power of the immune system to fight cancer.
This passage highlights the potential of immunotherapy in the treatment of solid tumors, particularly hepatocellular
carcinoma (HCC), a form of liver cancer. It emphasizes the unique immunological tolerance of the liver and its ability
to accept transplants while reducing immune responses to various antigens. However, this tolerance, combined with
the immunosuppressive environment of HCC, hinders the development of effective anti-tumor immune responses.
The passage mentions that the FDA has approved several immune checkpoint inhibitors (ICIs) targeting specific
proteins involved in immune regulation, such as PD-1, CTLA-4, and PD-L1, for the treatment of HCC and other
malignancies. Additionally, other promising immunotherapeutic approaches, including chimeric antigen receptor
(CAR) T-cell therapy, adoptive cell treatment, cytokine therapy, and cancer vaccines, are under development and offer
new hope for HCC patients. The passage concludes by mentioning that the review will provide an overview of the
current state of immunotherapy for HCC, followed by an analysis of the challenges, opportunities, and future
directions in this field of study.
Immunotherapy
Antibody based for HCC Therapeutic vaccine
Immune checkpoint Peptides (AFP, GPC3)
Inhibitors- anti-PD1/ PDL1/ DC Vaccine
CTLA4 Recombinant protein vaccine
Biospecific antibody/ Oncolytic viruses
EpCAM/CD3
Antibody-Drug conjugates
3.CAR-T
Chimeric antigen receptor T cell (CAR-T) therapy is a novel immunotherapy for cancer that involves genetically
modifying T cells to recognize specific tumor-associated antigens (TAA). It has shown success in treating
hematological cancers and has received FDA approval for certain types of leukemia, lymphomas, and multiple
myeloma. CAR-T therapy for liver malignancy, such as hepatocellular carcinoma (HCC), is currently being developed
due to the challenges posed by solid tumors and the tumor microenvironment. CAR-T cells can overcome limitations
of traditional T cells by bypassing MHC antigen presentation and targeting antigens like GPC3 and AFP that are
overexpressed in HCC. Clinical trials have demonstrated the effectiveness of CAR-T cell treatment in solid tumors, and
combining CAR-T therapy with immune checkpoint inhibitors (ICIs) has shown promise in increasing efficacy.
Targeting intracellular antigens with CAR-T cells has also shown effectiveness in treating HCC. Additionally, the c-Met
receptor, which plays a role in hepatocyte survival and proliferation, is being explored as a potential target for CAR-T
therapy.
The overexpression of c-Met, as well as other antigens such as NKG2DL, CD147, Mucin 1, EpCAM, and CD133, has
been identified in hepatocellular carcinoma (HCC). Researchers have developed CAR-T cells targeting these antigens
and have demonstrated their effectiveness in attacking HCC cells in preclinical models. Combination strategies, such
as targeting both c-Met and PD-L1, have shown significant cytotoxic effects on HCC cells. However, many of these
antigens are also expressed in low levels in healthy cells, posing challenges in achieving specificity and avoiding off-
target toxicities. Future research aims to identify new targeted antigens and improve the efficacy and safety of CAR-T
therapy for HCC.
Cytokines therapy
Cytokines play a crucial role in the immune response to cancer and have garnered interest as potential cancer
treatments.
1.Interleukin-10 (IL-10) is an anti-inflammatory cytokine that is produced by immune cells and has been
studied in hepatocellular carcinoma (HCC). Elevated levels of IL-10 have been associated with poorer post-operative
outcomes and reduced survival in HCC patients.
2.Interleukin-37β (IL-37β) is a cytokine that inhibits pro-inflammatory cytokine production and has
shown potential as a favorable prognostic marker in HCC. Higher levels of IL-37β have been associated with improved
overall survival and disease-free survival in HBV-related HCC patients.
3.CC Chemokine Ligand 20 (CCL20) plays a role in inflammation and has been implicated in HCC
development, invasion, and the attraction of regulatory T cells to the tumor microenvironment. Higher levels of
CCL20 have been associated with worse prognosis in HCC patients.
4.IL-6 is a cytokine that has been studied in the context of advanced HCC. Higher levels of IL-6 before therapy have
been associated with poor overall survival in sorafenib-treated HCC patients.
5.Angiopoietin-2 (ANG-2) is a regulator of vascular development and has been studied as a prognostic
marker in HCC. Higher levels of ANG-2 have been associated with shorter overall survival in HCC patients.
These cytokines have been studied for their associations with HCC progression, prognosis, and response to
treatment, providing insights into potential therapeutic targets and prognostic indicators for HCC patients. Further
research is needed to fully understand their roles and clinical implications.
Therapeutic vaccines
Tumor vaccines are being explored as a potential immunotherapy approach for hepatocellular carcinoma (HCC) to
enhance immune responses against tumor antigens. Clinical trials for HCC vaccines have shown disappointing results
in the past, but advancements in technology have enabled the identification of suitable tumor antigens. Peptide-
based and dendritic cell (DC)-based vaccines are two categories of HCC vaccination methods being studied. However,
current vaccine strategies face challenges such as tumor tolerance mechanisms, the immunosuppressive HCC
environment, and limited tumor-specific antigens. To improve vaccine efficacy, strategies like targeted vaccines and
the inclusion of additional tumor antigens are being investigated. Future HCC vaccination approaches may also
consider neoantigens for their tumor selectivity and potential immunogenicity.
1.Dendritic cells (DCs) are potent antigen-presenting cells that play a crucial role in processing and
presenting tumor-associated antigens (TAAs) to initiate immune responses.
Allogeneic DCs are commonly used in vaccines as they provide both the antigen and secondary co-stimulation for
effective T cell activation.DCs can be isolated from peripheral blood, cultured ex vivo, and activated with cytokines
like GM-CSF to generate primed DCs for reinfusion. Targeted strategies involve injecting DCs to activate effector cells,
induce tumor cell rupture, and enhance TAA secretion.
2.Peptide vaccines are another approach that involves administering specific peptide sequences derived
from TAAs to stimulate immune responses. However, clinical efficacy has been limited despite successful generation
of T cell responses in some trials.
3.Oncolytic viruses are emerging as a promising approach in tumor vaccines. These viruses selectively
replicate in cancer cells and can be administered through intra-tumoral injection. The oncolytic virus JX-594 has
shown potential in clinical trials for HCC, demonstrating a dose-related survival benefit.
Ongoing clinical trials are investigating the use of oncolytic viruses, such as Pexa-Vec (JX-594), in combination with
other therapies like sorafenib for advanced HCC.
Overall, DC-based vaccines, peptide vaccines, and oncolytic viruses offer potential strategies for enhancing immune
responses against HCC, but further research is needed to optimize their efficacy and explore their combination with
other treatments.
Conclusion
In conclusion, immunotherapy has emerged as a promising approach in the treatment of hepatocellular carcinoma
(HCC). Immune checkpoint inhibitors, adoptive cell therapy, CAR-T cell therapy, antibody-based therapy, cytokine
therapy, and therapeutic vaccines are among the immunotherapeutic strategies being explored for HCC. While
immune checkpoint inhibitors have shown significant success in clinical trials, other approaches such as adoptive cell
therapy, CAR-T cell therapy, and antibody-based therapy are still under development but hold great promise.
Cytokines play a crucial role in the immune response to HCC and offer potential targets for therapeutic intervention.
Additionally, tumor vaccines, particularly dendritic cell-based vaccines and peptide vaccines, show potential for
enhancing immune responses against HCC, although further research is needed to optimize their efficacy. Oncolytic
viruses represent a novel and promising approach in tumor vaccines, demonstrating encouraging results in clinical
trials for HCC.
Despite the progress made, challenges remain in the field of immunotherapy for HCC. The immunosuppressive tumor
microenvironment, limited tumor-specific antigens, and tumor tolerance mechanisms pose obstacles to achieving
robust and durable anti-tumor immune responses. Further research is needed to overcome these challenges, identify
new therapeutic targets, and improve treatment outcomes for HCC patients. The combination of different
immunotherapeutic modalities and the exploration of innovative strategies, such as targeting neoantigens, hold
promise for advancing the field of immunotherapy in HCC. Overall, immunotherapy offers new hope for patients with
HCC and has the potential to revolutionize the treatment landscape for this aggressive malignancy.
Refrences:
1.Mandlik, D. S., Mandlik, S. K., & Choudhary, H. B. (2023). Immunotherapy for hepatocellular carcinoma: Current
status and future perspectives. World journal of gastroenterology, 29(6), 1054–1075.
https://doi.org/10.3748/wjg.v29.i6.1054
2.Abu-Sbeih, H., Ali, F. S., Wang, X., Mallepally, N., Chen, E., Altan, M., Bresalier, R. S., Charabaty, A., Dadu, R., Jazaeri,
A., Lashner, B., & Wang, Y. (2019). Early introduction of selective immunosuppressive therapy associated with
favorable clinical outcomes in patients with immune checkpoint inhibitor-induced colitis. Journal for immunotherapy
of cancer, 7(1), 93. https://doi.org/10.1186/s40425-019-0577-1
3.Casadei-Gardini, A., Scartozzi, M., Tada, T., Yoo, C., Shimose, S., Masi, G., Lonardi, S., Frassineti, L. G., Nicola, S.,
Piscaglia, F., Kumada, T., Kim, H. D., Koga, H., Vivaldi, C., Soldà, C., Hiraoka, A., Bang, Y., Atsukawa, M., Torimura, T.,
Tsuj, K., … Cucchetti, A. (2021). Lenvatinib versus sorafenib in first-line treatment of unresectable hepatocellular
carcinoma: An inverse probability of treatment weighting analysis. Liver international : official journal of the
International Association for the Study of the Liver, 41(6), 1389–1397. https://doi.org/10.1111/liv.14817
4.Sangro, B., Sarobe, P., Hervás-Stubbs, S. et al. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev
Gastroenterol Hepatol 18, 525–543 (2021). https://doi.org/10.1038/s41575-021-00438-0
5.Sun, C., Sun, H. Y., Xiao, W. H., Zhang, C., & Tian, Z. G. (2015). Natural killer cell dysfunction in hepatocellular
carcinoma and NK cell-based immunotherapy. Acta pharmacologica Sinica, 36(10), 1191–1199.
https://doi.org/10.1038/aps.2015.41
6.Cui, J., Wang, N., Zhao, H., Jin, H., Wang, G., Niu, C., Terunuma, H., He, H., & Li, W. (2014). Combination of
radiofrequency ablation and sequential cellular immunotherapy improves progression-free survival for patients with
hepatocellular carcinoma. International journal of cancer, 134(2), 342–351. https://doi.org/10.1002/ijc.28372
7.Cao, J., Kong, F. H., Liu, X., & Wang, X. B. (2019). Immunotherapy with dendritic cells and cytokine-induced killer
cells for hepatocellular carcinoma: A meta-analysis. World journal of gastroenterology, 25(27), 3649–3663.
https://doi.org/10.3748/wjg.v25.i27.3649
8. Heimbach, J. K., Kulik, L. M., Finn, R. S., Sirlin, C. B., Abecassis, M. M., Roberts, L. R., Zhu, A.
X., Murad, M. H., & Marrero, J. A. (2018). AASLD guidelines for the treatment of hepatocellular
carcinoma. Hepatology (Baltimore, Md.), 67(1), 358–380. https://doi.org/10.1002/hep.29086
9. Terashima, T., Yamashita, T., Takata, N., Toyama, T., Shimakami, T., Takatori, H., Arai, K.,
Kawaguchi, K., Kitamura, K., Yamashita, T., Sakai, Y., Mizukoshi, E., Honda, M., & Kaneko, S.
(2020). Comparative analysis of liver functional reserve during lenvatinib and sorafenib for
advanced hepatocellular carcinoma. Hepatology research : the official journal of the Japan
Society of Hepatology, 50(7), 871–884. https://doi.org/10.1111/hepr.13505
10. Cheng, A. L., Hsu, C., Chan, S. L., Choo, S. P., & Kudo, M. (2020). Challenges of
combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. Journal
of hepatology, 72(2), 307–319. https://doi.org/10.1016/j.jhep.2019.09.025
11. Nakagawa, H., Mizukoshi, E., Kobayashi, E., Tamai, T., Hamana, H., Ozawa, T., Kishi, H.,
Kitahara, M., Yamashita, T., Arai, K., Terashima, T., Iida, N., Fushimi, K., Muraguchi, A., &
Kaneko, S. (2017). Association Between High-Avidity T-Cell Receptors, Induced by α-
Fetoprotein-Derived Peptides, and Anti-Tumor Effects in Patients With Hepatocellular
Carcinoma. Gastroenterology, 152(6), 1395–1406.e10.
https://doi.org/10.1053/j.gastro.2017.02.001
12. Lee, J. H., Lee, Y., Lee, M., Heo, M. K., Song, J. S., Kim, K. H., Lee, H., Yi, N. J., Lee, K. W.,
Suh, K. S., Bae, Y. S., & Kim, Y. J. (2015). A phase I/IIa study of adjuvant immunotherapy with
tumour antigen-pulsed dendritic cells in patients with hepatocellular carcinoma. British journal
of cancer, 113(12), 1666–1676. https://doi.org/10.1038/bjc.2015.430
13. Rizell, M., Sternby Eilard, M., Andersson, M., Andersson, B., Karlsson-Parra, A., & Suenaert,
P. (2019). Phase 1 Trial With the Cell-Based Immune Primer Ilixadencel, Alone, and Combined
With Sorafenib, in Advanced Hepatocellular Carcinoma. Frontiers in oncology, 9, 19.
https://doi.org/10.3389/fonc.2019.00019
14. Charneau, J., Suzuki, T., Shimomura, M., Fujinami, N., & Nakatsura, T. (2021). Peptide-
Based Vaccines for Hepatocellular Carcinoma: A Review of Recent Advances. Journal of
hepatocellular carcinoma, 8, 1035–1054. https://doi.org/10.2147/JHC.S291558
15. Lee, W. C., Wang, H. C., Hung, C. F., Huang, P. F., Lia, C. R., & Chen, M. F. (2005).
Vaccination of advanced hepatocellular carcinoma patients with tumor lysate-pulsed dendritic
cells: a clinical trial. Journal of immunotherapy (Hagerstown, Md. : 1997), 28(5), 496–504.
https://doi.org/10.1097/01.cji.0000171291.72039.e2