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Immuno Term Paper

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CENTRAL

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.

Current immunotherapies for HCC

Adoptive cell therapy Cytokines


 Cytokine- induce killer cell  IFN-alpha
 Tumor infiltrating lymphocytes  Pegylated interferon
 CAR-T/CAR-NK  IL-2
 TCR-T

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

Adoptive cell therapy


Adoptive cell transfer is a cutting-edge immunotherapy technique that aims to enhance the patient's immune
response against cancer cells. The approach involves modifying a patient's own immune cells, typically T cells, to
improve their ability to recognize and destroy cancer cells selectively. By unleashing the power of the immune
system, ACT offers a targeted and personalized approach to HCC treatment.

1.Cytokine-induce killer cell


CIK cells are created in the laboratory by using IL-2, interferon-alpha (IFN)-α, and anti-CD3 monoclonal antibodies to
stimulate human peripheral blood mononuclear cells (PBMC). These cells primarily consist of natural killer (NK) cells,
natural killer T (NKT) cells, and cytotoxic T lymphocytes (CTLs).
CIK cells have the unique ability to recognize and kill tumor cells without relying on the major histocompatibility
complex (MHC) system. Studies have demonstrated the effectiveness of autologous CIK cell therapy in reducing the
signs and features of HCC patients without significant adverse effects. Clinical trials have also shown that CIK cell
treatment can be used in inoperable primary HCC cases, as well as in patients who have undergone tumor removal,
leading to a reduction in recurrence rates and improved recurrence-free survival.

2.Tumour infiltrating lymphocytes


The immune response plays a crucial role in combating tumors, and TIL (Tumor-Infiltrating Lymphocytes) are a
significant component of this response. TILs, along with Tregs, T cells, NK cells, and B cells, form part of the host
immune response against tumors. Studies have shown that TILs are exceptionally effective in treating severe
metastatic cancer, being 50-100 times more effective than lymphokine-activated killer cells in curing mice in
experimental models.
In the context of primary hepatocellular carcinoma (HCC), a form of liver cancer, TIL treatment has been explored in
clinical trials. These TILs are derived from surgical tumor tissues and have the ability to recognize multiple antigens,
giving them a potent tumor-inhibitory effect compared to medications that target specific antigens or mutations.
Although TILs are not abundant in HCC, previous research has demonstrated their significant impact on tumor
recurrence and patient prognosis.

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.

Antibody based therapy


Antibody-based therapy is a promising approach for the treatment of hepatocellular carcinoma (HCC). Several
antibodies have been developed and tested for their efficacy in targeting specific molecules or pathways involved in
HCC development and progression.

1.Monotherapies with Immune checkpoints inhibitors


Inhibitory immunoreceptors called immunological checkpoints, such as TIGIT, LAG3, B and T lymphocyte attenuator,
and TIM3, are expressed on effector immune cells and can limit immune responses. HCC and other solid tumors
exploit these checkpoints to evade anti-tumor immune reactions. Monoclonal antibodies known as immune
checkpoint inhibitors (ICIs) can block the interactions between checkpoint proteins and their ligands, thereby
reactivating the immune response against tumors. Currently, ICIs primarily target CTLA-4, PD-1, and PD-L1, which are
expressed on various immune cells including T cells, NK cells, and dendritic cells. Binding of PD-1 to its ligands, PD-L1
and PD-L2, in HCC and other cancers can inhibit T cell activity and allow tumor cells to evade immune recognition.
Ramucirumab: Ramucirumab is a monoclonal antibody that specifically targets the vascular endothelial growth
factor receptor 2 (VEGFR-2). It has been shown to improve overall survival in patients with advanced HCC who have
previously received sorafenib.

2. Dual therapies with Immune checkpoint inhibitors


Atezolizumab and bevacizumab: Atezolizumab is an anti-PD-L1 antibody, while bevacizumab is an anti-VEGF
antibody. The combination of atezolizumab and bevacizumab has shown promising results in improving overall
survival in patients with unresectable HCC who have not received prior systemic therapy.

3. Bispecific antibody therapy


Bispecific antibodies (BsAbs) are created using recombinant DNA technology and can simultaneously bind two
antigens or epitopes. They have the ability to target immunological checkpoints and tumor-associated antigens
(TAAs), altering immunosuppression in the tumor microenvironment and enhancing immune cell action against
tumors. BsAbs bridge the gap between immune cells and tumor cells, attracting and activating immune cells to attack
tumor cells. Examples include EpCAM/CD3 bispecific antibodies and GPC3/CD3 bispecific antibodies, which have
shown efficacy in targeting HCC cells in preclinical studies. BsAbs offer advantages over monoclonal antibodies,
including synergistic effects and the ability to mediate specific biological effects. Additionally, innovative BsAb
formats like IgG-shaped TriFab allow for sequential antigen activation or targeted delivery of payloads. BsAbs hold
promise in enhancing targeted immunotherapy for HCC and other cancers.

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.

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