The New Era of immunothrapy in

gastric cancer
Dr Adham Abutaha
Siham weredat
Gastric cancer is the fifth most common cancer and the third
most common cause of cancer death globally.

Gastric cancer is diagnosed histologically after endoscopic

biopsy and staged using endoscopic ultrasound, and laparoscop
Types of Gastric cancer :
-Adenocarcinomas
-Lymphomas
-Hereditary (familial) diffuse gastric cancer
Adenocarcinomas of the stomach develop in the cells of
the innermost lining. Most stomach cancer cases, about 90
percent to 95 percent

Lymphomas are cancers of the immune system tissue that

may start anywhere lymph tissues are found, including in the
stomach

Hereditary (familial) diffuse gastric cancer: This type

of stomac cancer, which is caused by a genetic condition passed down
from parents to children, tends to grow in multiple parts of the
stomach and quickly spread to other areas of the body
 Gastric cancer subtype

Based on molecular profiles, GC includes four

subtypes defined by The Cancer Genome Atlas
(TCGA):

-Epstein–Barr virus (EBV)

-Microsatellite instable (MSI)
-Genomically stable (GS)
-Chromosomal instability (CIN)
 Epstein–Barr virus (EBV)
The EBV subtype highlights the viral etiology of gastric cancer; the TCGA
characterization of this subtype suggests potential therapeutic targets for
this group of tumors. EBV was discovered 50 years ago from Burkitt's
lymphoma. EBV is carried in the blood circulation without symptoms by
90% of the adult population

EBV may affect epithelial cells and become carcinogenicIt is estimated

that EBV is associated with 2% of all human tumors including
nasopharyngeal carcinoma, another major cancer type that is unique for
Chinese population especially in the southern areas of China such as
Guangdong Province.
 In recent years, it has been increasingly recognized that the
majority of gastric cancers are associated with infectious agents,
including H. pylori and EBV. EBV is found within malignant
epithelial cells in 9% of gastric cancer

The TCGA network reported that the EBV-positive gastric tumors

cluster together and exhibit a higher prevalence of DNA
hypermethylation
there is a strong predilection for phosphatidylinositol
3-kinase

PIK3CA mutations in EBV-negative gastric cancers are mostly

localized in the kinase domain , but were more dispersed in EBV-
positive gastric cancers. It will be very important for future work
to evaluate how EBV-positive and -negative gastric cancers
respond to the available PI3K inhibitors actively developed by
pharmaceutical companies
TCGA analysis also showed that immunosuppressant proteins
currently being evaluated as targets to augment antitumor
immune response, such as programmed death ligand 1/2 (PD-
L1/2), were elevated in EBV-positive tumors, suggesting that PD-
L1/2 antagonists represent new therapeutic options for the EBV
subtype of gastric cancer
 GS gastric cancers
-This subtype is characterized by mutations in the ras
homolog, (RHOA) gene or fusions involving Rho-family .
-The Rho family of GTPases regulates cell functions, including
adhesion, proliferation, and survival. Furthermore, the RhoA
signaling pathway is strongly associated with the ability of tumor
cells to invade and successfully establish metastases

-RhoA, when in the active(GTP)-bound form, acts through a

variety of effectors, including rho-associated coiled-coil-
containing protein kinase 1 (ROCK1), and protein kinase, to
activate signal transducer and activator of transcription 3 (STAT3)
to promote tumorigenesis
 chromosomal instability (CIN)
In the CIN subtype of gastric cancer, TCGA network identified
genomic amplifications of receptor tyrosine kinases (RTKs), many
of which are targetable. Angiogenesis may be highly relevant to
CIN subtype based on the recurrent amplification of vascular
endothelial growth factor A (VEGFA) gene. The VEGFR2 targeting
antibody ramucirumab has shown antitumor effects on gastric
cancer[9]. It will be interesting to investigate whether the
response to ramucirumab is predicted by
the VEGFA amplification.
Treatment options :
-Surgery
-Chemotherapy
-Radiation therapy
-Targeted therapy
-Immunotherapy
 Immunotherapy

Immunotherapy: is a broad category of cancer

therapies that triggers the body's immune system to
fight cancer cells.

These abnormal cells frequently change, or mutate,

helping them evade the immune system, which protects
the body from disease and infections. Cancer
immunotherapy drugs are designed to alert the
immune system about these mutated cells so it can
locate and destroy them.
 Types of immunotherapy

-Monoclonal or therapeutic antibodies

-CAR T-cell therapy
-Immune checkpoint inhibitors
immune checkpoint inhibitors are a type of drug that
removes natural blockades within the body that keep your immune system in
check. Without these natural blockades, it may overreact—like in
autoimmune diseases. But cancers will often use these blockades, or
proteins, to hide from the immune system. With these blockades deactivated
through checkpoint inhibitors, the door is opened, and your
body is able to respond more strongly to the cancer cell.

Checkpoint inhibitors work by blocking the receptors that cancer cells use to
send signals to T-cells. When the signal is blocked, T-cells may be better able
to differentiate a cancer cell from a healthy cell and launch an attacks
Some of biomarkers that found in cancer cell cancers
cells that may indicate the drug will produce a
positive
outcome.

-PD-L(programmed cell death )

-CTLA-4
-PD-L1 is a protein often found on some cancer cells. When
the PD-L1 protein on a cancer cell interacts with the PD-1
protein on an immune cell, the cancer cell is considered
healthy and is left alone.
-CTLA-4 is another type of protein found on certain T-cells
that can give cancer a free pass to spread. However, blocking
it can help T-cells recognize and attack cancer cells
Clinical trials of immunotherapy for gastric
cancer:
-Anti-PD-1/PD-L1 Monotherapy
-Anti-PD-1/PD-1 Antibody plus chemotherapy
-Anti-PD-1 Antibody plus HER2-Targeted
Therapy
-Anti PD-1 Antibody plus Anti-CTLA4antibody
CAR-T
Anti-PD-1/PD-L1 Monotherapy :

1-nivolumab
2- prmbrolizumab
3- avelumab
4- dostarilmab
 Nivolumab
-Nivolumab is approved as an option for third- or later-line
treatment of advanced gastric/gastroesophageal junction

-In the phase III ATTRACTION-2 trial, nivolumab as an anti-PD-1

monoclonal antibody improved overall survival (OS) compared
with the placebo in patients with AGC after two or More
previous lines of chemotherapy
 Nivolumab

Any-grade treatment-related adverse

events (TRAEs) had occurred in patients
treated with nivolumab:
pruritus ,diarrhea ,rash, fatigue, decreased
appetite, diarrhea, fatigue
 Avelumab
Avelumab (anti-PD-L1 antibody) failed to show
an OS improvement compared with
investigators’ choice of third-line chemotherapy,
which included paclitaxel or irinotecan in
patients with AGC
 pembrolizumab
-In the first-line setting (KEYNOTE-062),
pembrolizumab was non-inferior to
chemotherapy for OS in patients

-pembrolizumab did not significantly improve

PFS and OS compared with paclitaxel in
patients,but we showed ORR of 11.6% at
third-line or later-line in a phase II
 dostarlimab
dostarlimab (anti-PD-1 antibody) showed ORR
of 38.7% in MMR-D patients with non-
endometrial solid tumors that leading to FDA
accelerated approval to dostarlimab for
advanced dMMR solid tumors
 Anti-PD-1/PD-L1 Antibody Plus
Chemotherapy
-clinical trials showen addition of anti-PD-1
antibodies to first-line chemotherapy for AGC

-chemotherapy in combination with

pembrolizumab fail to show benefits in OS in
Populations
 Nivolumab plus chemotherapy
-Patients with nivolumab plus chemotherapy
achieved higher ORR and OR than in those
with chemotherapy
-FDA approved the addition of nivolumab to
standard chemotherapy (fluoropyrimidine and
oxaliplatin) as the first-line treatment for AGC
patients irrespective of PD-L1 CPS
-in ORIENT-16 conducted in China,chemotherapy in
combination with sintilimab (PD-1 inhibitor) have
benefit in OR
Japanese guidelines for the management of
patients with metastatic gastric cancer have
been stated as follows:

(1) nivolumab plus chemotherapy is recommended as first-line

therapy for AGC.
(2) given that CPS was associated with survival outcomes in
CheckMate-649, PD-L1 CPS evaluation should be conducted as
much as possible.

(3) in cases where CPS < 5 or unknown, the decision to treat with
nivolumab plus chemotherapy or chemotherapy alone should
be taken with consideration to the patient’s overall fitness
and access to subsequent therapies.
.
 Anti-PD-1 Antibody Plus HER2-
Targeted Therapy

-Human epidermal growth factor 2 (HER2, ERBB2) is a

membrane-associated receptor that dimerises with HER family
members and transduces extracellular signals to RAS-MAP kinase
and PI3 kinase-AKT intracellular signalling networks. HER2 is
overexpressed in several types of tumours, including gastro-
oesophageal
adenocarcinoma.

-In gastric cancer, HER2 acts as an oncogene. Protein

overexpression is associated with genetic amplification of
segments of chromosome 17 that may form tandem duplications
on chromosome 17 or double-minute chromosomes.
 HER2-Targeting
-Trastuzumab
-margetuximab
 Trastuzumab

-trastuzumab increases HER2 internalization

and cross-presentation by dendritic cell

-in a HER2-positive immunocompetent mouse

model, anti-PD-1 antibody could significantly
improve antitumor activity of trastuzumab
with the augment of antibody-dependent
cellular cytotoxicity
 -Phase II trials, evaluating the efficacy of first-line
chemotherapy plus trastuzumab combined with
pembrolizumab, have shown
promising results in ,gastric cancer

-phase III KEYNOTE-811 trial of pembrolizumab plus

trastuzumab and chemotherapy demonstrated a
statistically significant 22.7% improvement in ORR
in the pembrolizumab group compared with the
placebo group
 margetuximab
-the phase II trial of margetuximab, anti-HER2
monoclonal antibody ,demonstrated favorable
results when combined with pembrolizumab
with ORR of 24% .
Trastuzumab deruxtecan (T-DXd), an antibody-drug
conjugate consisting of an anti-HER2 antibody, a
topoisomerase I inhibitor, and a cleavable linker, was
shown to improve response rate and OS in patients
with HER2-positive AGC previously treated with
trastuzumab-containing chemotherapy compared with
third-line or later-line ,T-DXd activated dendritic cells,
increased the expression of MHC class I in tumor cells,
and enhanced the antitumor response to PD-1
blockade
 Anti-PD-1 Antibody Plus Anti-CTLA4
Antibody

-Cytotoxic T lymphocyte antigen 4 (CTLA-4), a

key negative regulator of T-cells other than PD-1/PD-L1, restricts
the antitumor immune response.
-Anti-CTLA-4 antibody binds to CTLA-4 on activated T cells and
prevents T cell inactivation in lymph nodes during the initial
stage of cancer-immunity cycle

-The anti-PD-1/PD-L1 antibody plus anti-CTLA-4 antibody

combination is expected to have a synergistic effect due to these
different mode of actions between the two antibodies toward
the tumor immune microenvironment
-combination therapy with ipilimumab (anti-CTLA-4
antibody) and nivolumab has demonstrated
antitumor activities
-In several malignancy, Nivolumab plus ipilimumab did
not improve OS compared with chemotherapy in
patients with PD-L1 CPS ≥ 5.
 CLDN18.2
Claudins are a family of proteins acting to maintain the
tight junction that controls the interchange of
molecules between the cells. They prevalently
distribute in gastric, pancreatic and lung tissues, which
can be applied in diagnosis and therapy

The subtype CLDN18.2, which is a stomach specific-

isoform, has emerged as an ideal target since Sahin has
discovered it as a highly selective molecule that widely
expresses only in cancer cells. This has paved the way
for treatment of gastric/GEJ adenocarcinoma
-It’s malignant carcinogenesis that leads to disruptions
in tight junctions, exposing CLDN18.2 epitopes on the
surface of tumor cells to be specifically targeted. Thus,
CLDN18.2 endows targeting therapy with specificity

-Zolbetuximab (IMAB362, claudixmab), which is the

first developmental drug aiming at the target, is a
structurally chimeric IgG1 monoclonal antibody that
specifically binds to CLDN18.2
 Chimeric antigen receptor T (CAR-T)

-CAR therapies utilize T-cells (CAR-T), a patient’s own

immune cells that are re-programmed to recognize and
kill cancer cells throughout the body. The process
involves the removal of some T cells from a patient, and
through laboratory processes, these T cells are re-
programmed to identify a patient’s cancer cells
Once the T cells have been programmed to identify a
patient’s cancer cells, they are replicated in the
laboratory, and infused back into the patient. These re-
programmed T cells circulate throughout the body,
identifying the cancer cells and mounting an immune
attack against them. Simultaneously, the T cells are
replicating within the body, so that more of the
immune cells can identify and attack the cancer cells.
CAR-T cell therapy has proven to be an effective
treatment for cancer
 Chimeric antigen receptor T (CAR-T)

- CLDN18.2-specific CAR-T cells achieved partial

or complete tumor elimination

- Most recently, a phase I study of CLDN18.2-

targeted CAR-T cell therapy demonstrated
promising results with ORR of 48.6% with
manageable safety profiles in gastrointestinal
cancer