Hello, my name is Mary Elias.

I'm a transplant hematologist

with the clinical and research focus

on how to biliary neoplasia.

And today I will be reviewing

tumor cell biodiversity within

the immune ecosystem of liver

cancer.

So I'll be going over

emerging immunotherapies for

cholangiocarcinoma, as well as

discuss the tumor immune

microenvironment and its therapeutic

implications in cholangiocarcinoma.

So we'll start off with the case

first. We have a 62

year old gentleman who presents with

abdominal pain, malaise and

a recent unintentional

20 pound weight loss slabs.

Labs are notable for an alkaline

phosphatase of six hundred eighty

four alty of 120

C and 99 as 620

and C T abdomen images

are shown.

So which of the following would you

recommend, would you referred

to medical oncology for

consideration of immunotherapy

or to refer for liver

transplantation?

Three. Referred to surgery for

consideration of a hep a tech to me

or referred to medical oncology

for consideration of gemcitabine and

cisplatin.

So the CT images demonstrated

a left sided mass

consistent with imaging features,

often in hepatic cholangiocarcinoma,

and the image on the right had

demonstrated no mental

nodule.

So this is consistent with

metastatic disease.

So in this case, we would refer

to medical oncology for

consideration of gemcitabine and

cisplatin.

Since this is metastatic disease,

liver transplantation or surgical

resection are unfortunately not

options.

And in terms of immunotherapy?

Well, that's what the talk is based

on. So I will go over where

we are in terms of immunotherapy

proclaimed your carcinoma and

where we're headed and what the

needs are for patients

with advanced cholangiocarcinoma,

for whom surgery or liver

transplantation or local regional

therapies are not an option.

The practice standard is systemic

chemotherapy with gemcitabine and

cisplatin, and

that's based on this landmark paper

that was published in the New

England Journal of Medicine in 2010.

And it showed that compared to Jim

said of being alone, the addition

of cisplatin offers a survival

advantage, with median progression

free survival of eight months

without a significant increase

in toxicity.

So what about immunotherapy for

cholangiocarcinoma?

So kind of. Carcinomas are overall

very lethal tumors with a five year

survival of less than 10 percent.

These are very dismal plastic tumors

with a dense tumor immune

microenvironment

that you can see in this photo

micrograph to your left.

And this tumor immune

microenvironment has an abundance

of immunosuppressive elements,

such as myeloid cells,

including tumor associated

macrophages, and

the response to immune checkpoint

blockade. Monotherapy has

been disappointing in humans,

and the interplay between the

myeloid cells and the adaptive

immune cells, which

which fight off the tumor cells

has yet to be elucidated.

So there have been limited results.

Phase two trials of

immunotherapy in cholangiocarcinoma.

This was a phase two single arm

trial that assessed the

immune checkpoint inhibitor

nivolumab in patients who had

biliary tract cancers, including

five with very highly

acclaimed jaw carcinoma and

the intention to treat population.

The median overall survival was

twelve point four months.

However, based on an independent

review, the objective response rate

was only 11 percent.

What about combination

immunotherapy?

So the combination of Anti

PD one, which is programmed

death one and

inhibition with nivolumab and

anti CTLA

four with ipilimumab, is

also being evaluated in

biliary cancers.

And this is phase two trial data

that indicated an overall survival

of five point seven months and

progression free survival of two

point nine months.

Now, although there were 13 patients

with very high alert and distal

cholangiocarcinoma, the responses

were exclusively observed in

patients who had intrahepatic Jeonju

carcinoma or gallbladder cancer.

And we know that the three different

subtypes of cholangiocarcinoma

have a distinct molecular

pathogenesis.

And these results indicate that the

response to immunotherapy also

varies based on the anatomic

location of cholangiocarcinoma.

So it's possible that patients who

don't respond, they have

what we would refer to as a non

T-cell infiltrated or an immune

cold microenvironment

that has an abundance of the

immunosuppressive elements I

mentioned earlier, such as tumor

associated macrophages or other

myeloid cells known as myeloid

derived suppressor cells.

And targeting these populations in

combination with immune checkpoint

blockade may result in improved

response.

The presence of tumor cells promotes

activation of cytotoxic T

lymphocytes, or CTL, with

consequent tumor lysis.

And one way in which cancer cells

overcome T cell cytotoxicity

is by induction of immune

checkpoints such as programmed death

one or PD one and its ligand

PD-L1 and in tumor

biology. These immune checkpoints

are important immune resistance

mechanisms, which limit T

cell cytotoxicity.

Moreover, these immune checkpoints

can be activated by cancer cells

themselves or by host immune cells,

such as tumor associated macrophages

or.

Although we know that Sikhs have an

abundance of tams, the Immunobiology

FCC has yet to be defined.

So in my lab, we've shown that PD-L1

positive tumor associated

macrophages increase

in cholangiocarcinoma and

these PD-L1 positive tams

that promote exhaustion of cytotoxic

T lymphocytes and increase tumor

progression.

However, inhibition of TAMS

promotes a compensatory emergence

of another type of myeloid

cell, which is which are known as

mylo derived suppressed our cells,

particularly a subset known as

granular, acidic myeloid drive

suppressor cells, or GM disease.

And when we inhibited both

GM discs and macrophages

in our mouse model of

cholangiocarcinoma, that potentiated

immune checkpoint blockade in

cholangiocarcinoma with

consequent reduction in tumor

burden and improvement in mouse

survival.

Now these results

point to why immune checkpoint

blockade, monotherapy

or even dual immune checkpoint

blockade results

have been disappointing.

And thus far it's

because cats have a very dense

tumor immune microenvironment that

has all these other

immunosuppressive elements that that

need to be taken into consideration.

And it's likely that effective

therapy immunotherapy for

cholangiocarcinoma will require

targeting of these

immunosuppressive cells, along

with combining

that with the immune checkpoint

blockade using anti PD

one inhibition or PD-L1

inhibition.

So in summary, these have a five

year survival of less than

five percent.

Systemic therapy with gemcitabine

and cisplatin remains the standard

of care for patients with advanced

GCA.

Immunotherapy has shown limited

efficacy in S.K.,

and cases are dismal plastic tumors

that have a very dense tumor immune

microenvironment that not only

has cytotoxic T lymphocytes,

but also has immunosuppressive

myeloid cells.

And we will likely need to

be able to target these.

In order for immunotherapy to

really be effective in

cholangiocarcinoma, thank

you so much for your time,

and I would just like to acknowledge

our wonderful laboratory

family, and

it's a pleasure to participate

in this wonderful showcase

of women in GI

with so many fabulous colleagues.