Adoptive

Immunotherapy
Chris Cunningham & Asad Usman
Mathematical Biology 463
Dr. Jackson

The Basics
What is the Immune Response?
The immune response involves a
coordinated set of interactions among
host cells and the protective molecules
when they encountering a foreign
particle

Purpose of Immune Response

To prevent unhealthy states and to
restore homeostasis
For example Prevent Cancer: the
uncontrolled growth of cells in the body

The Basics - Background

The most common treatment for cancer is
chemotherapy
Chemotherapy, though helpful, also causes
unwanted side effects
Chemotherapy focuses on irradiation of tumor cells
in order to decrease growth rate
However, some natural cells have high growth rate,
such as the skin, the stomach, and mouth, these
cells can be adversely effected by chemotherapy
An alternative solution has developed called:

Adoptive Immunotherapy

The Basics - Introduction

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What is Adoptive Immunotherapy:

Its is a form of immunotherapy used in
the treatment of cancer
An individual's own white blood cells
are coupled with a naturally produced
growth factor to enhance their cancerfighting capacity
Then, these are injected into tumor site
to increase immune response locally
Injections can be +/- Immune Cells and +/growth factor

Introduction to Model
Our model has three key biological
components from the immune
system:
1. Effector Cells
2. Tumor Cells
3. Cytokines Molecules that enhance
Effector Cells
Specifically IL-2

Immune Response
Acquired Immune Response
Immunity mediated by lymphocytes and
characterized by antigen-specificity and
memory
Cell Mediated - T lymphocytes (T cells)
Adoptive Therapy Injections
False-color scanning electron
micrograph of two lymphokineactivated killer (LAK) cells. In LAK
immunotherapy, a patient's
peripheral blood mononuclear
cells are removed and cultured
with interluekin-2 (IL-2) to allow
LAK cells to develop. (Photo
Science Library.)

Immune Biology
Effector Cells
T Lympocytes
Lymphocytes express highly specific
ANTIGEN RECEPTORS on their surface
Lymphocytes are highly specific for a
given structural motif
Usually CD8+ cells which kill target cells by
recognizing foreign peptide-MHC molecules
on the target cell membrane.

Model
dE/dt = The Change in Effector cell pop.
over time

Immune Biology
Tumors
Cancer cells must express ANTIGENS (foreign
particles) recognizable and accessible to the
immune system. - Antigenicity
The immune system must in turn be able to
mount a response against cells bearing such
antigens
Tumors possess a varying degree of Immune
Antigenicity that is unique to each tumor and
thus be rejected by Immunocompetent hosts.
Model
dT/dt = The change in Tumor cell pop. over time

Immune Biology
Cytokines
Low molecular weight protein mediators
involved in cell growth, inflammation,
immunity, differentiation and repair
Production triggered by presence of foreign
particles
Autocrine agent Act on cell that produced it

Types
Interleukins (ex. IL-2)
Meaning: They are chemical messengers between
(inter) Leukocytes

Interferons

Model
dI/dt = The Change in IL-2 [conc.] over time

Immune Biology
Interleukin-2
In Adoptive Immunotherapy IL-2 is
administered
High-dose bolus recombinant IL-2 (600,000
to 720,000 IU/kg IV)

Acts as a potent immunomodulator and

antitumor element
Positive results have led approval of
high dose IL-2 for patients with
metastatic melanoma and Renal cell
carcinoma.
Extensive multiorgan toxicity may occur

Cytokines
Structure of interleukin 2

Fig. 2

Fig. 1

Schematic overview of the highaffinity interleukin2

receptor complex, including the receptor chains,
downstream signaling components and target genes

Cytokines IL-2 Targets

This is a basic overview of the
mechanism of IL-2 activation

Adoptive Immunotherapy
Technique involves isolating tumorinfiltrating lymphocytes (TILs)
Primarily activated cytotoxic T-lymphocytes
Lymphocytes with antitumor reactivity found
within the tumor

Expanding their number artificially in cell

culture by means of human recombinant
interleukin-2.
The TILs are then put back into the
bloodstream, along with IL-2, where they
can bind to and destroy the tumor cells.

Adoptive Immunotherapy
Immunotherapy
IL2, alone, can be used as a cancer
treatment by activation of cells which
are cytotoxic for the tumor

Some success has been obtained

with renal cell carcinoma and
metastatic melanoma.
Rosenburg study

A.I.
This figure
shows adoptive
immunotherapy
isolation
techniques

The Immune Model

The Immune Pathway

Effector Cell

IL-2 Molecules

Think MichaelisMenton

1. IL-2 binds IL-2 Receptor

Step 1

Tumor
recognition site
Tumor
cells

Ste
p

IL-2 Receptor
4. Tumor Eating
Site Activated
6. Attack Mode!

Step 6

Step 4

2. Effector Cell with

bound IL-2

Step 3

Step 5

5. Locates Tumor

3. Effector Cell Activated

And Multiply

The Model
Change in
Effector cells
over time

Antigenicity
and size of
tumor

IL-2
Stimulation

Death
rate

Effector Cell
Injection

Logistic
growth rate
of Tumor

Change in
Tumor cells

Killing rate
by Effector
cells

Change in IL-2

Natural
production of IL-2

Death
rate

IL-2
Injection

Implications of Model
No Treatment Case
(1) For very low c, tumor reaches a
stable steady state.
(2) For intermediate c, tumor has large,
long-period oscillations.
(3) For high c, tumor has small, lowperiod oscillations.

No Treatment Case - Case 1

Very low antigenicity.

Days

No Treatment Case Case 2

Intermediate antigenicity.

Days

No Treatment Case Case 3

High antigenicity.

Days

Implications of Model
With Treatment Case
(1) A combination of adoptive immunotherapy
with IL-2 is effective for all tumors.

Implications of Model

Implications of Model

(faster!)

Implications of Model
With Treatment Case
In high doses, IL-2 therapy leads to a
runaway immune system.
In low doses, IL-2 therapy has no
qualitative effect on tumor size.

Implications of Model

Reality of IL-2 Therapy

High-dose IL-2 therapy alone has
been shown to cause a variety of side
effects.
Generally High Toxicity, e.g. Capillary
Leak Syndrome

Most of these are explainable by a

runaway immune system.
Question: IL-2 therapy does work in
some cases; why does the model not
predict this?

Our Contribution
In reality, once started, IL-2 therapy
is not administered at a constant rate
for all time.
Rosenberg Study
(1) Large Bolus Therapy
(2) Short Duration of Therapy
(3) Cessation of Therapy upon
appearance of side effects

We chose to incorporate (3).

Our Contribution

The original model contained a constant term for IL-2 injection; ours
becomes a function of the number of effector cells and time.

Treatment (x,t)
Treatment continues at a constant rate,
but only until a certain threshold level of
effector cells is reached.
This simulates the onset of side effects.
Since the threshold level will vary from patient to
patient, this threshold became a new parameter.

At that point, treatment ceases and the

model continues with no treatment.
In addition, the option to delay the start of
therapy for a certain number of days was
implemented.
This simulates the fact that treatment usually does
not start until the tumor size is large.

Implications of New Model

For high tumor antigenicity, the
tumor can be cleared by IL-2 therapy
for a relatively low threshold of
immune response.
The lower the antigenicity, the higher
the threshold needs to be.
The nastier the tumor, the tougher the
patient needs to be.

More animation!

High Antigenicity
(non-nasty tumor)

The tumor is eradicated for most values of immune threshold.

More animation!

Medium Antigenicity
(more nasty tumor)

The tumor is still eradicated for most values of immune threshold.

Low-Antigenicity Results
Rosenberg Study
Of the 19 patients with complete
regression, 15 have remained in complete
remission from 7 to 91 months after
treatment.

Question: Why 7 to 91 months?

Our model gives a possible
explanation.

Low-Antigenicity Results
Long-term dormant tumor
Our model predicts that for lowantigenicity tumors, IL-2 therapy with most
thresholds of immune response cause the
tumor to enter a dormant, undetectable
state.
During these periods, the qualitative result
is tumor regression.
However, the tumor re-appears after an
interval on the order of 2700 days,
90 months.

Low-Antigenicity Results

2700 days

For low values of the immune threshold, no long-term change in behavior occurs.
For most values of the immune threshold, a dormant tumor is produced.
For extreme values of the immune threshold, the tumor is eradicated.

Therapy Results - Images

Title: Adoptive-Cell-Transfer Therapy for the Treatment of Patients with

Cancer. Rosenburg SA

Tumor regression by adoptivecell-transfer therapy Activated

T cells can mediate the
regression of a large excess of
metastatic melanoma.

Computed tomography scans

of the trunk and pelvis of one
patient

The regression of bulky

metastases (arrows) in axillary
(top), pelvic (middle) and
mesenteric (bottom) lymph
nodes, mediated by adoptivecell-transfer therapy

Tumour deposits were

present before treatment and
substantially shrank or
completely resolved when
evaluated 8 months later

Therapy Results - Images

Obtained from a
tumor-bearing host

Title: Adoptive-Cell-Transfer Therapy for the Treatment of Patients with

Cancer. Rosenburg SA

Day 27 before IL-2

therapy (a, b)

Day 63 or 35 days after

IL-2 therapy (c, d)

At positions comparable
to a and b. Numerous
metastases (0.3 - 2 mm)
are detected before
therapy (a, b).

After successful therapy

with encapsulation and
rejection of the primary
tumor, the liver was
completely free of
metastases (c, d).

Conclusions

Adoptive Immunotherapy is a technique to manage cancer.

A mathematical model is presented that allows for tumor

regression or predicts the remission time given certain
parameters.

In the case for IL-2 therapy alone the model predicts unbound
behavior.

Actually, clinicians can control when IL-2 is stopped.

We introduce a new parameter Treatment(x,t) that incorporates a

time dimension.

This way we can resolve disparities in actual clinical data and the
predictions of the model.

In general, immunotherapy with IL-2 is on the rise and more

mathematical models will be neccesary to help practitioners
predict future reemergence times in order to restart therapy.

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Happy Finals!!!
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Bart Simpson is misunderstood!!!