Cancer Immunotherapy by

Interleukin-21: Potential Treatment

Strategies Evaluated in a
Mathematical Model
Antonio Cappuccio, Moran Elishmereni
and Zvia Agur
Presented by N9720001
2
Lineage of Immune Cells
3
Natural Killer Cells ()
4
How Does NK Cell Kill?
5
CD8+ T Cells (CD8+ T)
T stands for thymus
()

6
Cluster of Differentiation (CD)
7
Synergic Stimulate of CD8+ T Cell
Cancer Cell
8
Mouse Data
Nature 2001
RMA: T-cell lymphoma


9
Chromium
51
Cr () Release Assay
10
Human Data
Science 2002
Melanoma:

11
Assumptions for the Model
The tumor cells grow logistically in the absence of an immune
response.
Both NK cells and CD8+ T cells can kill tumor cells
Tumor cells have the potential to engender cytocidal activity in
previously naive and noncytotoxic cells.
As part of innate immunity, NK cells are always present and active
in the system, even in the absence of tumor cells.
As part of specific immunity, tumor-specific CD8+ T cells are
recruited once tumor cells are present.
Each NK cell and CD8+ T cell will eventually become inactivated
after some number of encounters with tumor cells.


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Logistic Function
The tumor cells grow logistically in the
absence of an immune response.
13
Model Equation Basics
Rate of change of tumor cell population =
(growth and death rate)
(cell-cell kill rate) and rate of change of
active effector cell populations = (growth
and death rate) + (recruitment rate) -
(inactivation rate).
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Equation for Tumor Cells
T: Tumor cell population
a: Tumor growth rate
b: Carrying capacity
N: Natural killer cell population
L: CD8+ T cell population
D: CD8+ T cell-tumor killing term
c: effectiveness of NK cell
d: effectiveness of CD8+ T cell
15
Equation for NK Cells
N: Natural killer cell population
: Background source rate for NK cell
f: Death rate of NK cell
g: Maximum NK cell recruitment rate
h: Steepness coefficient of NK cell recruitment curve
p: NK cell inactivation rate by tumor cells
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Equation for CD8+ T Cells
L: CD8+ T cell population
m: Death rate for CD8+ T cell
j: Maximum CD8+ T cell recruitment rate
k: Steepness coefficient of CD8+ T cell recruitment curve
q: CD8+ T cell inactivation rate by tumor cells
r: Rate of cross activation of CD8+ T cells by tumor cells
killed by NK cells
17
18
Data Fitting via Least Squares Fit
()
(Power Law vs. Rational Law)
Power Function


Rational Function

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Fractional Cell Kill Function (D)
Describing the interaction of effector cells
(NK and CD8+ T cells) and tumor cells.
Simplest form: -cNT (NK vs. Tumor) (O)
-dLT (CD8+ vs. Tumor) (x )
2nd try: -cN

T(O, at =1)
-dN

T(x )
d: Maximum lysis rate
s: Steepness of the curve
: Exponent

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NK Cell Fit the Power Function
Fig. 1a
RMA: T-cell lymphoma

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CD8+ T Cell Does Not Fit Power
Function
nn:
1st prime will control
2nd challenged with control
22
ll:
1st prime will ligand
tranduction
2nd challenged with ligand
tranduction

Note:
Ligand transduction by virus
23
Least Squares Fit Errors
24
Model Validation Using Human
Sample ( CD8+ T Cell)
Patient #9
Patient #10
Melanoma:
Cell Lysis indirectly estimated
(INF-)

25
Sensitivity Analysis (1%)
a: aggressiveness of
tumor
()
: effectiveness of T
cells
(T)
26
Model Simulation:
Effect of Vaccination ()
Vaccination (Control)

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Vaccination (Real)

Consistent with data in Nature, 2001
28
Model Simulation:
Threshold for Immune Efficacy
No CD8+ T Cell
: 10
4
:10
5
:10
6
Tumor cell challenged
29
No NK Cell
: 10
4
:10
5
:10
6
Tumor cell challenged
30
w NK Cell & T cell
: 10
4
:10
5
:10
6
Tumor cell challenged
31
References
1. Thomas J. Kindt, Barbara A. Osborne and Barbara A.
Osborne, Immunology, 6th ed. W. H. Freeman: 2006
2. Diefenbach A, Jensen E, Jamieson A, Raulet D. Rae1
and H60 ligands of the NKG2D receptor stimulate
tumor immunity. Nature 2001;413:16571
3. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer
regression and autoimmunity in patients after clonal
repopulation with antitumor lymphocytes. Science
2002;298:8504.

Thank You