J Pharmacokinet Pharmacodyn (2014) 41:461–478
DOI 10.1007/s10928-014-9386-9
ORIGINAL PAPER
Modeling cancer-immune responses to therapy
L. G. dePillis • A. Eladdadi • A. E. Radunskaya
Received: 1 April 2014 / Accepted: 17 September 2014 / Published online: 4 October 2014
Ó Springer Science+Business Media New York 2014
Abstract Cancer therapies that harness the actions of the
immune response, such as targeted monoclonal antibody
treatments and therapeutic vaccines, are relatively new and
promising in the landscape of cancer treatment options.
Mathematical modeling and simulation of immune-modi-
fying therapies can help to offset the costs of drug dis-
covery and development, and encourage progress toward
new immunotherapies. Despite advances in cancer immu-
nology research, questions such as how the immune system
interacts with a growing tumor, and which components of
the immune system play significant roles in responding to
immunotherapy are still not well understood. Mathematical
modeling and simulation are powerful tools that provide an
analytical framework in which to address such questions. A
quantitative understanding of the kinetics of the immune
response to treatment is crucial in designing treatment
strategies, such as dosing, timing, and predicting the
response to a specific treatment. These models can be used
both descriptively and predictively. In this chapter, various
mathematical models that address different cancer treat-
ments, including cytotoxic chemotherapy, immunotherapy,
and combinations of both treatments, are presented. The
L. G. dePillis (&)
Department of Mathematics, Harvey Mudd College, Claremont,
CA, USA
e-mail: depillis@hmc.edu
A. Eladdadi
Department of Mathematics, The College of Saint Rose, Albany,
NY, USA
e-mail: eladdada@strose.edu
A. E. Radunskaya
Department of Mathematics, Pomona College, Claremont, CA,
USA
e-mail: aradunskaya@pomona.edu
aim of this chapter is to highlight the importance of
mathematical modeling and simulation in the design of
immunotherapy protocols for cancer treatment. The results
demonstrate the power of these approaches in explaining
determinants that are fundamental to cancer-immune
dynamics, therapeutic success, and the development of
efficient therapies.
Keywords Mathematical model  Tumor 
Chemotherapy  Immunotherapy  Mixed chemo-
immunotherapy  Dosimetry  Pharmaceutical  Optimize
Introduction
The world-wide incidence of cancer and cancer-related
deaths increases each year, despite medical progress in the
diagnosis and treatment of many types of cancer [1].
According to recent studies by the American Association
for Cancer Research (AACR), the most promising avenues
in cancer research are epigenetics, cancer prevention and
immunotherapy [2].
Recent progress in cancer immunology and advances in
immunotherapy suggest that the immune system plays a
fundamental role in combating tumors, and hence can be
used as a vehicle to prevent or cure cancer [3]. Despite
these developments, a thorough understanding of the
complex dynamics of the tumor-immune system remains
tenuous. The multidimensional nature of tumor–immune
interactions requires cross-disciplinary approaches to cap-
ture more realistic dynamics of the essential biology [2].
One such approach combines cancer immunology with
mathematics to model aspects of these multifaceted inter-
actions. Using mathematical models to explore the
dynamics of different components of the immune system
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allows interdisciplinary teams of laboratory, computational
and clinical researchers to investigate the mechanisms
underlying an effective immune response to cancer as well
as to design improved therapy protocols. These therapeutic
strategies typically combine chemotherapy with immuno-
therapy to deplete cancer cells and simultaneously boost
the immune response.
Mathematical modeling is a powerful tool that can help
researchers and clinicians understand complex mechanisms
of cancer development and progression. Ideally, modeling
should lead to improved therapy strategies, and stimulate
the development of new ones. For example, pharmacoki-
netics/pharmacodynamics (PK/PD) modeling has been
used effectively to predict the effect and efficacy of drug
dosing over time. PK/PD has also been an essential com-
ponent of drug discovery and development. PK/PD models
are typically compartment models that use ordinary and/or
delay differential equations. These systems of equations
describe temporal changes within the compartments, and
trafficking between compartments. One goal of mathe-
matical models is dosimetry, or the accurate prediction of
dose-response by simulating different dosing schedules.
Mathematical modeling has been useful in guiding che-
motherapy and radiotherapy treatments [4–7] and com-
bined radiopharmaceutical therapy [8]. Mathematical
models can also illuminate the underlying mechanisms of
disease and drug response as well as the stochastic nature
of these processes [9–11].
In the pharmaceutical industry, it normally takes
10–15 years to develop and manufacture a new drug, at a
cost of 10M$–1.2B$. One in ten new drugs in clinical trials
is likely to be approved [12]. Of necessity, the pharma-
ceutical industry is becoming more innovative in reducing
the time and the cost of drug discovery and development of
new therapies. This development to production process is
streamlined by devoting greater resources to mathematical
and computational (in silico) modeling. Mathematical
models can also be used to personalize treatments by
identifying key system parameters that most strongly affect
treatment outcomes. Knowing these parameters is espe-
cially important when designing immunotherapies for
cancer, since effective protocols require ‘‘treatment per-
sonalization,’’ whereby doses and administration schedules
are tailored to the individual patient [13].
This chapter introduces the reader to mathematical
models of chemotherapy and immunotherapy. Immuno-
therapy can be considered a special type of chemotherapy.
However, traditional cytotoxic chemotherapy targets and
kills tumor cells directly. The goal of immunotherapy, on
the other hand, is to increase the effectiveness of the
immune response against a cancer. Thus, immunotherapy
is a treatment that indirectly targets tumor cells.
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J Pharmacokinet Pharmacodyn (2014) 41:461–478
Mathematical models of cytotoxic chemotherapy are
usually more straightforward than are models of immuno-
therapy. For example, kill rate parameters needed for
chemotherapy models can often be measured directly using
in vitro cell lysis assays. The immune system cannot be
ignored, however, when designing chemotherapeutic pro-
tocols, since the ability of the host to mount a prolonged
defense is crucial to a positive long-term outcome. The
immune system is a complex network of cells and chemical
signals, and mathematical models of immunotherapy must
describe multiple immune populations. Multiple self-reg-
ulating mechanisms can prevent the sustained enhancement
of a particular part of the immune response, so the design
of immunotherapeutic strategies involves tracking many
interacting factors.
In this chapter, models of cytotoxic therapy that take
into account the health of the immune system are pre-
sented, as well as how these models are adapted to describe
treatments that affect the immune response itself.
The breadth and depth of the work carried out by many
different researchers in modeling tumor–immune interac-
tions over the past two to three decades is vast. This
chapter is by no means a comprehensive review of this
body of work. Instead, it provides an overview and a brief
description of some of the existing mathematical models on
tumor–immune dynamics and therapies. Our hope is that
the reader will be inspired by this chapter to investigate
further both the mathematical models mentioned herein,
and other related works that space constraints prevent us
from summarizing. Interested readers are encouraged to
consult the cited literature for detailed model development,
analysis and simulation. A sample of other worthwhile
works can be found in references [14–33].
The aim of this chapter is to highlight the importance of
mathematical modeling and simulation in immune-modu-
lating therapies for cancer. Sect. 2 addresses mathematical
models of cytotoxic chemotherapy. Sect. 3 covers some
topics in immunotherapy. Sect. 4 presents a sampling of
models that combine chemotherapy and immunotherapy
treatments of cancer.
Modeling cytotoxic chemotherapy
Ordinary differential equations (ODE) models
In the early 1990s, Kuznetsov et al. [34] proposed a
mathematical model of the cytotoxic T lymphocyte
response to the growth of an immunogenic tumor. The
model was a two-population system of Ordinary Differ-
ential Equations (ODEs) that included exponential tumor
growth and Michaelis–Menten dynamics for tumor cell
J Pharmacokinet Pharmacodyn (2014) 41:461–478
Fig. 1 Simulations of the model in [34] illustrating the possibility
that a tumor could remain dormant for a time, but then escape
immune surveillance. This phenomenon is known as sneaking
through. Two simulations are shown: one with an initial population
of 6 9 106 effector cells (labeled ‘‘IC1’’ in red) and one with an
initial population of 6.9 9 106 effector cells (labeled ‘‘IC2’’ in blue).
Both simulations start with the same number of tumor cells (T(0) =
1.3 9 107 ). Left Panel The tumor populations in the two simulations
are shown over time. In both cases, the tumor values initially get very
small and remain there for a while: this is the ‘‘dormant’’ period. The
recruitment of effector cells. Model parameters were
determined based on the kinetics of growth and regression
of B-lymphoma BCL1 tumor cells in the spleen of mice.
Model analysis and simulations showed that for a certain
set of parameters, the course of tumor growth and its
clinical manifestation had a recurring profile. This recur-
ring profile took place over a 3- to 4-month cycle, a pattern
that is qualitatively similar to certain leukemias. A signif-
icant contribution of this model was that it captured the
clinically observed and not well understood phenomena of
tumor dormancy and sneaking through. This relatively
simple two-population model was able to provide one
possible explanation for these mysterious tumor behaviors.
The activity of the immune system against the tumor pro-
vides a feasible explanation that addresses both tumor
dormancy and sneaking through. See Figure 1.
A follow up study to Kuznetsov’s model was recently
conducted by Roesch et al. [36]. The authors fit their model
using data from [37–39]. This study shows that chemo-
therapy treatments for lymphoma that are too intense result
in less effective tumor control. The authors suggest that
cytotoxic chemotherapy that is too aggressive damages the
immune system and undermines tumor control. Roesch and
colleagues propose a modification of Kuznetszov’s two-
population ODE model that adds first-order loss terms,
allowing chemotherapy to damage both tumor and immune
cells. They then modify Kuznetsov’s model by assuming
that effector–tumor interactions are no longer well-mixed,
but that effector cells interact with only the surface of the
growing tumor, which in turn is assumed to be spherical. In
practice, this means that the authors modify three terms in
463
first trajectory (IC1) is in the basin of attraction of the low tumor
equilibrium, and the tumor population approaches a small value. The
second trajectory (IC2) is in the basin of attraction of the large tumor
equilibrium. The IC2 trajectory rapidly approaches the large tumor
equilibrium after coming through the initial dormant period. Right
Panel The same two trajectories are shown in the state space. The
dashed line shows the boundary between the basins of attraction of
the two equilibria. Note the logarithmic scale in the right panel.
Figure from [35] where more details can be found (Color figure
online)
the Kuznetsov system by replacing the tumor cell popula-
tion T with T 2=3 . This substitution takes place in the
Michaelis-Menten effector cell recruitment term, as well as
in the mass-action terms that represent the mutually
destructive interaction between effector cells and tumor
cells. Model simulations are then presented to confirm the
hypothesis that overly aggressive chemotherapy dosing can
damage the positive action of the immune response and
consequently reduce the degree of tumor control.
Studies by Thomlinson et al. [40] show that some cancer
treatments reveal an unexpected asynchronous response to
chemotherapy treatments in some patients. Although one
might expect a tumor to shrink initially after the adminis-
tration of a chemotherapy dose, some tumors were actually
observed to grow directly after treatment administration,
but then shrink at a later time. To address the question of
what could be driving such an asynchronous tumor
response to cytotoxic chemotherapy, de Pillis et al. [41, 42]
developed a mathematical model that describes the inter-
actions of the tumor-immune system and tracks three cell
populations using a nonlinear system of deterministic
ODEs. The three cell populations are tumor cells, immune
cells, and normal cells. For simplicity, this model assumes
homogeneity within each cell population, even though each
of these three cell types contains multiple subtypes. The
hypothesis was that competition for resources and the
presence of the immune response could be partly respon-
sible for the observed asynchronicity in the data. The
purpose of the study was to determine how chemotherapy
outcomes could be affected both by competition for
resources among the three cell populations and by the
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predator-prey behavior between the immune and tumor
cells.
A dynamical systems analysis of the model of [41, 42]
determined the different types of equilibria that existed in the
system. One interesting finding was that the only scenario
under which a completely tumor-free equilibrium would
persist was when the immune system was present and suf-
ficiently strong. In other words, the tumor-free equilibrium
was stable as long as the per-capita growth rate of the tumor
was dominated by the strength of the immune response.
Competition for resources by normal cells also played an
important role in maintaining the stability of the tumor-free
state. If, on the other hand, tumor growth was too aggressive,
then according to this model, no amount of chemotherapy
would be able to eliminate the tumor successfully.
Other types of biologically interesting equilibria also
exist in this model. For example, there are co-existing
equilibria, which are states in which all three cell types
exist in a stable state together in the system. Analysis
showed that there were zero, one, two or three of these
equilibria. Depending on the parameter values, there could
also be stable co-existing states in which the tumor cell
population is relatively small, and not growing larger. This
would be considered a harmless state. The goal of che-
motherapy, then, would be to drive the system either into a
zero-tumor state, or alternately, into one of these harmless
equilibrium states (see Fig. 2 in [41]).
The model developed in [41] was extended to include
chemotherapy dosing. In addition to the three cell popula-
tions, a fourth quantity representing a drug concentration in
the system was added. Each cell population equation was
then modified with a term to describe damage done to cells
by chemotherapy. The system of equations that represents
the tumor–immune–chemo interaction was given by:
dE rET
¼ s  dE  c1 ET  k1 ð1  eu Þ ð1Þ
dt rþT
dT
¼ a1 Tð1  b1 TÞ  c2 ET  c3 NT  k2 ð1  eu Þ ð2Þ
dt
dN
¼ a2 Nð1  b2 NÞ  c4 NT  k3 ð1  eu Þ ð3Þ
dt
du
¼ mðtÞ  d2 u: ð4Þ
dt
Here, E represents the population of effector immune
cells (such as CD8þ T cells); T is the population of tumor
cells; N represents a normal cell population. Parameter u
is the concentration of chemotherapy. The parameters and
their values are described in detail in [41, 42]. The rate of
damage to each cell population [represented by k1 ; k2 ; k3
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J Pharmacokinet Pharmacodyn (2014) 41:461–478
in Eqs. (1–3)] varied, with normal cells being damaged at
the lowest rate, and tumor cells being damaged at the
highest rate. With treatment terms included, simulation
with hypothetical dosing schedules was possible. The
relative mathematical simplicity of this model allowed for
the application of optimal control theory. Optimal control
theory is a mathematical approach that can automatically
search for improved treatment protocols. In an optimal
control problem, an objective must be chosen and repre-
sented by a function. In the case of this tumor model, the
objective used in [41] was to minimize the total tumor
size within a pre-determined time frame while ensuring
that the normal cell population was not too heavily
damaged. In this case, the objective was obtainable.
However, simulations yielded oscillations in cell popula-
tions sizes, a side effect that would not be particularly
desirable in the clinic.
Fortunately, the choice of the objective function is not
unique, and a different choice can lead to very different
outcomes. For example, it is possible to minimize the
tumor size while also minimizing oscillations in the cell
populations, as was done in [42]. In other cases, the
objective has been to minimize both tumor size and total
chemotherapy dosing simultaneously, as in [43]. In that
study, the authors carry out an in-depth analysis and
comparison of linear and quadratic objective functions.
Additionally, they explore how treatment outcomes differ
if, in addition to minimizing tumor burden, the time
endpoint of treatment is also optimized. Interestingly,
although optimal treatment protocols differed depending
on whether the objective functional was linear or qua-
dratic and on how the final time was chosen, one quali-
tative commonality emerged in all cases. In every case,
the most effective treatments were comprised of an initial
large (i.e. maximal tolerated dose) treatment bolus fol-
lowed by lower dose, longer term infusions of chemo-
therapy (see Figs. 3 and 4 in [43]). The authors point out
that this optimal control generated protocol actually
reflects certain clinical findings.
In [44], the models of [41, 42] are summarized in an
overview of best practices in mathematical modeling. In
chapter 4 of [44], the authors include figures from a
numerical simulation of the system of Eqs. (1–4) that
compares cases of tumor growth with no treatment, with
traditional ‘‘pulsed’’ chemotherapy given in regular doses
at equal intervals, and with optimally controlled doses of
chemotherapy (see Fig. 2).
In some applications, it is not sufficient to represent the
immune response with a single homogeneous population of
effector killer cells. It may be necessary to capture the
different dynamics of more than one immune cell popula-
tion. For example, in order to predict a system’s response
to a particular treatment that can boost the effectiveness of
J Pharmacokinet Pharmacodyn (2014) 41:461–478 465

No Chemotherapy
No Chemotherapy: I 0=0.15 No Chemotherapy: I 0=0.1
1 1
Immune Immune
0.9 Tumor 0.9 I0=0.1, T0=0.25, N0=1 Tumor
I =0.15, T =0.25, N =1
0 0 0 Normal
s=0.33, R=0.01, A=0.3 Normal s=0.33, R=0.01, A=0.3
0.8 0.8

0.7 0.7

Number of Cells
Number of Cells

0.6 0.6

0.5 0.5

0.4 0.4

0.3 0.3

0.2 0.2

0.1 0.1

0 0
0 50 100 150 0 50 100 150
Time in Days Time in Days
Traditional Pulsed Chemotherapy

Traditional pulsed chemotherapy: I0=0.15 Traditional pulsed chemotherapy: I0=0.1

2 2
Immune
Immune 1.8 Tumor
1.8 I =0.15, T =0.25, N =1 I0=0.1, T0=0.25, N0=1
0 0 0 Tumor Normal
s=0.33, R=0.01, A=0.3 Normal s=0.33, R=0.01, A=0.3
1.6 1.6 Drug Dose
Drug Dose
1.4 1.4
Number of Cells
Number of Cells

1.2 1.2

1 1

0.8 0.8

0.6 0.6

0.4 0.4

0.2 0.2

0 0
0 50 100 150 0 50 100 150
Time in Days Time in Days

Solution of Optimization Problem: Irregularly-space, Extended Doses

Optimal control chemotherapy: I0=0.15 Optimal control chemotherapy: I0=0.1
2 2

1.8 I0=0.15, T0=0.25, N0=1 1.8 I =0.1, T =0.25, N =1

0 0 0
s=0.33, R=0.01, A=0.3
s=0.33, R=0.01, A=0.3
1.6 1.6

1.4 1.4
Number of Cells

Number of Cells

1.2 1.2

1 1

0.8 0.8
Immune
Immune
0.6 0.6 Tumor
Tumor
Normal
Normal
0.4 0.4 Drug Dose
Drug Dose
0.2 0.2

0 0
0 50 100 150 0 50 100 150
Time in Days Time in Days
I0 = E(0) = .15 I0 = E(0) = .10

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b Fig. 2 A comparison of chemotherapy treatment protocols. This
figure depicts three different solutions of the model system given by
Eqs. (1) through (4). Top row The dose function, mðtÞ, which
describes the rate of drug delivery, is zero (no treatment). The left
graph shows a solution with an initial value describing a patient with
stronger initial immune strength (E(0) = 1.5 9 105 cells), while the
right graph shows a patient with weaker initial immune strength (E(0)
= 1 9 105 cells). Without treatment, both solutions show the tumor
population converging to a high tumor equilibrium. Center row The
dose function, mðtÞ, describes regularly spaced treatments: a bolus
injection every 3 days for 90 days. The left panel shows that this
treatment does control the tumor in the patient with the stronger
immune system, but it is ineffective in the case of the patient with the
weaker immune system, shown in the right panel. Bottom row The
dose function, mðtÞ, is the solution to an optimal control problem in
which the objective is to minimize final tumor size while keeping the
immune cell population above a specified threshold. Function mðtÞ in
this scenario is an irregularly varying function, and in both the case of
the stronger and the weaker immune response, shown in the left and
right panels, the tumor is reduced to zero. Note that the total amount
of drug delivered (the area under the graph of the function mðtÞ) is the
same in the second and third rows. Figures reproduced from Fig.12 of
[44]
the cytotoxic immune cell response, it is necessary to
model the kinetics of effector-cell lysis of target cells. In
[45], the authors show that different cytotoxic immune cell
types operate using distinct cell lysis kinetics.
There are two main branches of the cellular immune
response: the innate and the adaptive response. Natural
Killer (NK) cells are a type of cytotoxic lymphocyte
critical to the innate branch of the immune response. A
normal cell will express self-antigens through Major
Histocompatibility Complex I (MCH-I) receptors on its
surface. When the NK cell contacts the target cell, if an
MHC-I-self-antigen connection is made to the target cell,
the kill signal in the NK cell is deactivated. The NK cell
and the target cell then separate and go their respective
ways. However, if the target cell is not expressing self-
antigens in the MHC-I receptor, or if the MHC-I receptor
has been down-regulated on the cell, as may be the case
for mutated cancer cells, then the MCH-I connection
cannot be made with the NK cell. In this event, the NK
cell’s cytolytic response is triggered, and the target cell
can be eliminated.
Part of the adaptive (or specific) branch of the cellular
immune response is carried out by CD8þ T cells. Unlike the
NK cells, these T cells must first be activated before going
after target cells. In the case of cancer, the T cells have to
be trained to recognize tumor-specific antigen that is
present in MHC-I receptors that are on the surface of the
tumor cell. When the T cell binds to the MHC-I-tumor-
antigen complex, a kill signal is triggered, either through
the secretion of granulocytes, or via the Fas/FasL binding
mechanism (see, e.g., [46]). Some tumor cells are able to
evade T-cell attack by down-regulating expression of
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J Pharmacokinet Pharmacodyn (2014) 41:461–478
MHC-I receptors. However, this down-regulation will
make them potential NK cell targets.
In [45], the authors develop a three-population model
that tracks tumor cells and two separate killer immune cell
populations: the NK cells, and the CD8þ T (killer T, or
cytotoxic T) cells. The model is validated using laboratory
mouse data published in [47], and modeling terms are
introduced that reflect the distinct dynamics governing the
NK and CD8þ T cell populations. In particular, the authors
found that the laboratory data required a new functional
form to represent how the T cells killed the tumor cells. If
we let T(t) represent the tumor cell population and N(t) the
NK cell population at time t, then a mass-action dynamic is
described by the following differential equation:
dT
¼ aNT: ð5Þ
dt
Here, a is a parameter that can be adjusted to fit to a
particular data set. Fits to two sets of data are shown in
Fig. 3. These data are from [47], and result from two lysis
assays. In both assays, initial immune cell to tumor cell
ratios ranged from 6:1 up to 100:1. The percent of tumor
cell lysis after four hours was measured. For Data Set 1,
which has lysis data for control cells, the parameter a is
1.9 9 10-4 Data Set 2 has lysis data for tumor cells that
have been transduced with immune-stimulating ligands. In
this case, the value of a is 1.4 9 10-3, nearly ten times
higher than in the control case.
The mass-action form of Eq. (5) was sufficient to
describe the data reflecting the NK killing of tumor cells in
the mouse models published in [47]. However, this form
could not adequately describe the action of the CD8þ T
cells. In order to address this issue, the authors developed
what later came to be known as the dePillis-Radunskaya
Law. This law states that the ratio of the immune cells to
the tumor cells should be taken as the dependent variable in
the per-cell kill rate.
In particular, if we let L represent the CD8þ T lympho-
cytes (‘‘L’’ for lymphocyte), the kill term in the differential
equation for T takes the form:
dT ðL=TÞk
¼ d T: ð6Þ
dt s þ ðL=TÞk
The exponent k represents how the lysis rate depends on
the lymphocyte to tumor ratio. The parameter s is the value
at which the tumor size curve reaches half its maximum.
Therefore, increasing s shifts the curve to the right.
Parameter d gives the maximum cell lysis rate. The ratio-
dependent kill rate was validated using data from several
independent sources, in particular those published in [47,
48]. For detailed parameter estimates see [45]. A compar-
ison of the mass-action and ratio-dependent kill rates is
shown in Fig. 4.
J Pharmacokinet Pharmacodyn (2014) 41:461–478
Fig. 3 Graphs showing a least-
squares fit to data from [47]
using the mass-action kill rate
given in Eq. (5)
Fig. 4 A comparison of the
Mass Action Law (Eq. (5)) and
the dePillis-Radunskaya Law
(Eq. (6)). The immune cell
population is given as a multiple
of the tumor cell population
Agent-based and cellular automata models.
Mathematical modeling techniques other than ODEs have
also been used for modeling cytotoxic chemotherapy. A
cellular automaton (CA) model assigns a state to each
element of a grid, and all states are updated according to
rules that depend on the current state of the grid element as
well as the state of neighboring grid elements. Each com-
putational grid element might represent one biological cell,
or a small portion of physical space containing a collection
of cells. A CA model is quite flexible, since it can describe
the interactions of individual cells with their neighbors,
rather than treating the populations as homogeneous.
In a study by Castiglione et al. [49], the authors examine
the processes by which chemotherapeutic agents such as
paclitaxel can induce hypersensitive responses in a patient.
467
An allergic reaction from a patient can force treatment to
be halted. The authors use a Cellular Automata (CA) model
of the immune system to investigate how the allergic drug
schedule, dose fractionation, dosing interval, and rate of
administration affect the resulting symptoms of hypersen-
sitivity. The authors explore a wide variety of other dose
scheduling scenarios that can help to reduce the allergic
response in a patient. For example, simulations show that
for an equal total drug dose split into two doses, lower
levels of histamine are released when the first dose is lower
than the second dose (and similarly, higher histamine levels
are released when the first dose is higher). They point out,
however, that a larger second dose is not advisable unless
the sensitization is made with a very low first dosage.
Simulations also showed that controlling the dosing inter-
val can modify histamine release. The standard dosing
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interval of two weeks actually maximizes histamine
release. Simulations provide dose-dependent predictions
for how far apart dosing should be in order to minimize
histamine release. Overall, their results suggest that there
may be an optimal dosing schedule that should be used
during anti-cancer therapies that will minimize the allergic
response in patients.
An agent-based model (ABM) is a generalization of a
CA model. In an agent-based model, each cell is assigned
characteristics (cell type, stage in cell cycle), and the state
is updated according to rules that describe the interaction of
cells with one another, as well as with the environment or
treatments. There are several distinctions between ABM
and CA models. First, ABM models are often ‘‘off-lattice,’’
which means that the ‘‘agents’’ don’t necessarily position
themselves regularly through space. In CA models, on the
other hand, the state variables are values, possibly multi-
dimensional, that are assigned to nodes of a lattice or a
graph. In particular, in an ABM, multiple agents can
occupy the same position in space, and agents’ locations
relative to one another can change over time. In a CA, the
time step is regular, and all cells are updated at the same
time. In an ABM, the agents’ states can be updated at
arbitrary times, potentially triggered by the environment or
by other cues. Thus, ABMs can describe a much richer
variety of processes. While ABMs allow for a great deal of
flexibility, they usually must also track of a huge number of
variables. Both CA and ABM models can make use of
probabilistic rules for describing a cell’s propensity for
changing from one state to another. However, modeling
individual cells is computationally costly. Just the
description of the initial state requires specifying the
individual states of millions of (simulated) cells.
Roeder et al. [50] present an agent-based model of
chronic myelogenous leukemia (CML), extending a pre-
vious model due to [51]. Subsequently the authors in [52,
53] simplified the model presented in [50] to study Gleevec
(imatinib), a treatment for CML. In this study, in order to
address some issues of computational cost, individual cells
were no longer tracked. Instead, an age-structured model
was developed in which the number of cells of each type in
each stage are the system variables. Figure 5 illustrates
how an ABM could be reconfigured as an age-structured
model. The structuring of the population allows the model
to describe the action of imatinib on only the proliferating
cells in the G1 stage of the cell-cycle. The lumping of the
agents, or cells, into compartments, dramatically reduces
the number of computations required at each time step. A
further reduction in complexity was achieved by replacing
the stochastic rules in [50] by a deterministic rule that
describes the average behavior of the cell populations in
each stage. This results in a large system of difference
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J Pharmacokinet Pharmacodyn (2014) 41:461–478
equations, but one that can be analyzed using techniques
from dynamical systems theory.
These studies show that a difference equation approxi-
mation of the agent-based model can closely replicate the
behavior of the original agent based model under a wide
range of conditions and can run in a few minutes as
opposed to a few days. Furthermore, the reduced com-
plexity of the system allowed for a sensitivity analysis of
the parameters of the original system, identifying those that
were most important in determining treatment outcomes.
The authors then extended the model to derive an
analogous partial differential equation model of CML with
imatinib treatment. The authors used parameters from [50]
based on human data of stem cell turnover and the response
of CML under treatment by Gleevec. In [54], the authors
used a delay differential equation of a T cell response to
chronic myelogenous leukemia during Gleevec treatment
to investigate whether strategic treatment interruptions can
improve therapeutic outcome. This study concluded that
strategic treatment interruptions might drive a potent and
prolonged anti-cancer T cell response, leading to extended
cancer remission. Thus, strategic treatment interruptions
might serve as a feasible treatment approach.
Modeling immunotherapies
The goal of immunotherapy is to boost the system’s own
immune defense against the tumor. The benefits to this
approach over cytotoxic chemotherapies include relatively
lower toxicity, and, in some cases, the ability to target
tumor cells that cytotoxic drugs are unable to reach. Some
of the earliest successes with immunotherapy have been in
the treatment of metastatic kidney cancer and metastatic
melanoma, particularly in cases when the disease did not
respond to chemotherapy [55]. In the case of glioblastoma
multiform (GBM), a common and very aggressive brain
cancer, it is difficult to get drugs through the blood brain
barrier, and the GBM cells are resistant to radio-therapy. A
variety of immunotherapies for GBM are now being tested
in clinical trials [56].
In their seminal work [57], Kirschner and Panetta pro-
pose a three-population ODE model to capture IL-2 treat-
ment of cancer. The model tracks tumor cells, a population
of activated immune-effector cells (meant to capture the
activity of cytotoxic T cells, macrophages, and natural
killer cells in one population), and a concentration of the
cytokine IL-2 (Interleukin-2). IL-2 is one of a number of
cytokines that have been evaluated in cancer immuno-
therapy. IL-2 is produced within a host (endogenously) as
part of natural immune activity. In addition, concentrations
of cloned IL-2 have been used as part of external
J Pharmacokinet Pharmacodyn (2014) 41:461–478
Fig. 5 An agent-based model
consisting of N cells, each with
its own characteristics
(‘‘states’’) can be approximated
by an age-structured model,
where the N cells are classified
into a relatively small number of
types. This reduces
computational complexity, and
can make the model tractable to
analysis
(exogenous) cancer treatment regimens [58, 59]. Rosen-
berg and colleagues found that in the presence of high
concentrations of cloned IL-2, large numbers of activated
lymphoid cells were generated that could kill certain tumor
cells [58]. In the Kirschner and Panetta model, endogenous
IL-2 is stimulated through interactions between the effector
and tumor cell populations, but is tumor-cell saturation
limited through the use of a Michaelis–Menten term.
Exogenous IL-2 treatment can be introduced into the sys-
tem through an independent source term. Additionally,
adoptive cellular immunotherapy (ACI) - representing
either tumor infiltrating lymphocyte (TIL) or lymphokine
activated killer cell (LAK) injections - can be simulated
through a source term in the effector cell equation. The
authors observe that according to their model, treatment
with IL-2 can be somewhat unstable: too little IL-2 does
not sufficiently boost immune activity, while too much can
cause pathological effects. The model is able to evidence
both short-term oscillations in tumor size, as well as longer
term tumor relapse. The authors find that IL-2 treatment
alone at any dose is not able to control tumor growth, but
that the right amount of IL-2 in combination with some
form of ACI can lead to successful tumor clearance.
In another study by Cappuccio et al. [60], the authors
investigate the effect of IL-21 immunotherapy treatments
on tumor control. IL-21 accelerates the transition from the
innate NK-cell-mediated immune response to the adaptive
CD8þ T cell-mediated anti-tumor immune response, the
latter of which has been shown to be more effective in
tumor control. The model is a six-population system of
ODEs that tracks IL-21 concentration, NK cell population
in the spleen, CD8þ T cell activity in the lymph nodes, a
CD8þ T cell memory element, a cytotoxic protein that
affects tumor lysis, and overall tumor mass. The model is
able to capture experimental growth dynamics in B16
melanoma as well as in MethA and MCA205 fibrosarco-
mas. The authors show that there is a strong dependence of
the NK-cell/CD8þ T-cell balance on tumor immunogenic-
ity. Model simulations support the clinical use of IL-21 as a
469
stimulator of cellular immunity against cancer, and the
authors outline a strategy for selecting IL-21 immuno-
therapy as a function of tumor immunogenicity.
Bellomo et al. have produced a number of works and
reviews related to modeling tumor–immune interactions,
c.f. [61–65]. For example, in [63], the authors provide a
review of certain generalized kinetic models of the cellular
immune response to tumor. The authors present details of
progression models (in which endothelial cells lose dif-
ferentiation and begin to progress toward tumor behavior),
and mean field models (in which cells can sense the pre-
sence of other cells within a certain distance, and in which
cell proliferation or death processes are determined by
interactions with these neighboring cells). They also dis-
cuss some approaches to modeling immunotherapeutic
strategies.
Immunotherapies for cancer operate via several different
pathways. Some therapies aim to promote the response
from cytotoxic T-lymphocytes, such as CD8þ T cells, by
attaching immune-stimulating adjuvants such as a virus or
bacteria to a patient’s own irradiated tumor cells. Alter-
nately, the immune cascade can be triggered by injecting
either trained dendritic cells or peptides found on tumor
cells into an individual. A third option is to transfer acti-
vated immune cells directly to the patient [55]. Antibodies
can also be used to stimulate NK cells through antibody-
dependent cell-mediated cytotoxicity (ADCC), a mecha-
nism that allows the NK cells to recognize tumor cells
bound to specific antibodies [3]. Other immunotherapies
attempt to down-regulate the activity of immuno-suppres-
sive cells, such as regulatory T cells (T-regs) [66].
In [67], the authors combine laboratory experiments
with mathematical models to further an understanding of
the effect of immunotherapies on cancer progression. In
particular, their work delves into the details of the kinetics
of the adaptive cellular response. In [67], two types of
immune cells in the adaptive response are modeled: the
CD8þ ‘‘killer’’ T-cells and the CD4þ ‘‘helper’’ T-cells.
These two types of T-cells respond to a cancer vaccine in
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Fig. 6 Flow diagram
illustrating the five phases of the
T-cell cascade: (1) naive, (2)
rapidly proliferating, (3)
circulating, (4) apoptotic, (5)
memory. The proliferation
cascade is triggered by the
APCs (upper compartment).
The three connection times
appear as delays in the
differential equations. In the full
model, these five phases are
tracked for two types of T cells:
CD8þ and CD4þ T-cells. From
[67], Fig. 1
the form of a peptide injected into the system. The peptide
vaccine activates Antigen-Presenting Cells (APCs) that
travel to the lymph organs and stimulate the proliferation of
T-cells that are trained to recognize the specific peptide
that is found on the tumor cells. Some of the new cells will
move into the system and locate the tumor cells. The
proliferation, or expansion, phase is followed by a con-
traction phase, where the new, active T-cells begin to die
quickly. Some of these T-cells will become memory cells,
able to be quickly stimulated when the same antigen is
presented at a later time.
In order to capture the delays inherent in this cellular
immune response, as well as the different phases of the
cascade, the mathematical model in [67] consists of a
system of eleven differential equations, with five delays.
Each equation represents one of the five phases in the
T-cell cascade: Naive, Proliferating, Apoptotic (dying
quickly), Circulating and Memory cells. This gives ten
equations to describe the dynamics of the two cell types:
Helper Cells (CD4þ ) and Killer Cells (CD8þ ). The flow
between cell phases for one cell type, as well as the trig-
gering of the immune cascade by APCs, is shown in Fig. 6.
The model focuses on the kinetics of these cells in the
spleen, in response to the presence of a weak antigen, such
as a cancer vaccine. The eleventh equation describes the
dynamics of the APCs. An important assumption in the
introduction of the delays is that once the APCs are in
contact with the T-cells, they do not disassociate. Fur-
thermore, the rate of cell death in the naive, proliferating
and memory phases is assumed to be much slower than the
connection times represented by the delays. This model
was informed by laboratory experiments on mice, where
labeled immune cells could be counted at various time
points (data shown in [67]). These experiments led to the
question of whether there was a way to maximize the
immune response to a vaccine treatment. We address this
question in Sect. 3.1.
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J Pharmacokinet Pharmacodyn (2014) 41:461–478
Predicting optimal treatment protocols
Once a model is calibrated to data, it can be used to test
different treatment protocols. Since cancer vaccines are
weak antigens, one vaccination is not sufficient to elicit an
effective immune response. It is important to ask, then,
when the best time would be to administer a boost, i.e., a
subsequent vaccine dose. For the model developed in [67],
a heuristic optimization technique was implemented to
determine an optimal post-vaccination boosting time. The
results of the mathematical optimization showed that a
boost should be administered 3 days after the initial vac-
cination. The ‘‘Day 3 hypothesis’’ was then tested in the
laboratory. Laboratory results confirmed that indeed, the
cellular response was greater after a boost on Day 3 than it
was after a later boost. For example, a boost on Day 6,
which was just before the peak of the initial response, was
significantly less effective. See Fig. 7.
Modeling immune cell trafficking & dendritic cell
vaccines
With an understanding of the kinetics of the cellular
response to a weak antigen, a model of the effect of a
Dendritic Cell (DC) vaccine, such as the DC vaccine cur-
rently studied for the treatment of prostate cancer [68], can
be developed. In [69], the authors extend a calibrated
model of dendritic cell trafficking developed by Ludewig
et al. [70] by adding a tumor compartment to blood and
spleen compartments. The model bears similarities to the
model described in [67], in that it also includes delay dif-
ferential equations to describe dendritic cell activation in
the spleen. However, in [69] the kinetics in the spleen are
simplified, and only the CD8þ T cells (the ‘‘killer cells’’)
are tracked. After calibrating the model to published
experimental data, the model was used to investigate dif-
ferent treatment strategies. In addition to exploring the
J Pharmacokinet Pharmacodyn (2014) 41:461–478 471

Fig. 7 Model simulations showing the increased cellular response (in after the initial vaccination (right panel). The vertical lines show the
total number of CD8þ cells) if a vaccine boost is given 3 days after timing of the vaccinations, time is in days. From [67], Fig. 8
the initial vaccination (left panel), compared to a boost given 6 days

Fig. 8 Fractionated Dosing comparison. Intratumoral injections. Compare DC dosing schedule from [71] (left panel) to hypothetical fractionated
dosing schedule (right panel). Figure reproduced from [69]

Fig. 9 Fractionated Dosing comparison. Intravenous injections. Compare DC dosing schedule from [71] (left panel) to hypothetical fractionated
dosing schedule (right panel). Figure reproduced from [69]

effect of varying dose, the model can also allow for a blood stream were the most effective strategy for slowing
comparison of the effects of injecting the DCs into the the growth of the tumor. Fig. 8 illustrates that fractionated
blood, or directly into the tumor. The conclusions of this in intratumoral dosing does not improve outcomes, but Fig. 9
silico study were that fractionated doses injected into the shows that fractionated intravenous dosing is more

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Fig. 10 Prophylactic
vaccination and the effect of
varying immune strength
parameter d. Vaccinate with DC
treatments, days 0 and 7,
1 9 105 DCs per dose. Tumor
challenge on day 21, with
2 9 105 tumor cells. Dosing
follows Preynat [72]
experiment. With d = 1, tumor
is controlled as a result of
vaccination. Figure reproduced
from [69]
effective in controlling tumor growth. Model simulations
also revealed an important parameter, the maximal kill
rate, d, given in Eq. (6). If this parameter is above a critical
value, then the tumor can be eradicated with a sufficiently
large dose of the DC vaccine; if d is less than this critical
value, then the tumor will always escape immune surveil-
lance (see Fig. 10). Thus, model simulations uncovered a
potential target for therapy: adjuvants that increase the
effectiveness of the CD8þ T cells should be administered in
conjunction with the DC vaccine.
A model that explores immunotherapy targeting
immuno-suppressive cells was described in [73]. This
model includes regulatory T-cells (T-regs), which suppress
the response of effector cells, such as CD8þ T-cells. The
model also includes a variable that describes T-reg down-
regulating treatment with the drug sunitinib. The model
successfully replicates the results of clinical studies from
[74, 75]. Simulated scenarios highlight certain patient
characteristics that are most important in predicting a
positive response to sunitinib of treatment.
Heterogeneity of patients’ responses is the focus of the
model described in [76]. B Cell Chronic Lymphocytic
Leukemia (B-CLL) is a disease of the immune system.
Predicting a patient’s response to existing therapies for
B-CLL has been extremely difficult, if not impossible. A
careful parameter fitting study using data from [77], as well
as a sensitivity analysis, revealed that the recruitment rate
of T-cells, along with the turnover rate of the tumor cells,
were the most important prognostic indicators. Thus, the
model suggests that treatments should target the T-cell
recruitment rate, and that assays that can estimate tumor
cell proliferation and death rates could help in guiding
patient-specific treatments.
The models presented so far in this section assume
populations of tumor and immune cells that are well-mixed
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J Pharmacokinet Pharmacodyn (2014) 41:461–478
in a few compartments, such as the spleen, blood or tumor.
More recent studies in modeling immunotherapies include
[78], in which the authors develop a space and time
dependent model representing tumor–lymphocyte interac-
tions, and they also explore the effects of immunotherapy.
They find that chemotactic lymphocyte guidance plays
only a minor role in tumor control, but a lymphocyte
blockade of advancing tumor cells can effectively control
tumor growth. The authors suggest that including an anti-
migratory agent as part of tumor therapy could be critical
to tumor control.
In [79], the authors investigate Interleukin-27 as a
potential anti-tumor agent. Tumor cells transfected with
IL-27 have been shown to cause CD8þ T cells to promote
the secretion of the anti-tumor cytokine IL-10, but at the
same time IL-27 tends to inhibit CD8þ T secretion of
Interferon-c, which then inhibits anti-tumor activity. The
authors present a mathematical model consisting of a sys-
tem of partial differential equations that assumes a spher-
ical tumor and tracks IL-27, IL-10, Interferon-c, tumor cell
density, and tumor-antigen specific CD8þ T cell density.
Tumor cell proliferation is assumed to follow a logistic
growth curve, immune inhibition of tumor growth is satu-
ration-limited, and all chemical and cell concentrations are
allowed to diffuse through space. The numerical simula-
tions presented are in qualitative agreement with experi-
mental data. The authors propose continuous injection
protocols that tend to reduce tumor load more effectively
than do intermittent injections. However, based on the
underlying PDE model, tumor load reduction is temporary,
and the tumor burden is only decreased while treatment is
ongoing.
In [80], the authors build on the 1994 two-population
ODE system of Kuznetsov [34], which tracks CD8þ T
effector cell and tumor cell populations. In [80], the authors
J Pharmacokinet Pharmacodyn (2014) 41:461–478
add a third population representing helper T cells. Helper T
cells are called HTCs in that work, but as we have seen in
other works, the CD4þ T cells are referenced as synony-
mous with the helper T cell population, as was done in
[67]. The authors of [80] use a simplified version of the
Kuznetsov model as proposed by Galach [81], in which the
Michaelis-Menten immune recruitment term is replaced
with a simpler bilinear term. This simplification makes the
dynamical systems analysis more tractable. In addition,
following the treatment modeling approach of Kirschner
and Panetta [57], the authors add a constant source term in
the effector cell population. This term represents the
incorporation of TIL injections as a treatment to boost anti-
tumor immune activity. Dynamical systems analysis and
simulation results show that the activity of HTCs could
affect the long term periodic oscillation behaviors of
tumor–immune system interactions. With this model,
tumor cells can be completely eradicated from the patient’s
body using TIL treatment.
Modeling combination chemo-immunotherapy
Combining chemotherapy with immunotherapy can be
important in at least two ways: protecting the patient from
opportunistic infection, and combating the cancer itself.
Cytotoxic treatments make the patient prone to dangerous
infections since chemotherapy depletes the immune sys-
tem. For this reason alone, it is desirable to strengthen the
immune system after an immune-depleting course of che-
motherapy. However, as we have described previously, it is
also desirable to harness the body’s own defenses in the
fight against the cancer. Maintaining a strong immune
system, especially during chemotherapy, may be essential
to successfully controlling tumor growth.
In [82], the authors built a model based on the model in
[45] to explore possibilities for therapy protocols that
combine cytotoxic chemotherapy with immune therapy.
This model tracks six populations: Tumor cells, NK cells,
CD8þ T lymphocytes, circulating lymphocytes, cytotoxic
chemotherapy concentration, and exogenous IL-2 concen-
tration. Recall that IL-2 is a naturally occurring cytokine
that has been evaluated as a cancer immunotherapy [58].
With this model, the authors were able to explore combi-
nation therapy protocols. Immune therapy consisted of
boosting both the CD8þ T cells [83] and injecting IL-2 [84].
Chemotherapy was represented by a systemic, cytotoxic,
non-cell-cycle specific medication, such as some alkylating
agents. The authors were able to simulate scenarios in
which chemotherapy alone or immunotherapy alone was
not sufficient to eradicate a tumor, but in combination, the
treatments successfully eliminated all tumor cells. Their
473
results reflected certain clinical findings [85] in which
immunotherapy was shown to be most effective when
administered in conjunction with chemotherapy. See
Fig. 11.
In follow up work [86], the authors further refine the six-
population model, expand the action of IL-2 on other cell
populations, and include CD8þ T cell self-regulation. The
authors carefully calibrated all model parameters to data
from [48] to reflect metastatic melanoma and known
immune levels for two patient data sets. The authors
showed that patient-specific efficacy of immunotherapy
depended on parameters that could actually be determined
by existing assays.
An important question to ask when exploring combi-
nation treatment approaches is whether there is a way to
improve or even optimize treatment scheduling. In [87], the
authors modify the model of [82] slightly to account for
endogenous as well as exogenous IL-2, and carry out a
detailed mathematical analysis of a theoretical optimal
control strategy for administering the three treatments
introduced in [82]. In a subsequent work [88], the authors
build upon the mathematical analysis of [87], and deter-
mine conditions under which an optimal solution combin-
ing the three treatments can be found. In this work,
numerical experiments that explore the interactions among
the three treatments are presented. The authors find that for
tumors that may be too small to be detectable, treating
mainly with TIL therapy is most effective at eliminating
the tumor while reducing side effects. However, for larger
tumors, the combined actions of chemotherapy and TIL
therapy were needed for most effective tumor control.
Interestingly, TIL and chemotherapy treatments were
found to be far more effective than IL-2 treatments in the
scenarios tested, and the optimal strategy rarely included
IL-2 in the proposed protocol.
Another treatment approach includes targeted therapies
in the form of monoclonal antibodies (mAb), which have
been used in a variety of immunotherapeutic approaches
for treating different cancers. Monoclonal antibodies are
able to target cancer cells in at least two ways: mAbs can
target tumor cells directly (by blocking a growth signal to
the cancer cell by binding to the growth factor receptors),
or indirectly (by making tumor cells much more suscepti-
ble to destruction by both NK cells and chemotherapy). For
example, in about 20–30 percent of women with metastatic
breast cancer, the cancer cells have mutated so that there is
an increased expression of HER2, an epidermal growth
factor like receptor. Herceptin, an anti-HER2 monoclonal
antibody, was created to target the HER2 receptor, and is
now commercially available to treat HER2 positive breast
cancers [58]. In [89], the authors extend the six-population
model of [86] to allow an exploration of mAb treatments
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Fig. 11 Model parameters for these simulations are taken from fitting
the model to mouse tumor growth data. Top Left No treatment.
Immune system without intervention where the tumor reaches
carrying capacity and the mouse ‘‘dies’’. Top Right Chemotherapy.
The immune system response to high tumor with chemotherapy
administered for one day in a fourteen day cycle. Bottom Left
for colorectal cancer. Parameter values and simulated
scenarios were constructed so they could compare the
effectiveness of two separate mAb treatments, cetuximab
and panitumumab, either alone, or in combination with the
chemotherapy treatment irinotecan. The model also
allowed for a range of patient-specific parameters to
account for individual variations in immune system
strength and sensitivity to chemotherapy. Treatment out-
comes were obtained not only for individuals, but also for
groups of virtual patients represented by a biologically
reasonable range of patient-specific parameters. Numerical
experiments produced results that closely matched pub-
lished clinical trials data for tested protocols. Figure 12
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J Pharmacokinet Pharmacodyn (2014) 41:461–478
Immunotherapy. Immune system response to high tumor with the
administration of immunotherapy from days 7 to 8. Bottom Right
Combination therapy. Chemotherapy and immunotherapy as previ-
ously described given simultaneously effectively control of the tumor.
Figures reproduced from Fig. 6 in [82]
shows a comparison between reported response rates and
simulated response rates in clinical trials for irinotecan,
cetuximab and panitumumab. These clinical trial outcomes
can be found in [90–93].
Hypothetical treatment scenarios that yield a response
rate in the virtual patient population are presented in
Fig. 13. In this figure, results of two hypothetical treat-
ments combining irinotecan and cetuximab are compared
to a combination treatment scenario that was tested in a
clinical trial [92]. Details of the different dosing schedules
are outlined in Table 1.
In other studies such as in [94], the authors develop a
delay differential equation model of an anti-cancer T cell
J Pharmacokinet Pharmacodyn (2014) 41:461–478
Fig. 12 Clinical trial simulations compared to reported clinical trial
results for irinotecan monotherapy, cetuximab monotherapy, and
panitumumab monotherapy. Simulation results closely match pub-
lished results for both cetuximab and panitumumab monotherapies.
Sixty four different patients were simulated by sampling from
Fig. 13 Response rates from clinical trial simulations, comparing
standard treatment to an experimental treatment schedule combining
irinotecan and cetuximab. NR, No Response. PR, Partial Response.
CR, Complete Response. 320 individuals simulated. Dosing details in
Table 1. Figure reproduced from [89]
response against Chronic Myelogenous Leukemia (CML)
during Gleevec (imatinib) treatment. This study suggests
that imatinib treatment induces a transient anti-cancer T
cell response as leukemia enters remission and that the
transient immune response can be augmented and pro-
longed using properly-timed cancer vaccines. The authors
utilize experimental data to calibrate the model, which
describes the rise and fall of anti-cancer immune
475
distributions of parameters that reflect individual response strengths to
chemo and immunotherapies. For irinotecan monotherapies, the
reduced response seen in our simulations is intended, since the
patients receiving mAb therapy are often not as responsive as most
patients to other treatments. Figure reproduced from [89]
Table 1 Response Rates: Combination Therapies
Treatment Medication & dosing
Standard [92] Irinotecan: 125 mg/m2 once weekly; Cmab:
400 mg/m2 load; 250 mg/m2 weekly
Hypoth. Treatment 3 Irinotecan: 125 mg/m2 once weekly; Cmab:
from [89] 400 mg/m2 load; starting day 4, 250 mg/m2
weekly
Hypoth. Treatment 4 Irinotecan: 350 mg/m2 once every three
from [89] weeks; Cmab: 500 mg/m2 once every two
weeks
A comparison of published and hypothetical dosing schedules. Pmab
panitumumab, Cmab cetuximab. See Fig. 13 for a graphical com-
parison of outcomes
populations over time. This study simulates different pos-
sible vaccination schedules during imatinib treatment and
concludes that combining imatinib treatment with cancer
vaccination could greatly improve treatment outcome. The
same research group in a different study [95] considers a
system of nonlinear delay-differential equations (DDEs)
that models the dynamics of the interaction between CML,
imatinib, and the anti-leukemia immune response. The
group develops several computational methods that can
help identify the model parameters that affect the dynamics
of the anti-leukemia immune response during imatinib
treatment. The parameters representing T-cell proliferation
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after stimulation by the presence of the leukemic cells, as
well as the background rate of production of the T-cells,
are found to be the most important in predicting the disease
outcome. These results differ somewhat from the parameter
sensitivity analysis in [96], which considered a model of a
solid tumor with a dendritic cell vaccine. In that analysis,
the progression of the disease is most sensitive to the
parameter representing the kill rate of the tumor cells by
the immune cells.
Summary and conclusion
In this chapter, we have described a sampling of some of
the variety of work being done in mathematical modeling
and simulation of chemotherapy, immunotherapy and
mixed chemo-immunotherapies for cancer.
Cancer is the leading cause of death worldwide.
Enhancing the immune response by the effective admin-
istration of immunotherapies is a promising avenue for
increasing survival times as well as improving the quality
of life for cancer patients. However, the interaction of these
therapies with other treatments, such as surgery, radiation
and cytotoxic drugs, is still poorly understood. Further-
more, a patient’s response to treatments varies widely, and
it is important to develop predictive tools to determine the
best treatment strategy for each patient. Mathematical
models can help to unravel the interactions between
treatments, understand dose-response profiles, and safely
test a variety of treatments in silico, as a precursor to
clinical trials. The ultimate goal of these modeling studies
is to provide a framework for a new age in dosimetry.
In collaboration with pharmaceutical scientists, we hope
to use mathematical modeling and simulation in conjunc-
tion with laboratory tests and clinical trials to efficiently
answer two central questions in therapy design: How much
and how often?
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