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
Adoptive Immunotherapy
?
?
?
?
?
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)
Cytokines
Structure of interleukin 2
Fig. 2
Fig. 1
Adoptive Immunotherapy
Technique involves isolating tumorinfiltrating lymphocytes (TILs)
Primarily activated cytotoxic T-lymphocytes
Lymphocytes with antitumor reactivity found
within the tumor
Adoptive Immunotherapy
Immunotherapy
IL2, alone, can be used as a cancer
treatment by activation of cells which
are cytotoxic for the tumor
A.I.
This figure
shows adoptive
immunotherapy
isolation
techniques
Effector Cell
IL-2 Molecules
Think MichaelisMenton
Step 1
Tumor
recognition site
Tumor
cells
Ste
p
IL-2 Receptor
4. Tumor Eating
Site Activated
6. Attack Mode!
Step 6
Step 4
Step 3
Step 5
5. Locates Tumor
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.
Days
Days
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
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
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.
More animation!
High Antigenicity
(non-nasty tumor)
More animation!
Medium Antigenicity
(more nasty tumor)
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.
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.
At positions comparable
to a and b. Numerous
metastases (0.3 - 2 mm)
are detected before
therapy (a, b).
Conclusions
In the case for IL-2 therapy alone the model predicts unbound
behavior.
This way we can resolve disparities in actual clinical data and the
predictions of the model.
Sources
Rosenberg, SA, Yang, JC, White, DE, et al. Durability of complete responses in patients with
metastatic cancer treated with high-dose interleukin-2: Identification of the antigens mediating
response. Ann Surg 1998; 228:307.
Rosenberg, SA, Yang, JC, Topalian, SL, et al. Treatment of 283 consecutive patients with metastatic
melanoma or renal cell cancer using high-dose bolus interleukin-2. JAMA 1994; 271:907.
Nicola NA (ed) (1994) Guidebook to Cytokines and their Receptors. Oxford: Oxford University Press.
Rosenberg SA. Lotze MT. Muul LM. Chang AE. Avis FP. Leitman S. Linehan WM. Robertson CN. Lee
RE. Rubin JT. et al. A progress report on the treatment of 157 patients with advanced cancer using
lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. [Journal Article]
New England Journal of Medicine. 316(15):889-97, 1987 Apr 9.
J.C. Arciero, T.L. Jackson, and D.E. Kirschner. A mathematical model of tumor-immune evasion and
siRNA treatment. [Journal Article] Discrete and Continuous Dynamical Systems: Series B. 4(1) 3958, 2004 Feb.
Dudley ME. Rosenberg SA. Adoptive-cell-transfer therapy for the treatment of patients with cancer.
[Review] [97 refs] [Journal Article. Review. Review, Tutorial] Nature Reviews. Cancer. 3(9):666-75,
2003 Sep.
Chang W., Crowl L., Malm E.,Todd-Brown K., Thomas L., Vrable M. Analyzing Immunotherapy and
Chemotherapy of Tumors through Mathematical Modeling. [Book] Department of Mathematics:
Harvey-Mudd University, 2003 Summer.
Happy Finals!!!
Thanks
Bart Simpson is misunderstood!!!