Adoptive Immunotherapy

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Adoptive Immunotherapy

• Chris Cunningham Asad Usman
• Mathematical Biology 463
• Dr. Jackson

2
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

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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

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The Basics - Introduction
? ? ? ? ?

• 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 cancer-fighting capacity
• Then, these are injected into tumor site to
  increase immune response locally
• Injections can be /- Immune Cells and /-
  growth factor

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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

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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
lymphokine-activated 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.)
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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

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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

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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

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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

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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
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Cytokines IL-2 Targets

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

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Adoptive Immunotherapy

• Technique involves isolating tumor-infiltrating
  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.

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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

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A.I.
This figure shows adoptive immunotherapy
isolation techniques
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The Immune Model
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The Immune Pathway
Think Michaelis- Menton
Effector Cell
IL-2 Molecules
1. IL-2 binds IL-2 Receptor
2. Effector Cell with bound IL-2
IL-2 Receptor
Tumor recognition site
4. Tumor Eating Site Activated
Tumor cells
6. Attack Mode!
3. Effector Cell Activated And Multiply
Step 6
5. Locates Tumor
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The Model
Antigenicity and size of tumor
IL-2 Stimulation
Death rate
Change in Effector cells over time
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
IL-2 Injection
Death rate
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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, low-period
  oscillations.

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No Treatment Case - Case 1

• Very low antigenicity.

Days
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No Treatment Case Case 2

• Intermediate antigenicity.

Days
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No Treatment Case Case 3

• High antigenicity.

Days
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Implications of Model

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

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Implications of Model
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Implications of Model
(faster!)
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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.

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Implications of Model
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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?

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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).

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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.
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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.

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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.

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More animation!
High Antigenicity (non-nasty tumor)
The tumor is eradicated for most values of immune
threshold.
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More animation!
Medium Antigenicity (more nasty tumor)
The tumor is still eradicated for most values of
immune threshold.
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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.

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Low-Antigenicity Results

• Long-term dormant tumor
• Our model predicts that for low-antigenicity
  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.

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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.
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Therapy Results - Images

• Tumor regression by adoptive-cell-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
  adoptive-cell-transfer therapy
• Tumour deposits were present before treatment
  and substantially shrank or completely resolved
  when evaluated 8 months later

Title Adoptive-Cell-Transfer Therapy for the
Treatment of Patients with Cancer. Rosenburg SA
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Therapy Results - Images

• Obtained from a tumor-bearing host
• 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).

Title Adoptive-Cell-Transfer Therapy for the
Treatment of Patients with Cancer. Rosenburg SA
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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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Sources

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• 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
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Happy Finals!!!

• Thanks
• Bart Simpson is misunderstood!!!