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  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 ??????????

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 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.)

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 Schematic overview of the high–affinity interleukin–2 receptor complex, including the receptor chains, downstream signaling components and target genes Fig. 1 Fig. 2

Cytokines – IL-2 Targets  This is a basic overview of the mechanism of IL-2 activation

Adoptive Immunotherapy  Technique involves isolating tumor- infiltrating lymphocytes (TIL’s) 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 IL–2, 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 IL-2 Receptor Tumor recognition site Tumor cells Step 1 Step 2 1. IL-2 binds IL-2 Receptor 2. Effector Cell with bound IL-2 3. Effector Cell Activated And Multiply 4. Tumor Eating Site Activated 6. Attack Mode! Think Michaelis- Menton 5. Locates Tumor Step 3 Step 4 Step 5 Step 6

The Model Change in Effector cells over time Antigenicity and size of tumor Death rate IL-2 Stimulation Effector Cell Injection Change in Tumor cells Logistic growth rate of Tumor Killing rate by Effector cells Change in IL-2 Natural production of IL-2 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, low- period 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

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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.

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! The tumor is still eradicated for most values of immune threshold. 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.”  Question: Why 7 to 91 months?  Our model gives a possible explanation.

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.

Low-Antigenicity Results 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 days

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

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 ( 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

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.

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.  Ostrand–Rosenberg S (1994) Tumor immunotherapy:the tumor cell as an antigen–presenting cell. Current Opinion in Immunology 6: 722–727.  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.  Kirschner D. Panetta JC. Modeling immunotherapy of the tumor-immune interaction. [Journal Article] Journal of Mathematical Biology. 37(3):235-52, 1998 Sep.  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) , 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.

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