Adoptive Immunotherapy The Basics The Basics – Background Adoptive Immunotherapy The Basics – Introduction

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Adoptive Immunotherapy The Basics The Basics – Background Adoptive Immunotherapy The Basics – Introduction

Gross, Terri, On-Air Personality has reference to this Academic Journal, PHwiki organized this Journal 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 in addition to the protective molecules when they encountering a as long as eign particle Purpose of Immune Response To prevent unhealthy states in addition to to restore homeostasis For example – Prevent Cancer: the uncontrolled growth of cells in the body The Basics – Background The most common treatment as long as 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, in addition to 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 as long as m 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 in addition to +/- 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 in addition to characterized by antigen-specificity in addition to 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 in addition to 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 as long as a given structural motif Usually CD8+ cells which kill target cells by recognizing as long as eign 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 ( as long as eign particles) recognizable in addition to 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 in addition to 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 in addition to repair Production triggered by presence of as long as eign 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 in addition to antitumor element Positive results have led approval of high dose IL-2 as long as patients with metastatic melanoma in addition to 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 in addition to 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 Exp in addition to ing 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 in addition to destroy the tumor cells. Adoptive Immunotherapy Immunotherapy IL–2, alone, can be used as a cancer treatment by activation of cells which are cytotoxic as long as the tumor Some success has been obtained with renal cell carcinoma in addition to 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 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 6 The Model Change in Effector cells over time Antigenicity in addition to size of tumor Death rate 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 as long as all tumors. Implications of Model

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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

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 as long as 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 as long as IL-2 injection; ours becomes a function of the number of effector cells in addition to time.

Conclusions Adoptive Immunotherapy is a technique to manage cancer. A mathematical model is presented that allows as long as tumor regression or predicts the remission time given certain parameters. In the case as long as 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 in addition to the predictions of the model. In general, immunotherapy with IL-2 is on the rise in addition to 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 in addition to their Receptors. Ox as long as d: Ox as long as d University Press. Ostr in addition to –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 in addition to interleukin-2 or high-dose interleukin-2 alone. [Journal Article] New Engl in addition to 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, in addition to D.E. Kirschner. A mathematical model of tumor-immune evasion in addition to siRNA treatment. [Journal Article] Discrete in addition to Continuous Dynamical Systems: Series B. 4(1) 39-58, 2004 Feb. Dudley ME. Rosenberg SA. Adoptive-cell-transfer therapy as long as 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 in addition to Chemotherapy of Tumors through Mathematical Modeling. [Book] Department of Mathematics: Harvey-Mudd University, 2003 Summer. Happy Finals!!! Thanks Bart Simpson is misunderstood!!!

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