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92 Cards in this Set
- Front
- Back
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What are the 2 goals of cancer immunotherapy?
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1. To activate tumor-specific immunity
2. To break tumor-mediated tolerance |
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What is the significance of finding intratumoral Tcells?
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They allow optimal debulking - removal of a tumor.
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How do we know that the immune system plays a role in cancer?
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Because immunity to tumors can be induced in animal systems
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What happens if you inject a rat with live tumor?
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It dies
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What happens if you inject a rat with irradiated tumor vaccination, then inject live tumor?
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It is immunized and lives!
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What happens if you take the Tcells that were cultivated by the vaccination from one rat, and transfer into another rat?
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That other rat will also live by passive transfer of immunity.
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How are tumors antigenic?
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They bear new antigens and modulated self antigens
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What are 4 ways that tumors can look antigenic?
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1. Mutated self protein
2. Oncogene or mutated tumor suppressor gene products 3. Over/aberrantly expressed self proteins 4. Oncogenic virus expression |
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What type of lymphocytes respond to antigens on tumors?
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CD8 CTLs
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What does the killing of tumor cells bear mechanistic similarity to?
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Anti viral killing
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How is the anti-tumor Tcell response induced?
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By cross-priming
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What is cross-priming?
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The expression of tumor antigens on MHC class II of host APCs, but activation of CD8+ Tcells!!
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What else do those APCs present the tumorigenic antigen to?
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Helper T cells, which secrete cytokines to also aid in differentiation of Tumor specific T cells.
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What is a TIL?
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A tumor-infiltrating lymphocyte
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What is adoptive immunotherapy?
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Culturing lymphocytes from tumors that were surgically removed.
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How are lymphocytes cultured?
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By isolating from resected tumors, and expanding in vitro with IL-2, then putting into the patient.
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How is adoptive immunotherapy with TILs useful?
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-As Therapeutic Effector cells
-As tools for tumor Ag identification |
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Is adoptive immunotherapy with TILs very useful?
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Not yet
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If a woman had melanocarcinoma and was cured with Anti-melanocyte Tcells, what would you see?
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No melanocytes left on her body!
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So anti-tumor immunity may essentially be equivalent to:
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Limited Autoimmunity!
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Why is anti-tumor immunity not so simple as using TILs?
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Because Tumors can evade the immune system!
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What are the 8 ways that Tumors can avoid immune recognition?
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1. Loss of MHC Ag expression
2. Downreguln of APC machinery 3. Expression of local inhibitory molecules 4. Expression of FasL/Fas 5. Mutation of target Ag's 6. Loss of CAMs/ligands 7. Induction of Tregs 8. Expression of negative costimulatory molecules |
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What are some local inhibitory molecules that tumor cells can secrete?
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IL-10, IL-6, TGF-b
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What are 2 negative costimulatory molecules that tumor cells can express?
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-PD-1
-B7-H1 |
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How can tumors evade the immune system, apart from avoiding recognition?
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Tumors can induce tolerance
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What are the 3 ways that tumors induce immune tolerance?
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1. By physical deletion of reactive lymphs
2. Induction of anergy 3. Immune ignorance |
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What is Deletion?
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The removal of responding lymphocytes by delivering apoptotic signals
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What are 2 ways by which apoptotic signals can be given to lymphocytes by tumors?
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1. Aberrent T-cell signalling
2. Direct apoptotic signalling |
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What does "aberrent T-cell signalling" refer to?
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Triggering a TCR in the absence of IL-2
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How can tumors give direct apoptotic signalling?
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By expressing FasL, which activates the Fas on activated lymphocyte CTLs
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What will you see in a Fas-deficient tumor?
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Slower progression because it can't evade the immune system as well.
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How do tumor cells induce anergy in Tcells?
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There is something that makes the Tcells change and become Antigen-specifically UNRESPONSIVE.
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How do Tumor cells achieve ignorance?
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They are antigenic, so there are immune cells specific for the tumor, but not immunogenic - they just don't do anything.
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So what are the 2 goals of Immune-based Cancer Therapy?
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1. To break tolerance of the immune system for the tumor
2. To induce Ag-specific immune cells that will carry out long-lived effector mechanisms. |
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What are the 3 key organizing principles of immunotherapy revealed by a review of history?
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1. Danger
2. Cross-priming 3. A new inflammatory mileau |
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What did William Coley find in his injecting patients with bacteria?
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That a fever had an effect on treating tumors.
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What is it about a fever that allows a tumor to elicit an immune response?
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Fever induces "Danger signals" that activate the cells of the immune system.
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What do the danger signals result in?
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Cytokine and costimulatory molecule expression by Th and CTL's
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What do these Danger Signals do?
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Inform the host of a breach of integrity.
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What components of immunity are alerted by the danger signals?
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Both innate and adaptive
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How exactly does bacteria send the danger signals?
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By the recognition of its PAMPS by PRRs on macrophages, which then secrete IL-1, TNF, and IL-12 and activates immunity!
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What is IL-12 secreted by exactly?
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-Macrophages
-Dendritic cells |
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What does IL-12 do?
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Activates NK cells and T cells to secrete IFN-y, increase their cytolytic activity, and differentiate into Th1 cells.
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What exact cells secrete IFN-y?
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NK cells and T cells
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What does IFN-y do?
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Activates macrophages
Stimulates some antibody responses |
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What is IL-15 similar to?
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IL-12
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What cells secrete IL-15?
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Macrophages and others
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What does IL-15 do?
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Stimulates NK cells and Tcells to proliferate.
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What is the role of danger signals activating the innate immune system?
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To recognize tumors by non-MHC restricted mechanisms.
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What happens to APC's when danger signals are sent out in a cancer lesion?
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Cross-priming occurs
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What is Cross-priming?
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The presentation of tumor Ag on both MHC I and II, and presnetation to either CD4 or CD8 cells
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Why does cross-priming occur?
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Because tumor cells are often poorly presented by APCs
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So, what are the 4 things that need to happen in order to break tolerance of tumors?
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1. New cells at tumor - fresh macrophages/dendritic cells
2. Need cytokines to activate Th1 cells and APCs 3. New Ag presentation - cross priming 4. Innate immunity - activated by danger signals. |
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How do we stimulate danger signals?
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By giving an adjuvant
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So to produce a tumor vaccine, does it work to merely inject tumor antigen to stimulate the immune response?
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No; because of the tolerant state.
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What does a tolerance-breaking environment have to include or induce?
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The expression of T-cell activating costimulatory signals (B7, ICAM, and LFA)
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What is the use of a Bone marrow transplant?
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Alters the entire immune system and allows for maximum dose escalation of chemo.
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What do you have to do after the maximum dose chemo in a BMT?
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Rescue the bone marrow with stem cells.
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What 2 conditions must be balanced in a BMT?
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-GVHD
-Graft vs leukemia effect |
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When is GVHD useful?
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When self antigens recognized by the grafted Tcells are those that are present on leukemic cells.
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What is Adoptive immunotherapy?
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The transfer of immune activating or immune competent cells into a cancer patient.
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What do you have to know first, to be able to grow anti-tumor cells?
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What the specific Tcell target is.
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Where are the immune effectors for adoptive immunotherapy generated?
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Somewhere OTHER than in the host's own immune system.
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What is an example of a disease in which adoptive immunotherapy is used?
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Post-Transfusion Lymphoproliferative disease
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What is EBV-LPD?
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Epstein barr virus associated lymphoproliferative disorder
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What does EBV do in immunodeficient hosts?
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Drives unchecked proliferation of Bcells - Bcell lymphoma
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Why does Bcell lymphoma develop in immunodeficient hosts with EBV?
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Because they lack CTLs
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How does adoptive immunotherapy combat EBV-LPD?
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By culturing lymphocytes against EBV in vitro, then transferring the effector cells into the patient.
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How are Tumor Infiltrating Lymphocytes (TILs) used in adoptive immunotherapy?
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They can be used to help screen and identify tumor antigens in patients.
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So what are the 3 types of cells used in adoptive immunotherapy?
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1. Ag-specific T cells
2. TILs 3. NK Cells |
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What are the 3 main functions of NK cells?
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1. Provide Th1 cytokines (IFNy)
2. ADCC 3. Direct killing |
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What types of receptors are on NK cells?
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Both inhibitory and activating
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What do we call the receptors that mediate NK action?
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KIRs - killer cell Ig-like receptors
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What happens when the KIR is bound?
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The NK cell is inhibited by the KIR inhibitory signal
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What happens when the KIR is not bound?
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It kills the cell it sees.
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What are NK cells useful as in terms of Adoptive immunotherapy?
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Protecting against bone marrow graft rejection.
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What does the KIR receptor RECOGNIZE?
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Class I MHC - HLA-C
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So what feature on a cell activates NK cell killing?
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LACK of MHC class I, HLA-C
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What if you give a BMT that has cells that have a different allotype of Class I MHC HLA-C?
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It would trigger NK cell killing
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Would that be useful to give a cell that induces killing?
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Yes, if you want to treat leukemia.
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What type of leukemia is treated by NK alloreactive cell donations? Which one is not?
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-AML is treated against rejection and relapse
-ALL is not affected. |
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What is the manipulation of KIRs to induce alloreactivity and treat AML called?
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KIR haplo-mismatch
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What are 3 types of Humoral immunotherapy that can be used to combat cancer?
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1. Normal unconjugated Ab
2. Immunotoxins 3. Tcell binding antibodies |
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What is Rituximab, and what does it bind?
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Anti-CD20; binds B-lymphomas
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What is Herceptin for?
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Breast cancer
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What is Erbitux for?
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Colorectal cancer
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What does Unconjugated Ab treatment require/rely on?
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-Complement
-ADCC -Innate cells |
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What is an immunotoxin?
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An antibody that is bound to a toxin and directly targets the tumor.
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What is a Tcell binding antibody?
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An antibody that binds to both T cells AND tumor antigen to target the Tcells to the tumor.
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What are some limitations to Humoral immunotherapy?
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-Humanization hurdle
-Nonspecific toxicity -Mutation of the target -Downregulation of target protein expression |
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What is an added bonus of humoral immunotherapy?
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When the Ab-Ag complex is phagocytosed by FcR binding, it aids in cross-presentation leading to Tcell responses.
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Why aren't cytokines used?
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Because they have big bad systemic side effects.
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