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92 Cards in this Set

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