ICL 8.2: Cancer and Editing Flashcards
what is cancer?
cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells
if the spread is not controlled, it can result in death
what is metastasis?
migration of cancer cells from the original tumor site through the blood and lymph vessels to produce cancers in other tissues
metastasis is also the term used for a secondary cancer growing at a distant site
where are immune cells located?
blood and lymph
what are cancer cells?
cancer cells are normal “self” cells that have had a genetic mutation, most likely in something that regulates cell cycle checkpoints
so since they’re self cells, your immune often doesn’t see anything wrong with them
however, we can train our immune system to recognize them through cancer immunotherapy!
how can we make the immune system see the cancer cells?
cancer immunotherapy
what experiment was done to show that our immune response to tumors is immunologically specific?
- mice were irradiated with dead tumor cells
- then the mice were injected with the same liver tumor ells
- overtime the mice never developed cancer!
however if they went back and gave live tumor cells from a different cell line, the mice got cancer!
this shows that the immune system is antigen specific
what is immunoediting?
it’s dynamic process that consists of immunosurveillance and tumor progression
it describes the relation between the tumor cells and the immune system
what are the three steps of immunoediting?
- elimination
- equilibrium
- escape
how do cancer cells turn into full fledged cancer?
normally, cancer formation is when there’s a group of cells that start dividing abnormally
with cancer editing, there are immune cells out checking for bad cells and they find cells that have been transformed and respond to them by killing them = elimination
in some cases, the cancer cells have mutations and can outsmart the immune system for a bit but ultimately you’re in equilibrium
then, sometimes the cancer cells get even more mutations and either the immune system doesn’t recognize them or the mutations go on for so long that your immune system gets tired = escape
the escape phase is when someone would be in the clinic and actually officially have cancer
all the other stuff is happening every single day in your body normally!
how can leukocytes be bad and actually promote cancer?
usually infiltrating leukocytes are a good thing because it means your immune system is trying to stop the abnormal cells
but sometimes there are cancers that thrive on leukocyte infiltration –> the tumors can use the leukocytes as growth factors to grow even more
what do PD-1 and PD-L1 do?
PD-L1 are “don’t kill me” signals expressed by host cells
PD-1 on T cells is inhibitory and tells T cell to move on and not kill the cell
what does Treg do?
it suppressed CD8 and CD4 responses which stops your immune response
some tumors secrete cytokines to recruit Treg!!!
how is anti-PD-1 medications used to treat cancer?
PD-1 on T cells is inhibitory and tells T cell to move on and not kill the cell
if you block PD-1 then the T cell won’t have anything turning it off and it’ll go out and kill tons of things
this is good because it means that the t cell can go kill cancer cells! it increases the immune-based killing of tumor cells
what happens if you block CTLA4?
CTLA4 prevents T cells from being activated and destroying self cells
but if you block CTLA4 with anti-CTLA4 medications then the T cell can go out and kill tons of cancer cells
what are the 4 types of cancer immunotherapy?
- cytokine therapy
- monoclonal antibody therapy
- cancer vaccine
- cell therapy
what are cytokines?
proteins that activate the immune system
how can you use cytokines to treat melanoma and renal cell carcinoma?
you can treat them with IFNα and IL-2
IFNα and IL-2 help with T cell proliferation
they also expand NK cell population which helps kill tumor cells
it’s really effective on tumors that lower MHC expression since this is what NK cells pick up on
the issue is that people have flu-like symptoms for 4 months and there’s only a 15% response rate
what are monoclonal antibodies?
they are antibodies that recognize proteins expressed on tumors (tumor antigens)
how do monoclonal antibodies work?
various mechanism:
- opsonization for phagocytes
- delivering radiation/chemical
- blocking growth factor signaling (ex. TGF)
what is anti-CD3 used for?
it’s a monoclonal antibody used for prevention of transplant rejection
anti-CD3 binds to CD3 which usually opsonizes antigens and marks them for the immune system
what is Rituximab used to treat?
non-Hodgkin lymphoma
it’s anti-CD20
what is Gemtuzumab ozogamicin used to treat?
aka mylotarg
used to treat AML
it’s a conjugated anti-CD33 antibody
how does mylotarg work?
it’s anti-CD33 + calcicheamicin
calicheamicin can intercalate into DNA and disrupt the DNA
when that complex is exposed to cancer cells it binds to tumor cell and kills it
what’s the problem with mylotarg?
people were dying of vein occlusion in the liver….
also calicheamicin is kinda toxic so maybe we shouldn’t be putting that into people’s bodies
how does Rituximab work?
it a naked monoclonal antibody that is NOT conjugated (mylotarg is conjugated)
it binds to CD20 on normal and abnormal B cells
it blocks growth factor receptors or it can induce cytotoxicity/apoptosis
rituximab can also activate complement and kill B cells via MAC formation
what is the problem with Rituximab?
it binds to CD30 on both normal and abnormal B cells
so it’s also going to opsonize your healthy B cells and kill them…
this is great if you have a B cell lymphoma but you should still give immunoglobulin to make up for the fact there’s no B cells around to produce antibodies
what are the pros and cons of naked monoclonal antibody therapy?
they effectively kill all cells expressing the antigen which is great for getting kid of cancer cells and non-immune cancers
however, it also kills normal cells and can lead to some loss of normal tissue and local inflammation
how do you engineer monoclonal antibodies to be specific for what you want?
- if you alter the Fab region it will change the antigen specificity and make the antibody stay bound for longer
- or you can alter the Fc region which will effect complement activation
what is bi-specific antibody therapy?
when one antibody has two specificities
one end of the antibody binds to the cancer antigen (anti-HER2/neu) and the other end binds to the effector cell (CD8 T cell, NK cell, macrophage/monocyte)
or sometimes the second end will be engineered to bind to another cancer antigen
once both things are bound to the antibody, cancer cell killing occurs
what’s the point to making a bi-specific antibody?
you want to hook up the cancer cell with effector cell to induce ADCC
then you can use another bi-specific antibody to hook another tumor cell to the tumor cell that’s bound to the effector cell to make a chain
cross-linking the two cancer antigens induces apoptosis!
basically you’re trying to bring an NK cell in close proximity to tumor cells to improve killing
if you wanted to kill a T cell lymphoma, what would you target?
CD4 or CD8
if you targeted CD3 you’d kill all T cells including the healthy ones
so if you target CD4 for example, then you would only be partially immunosuppressed but still be killing off some of the cancer
what is anti-idiotype therapy?
you’re using the immune system to fight the immune system!
you generate antibodies against antibodies!
use the antigen-binding domain of cancerous B cells as an antigen and produce monoclonal antibodies that will activate ADCC against cancerous B cells
if you could get something to bind to the antigen-binding site of the antibody and recognize it as foreign, you could get rid of B cell lymphomas
once the anti-idiotype monoclonal antibody binds to the cancerous B cell antibodies, it will illicit a response from effector cells and phagocytes that will kill the B cell
antigen binding domain of antibodies = idiotype
what does ADCC stand for?
antibody-dependent cellular cytotoxicity
why doesn’t anti-idiotype therapy work for MM?
in MM the B cells are secreting antibodies, they don’t have antibodies on their surface
however, in B cell lymphoma, there are antibodies on the surface of the B cells that can be targeted by anti-idiotype therapy!
what are prophylactic vaccines?
they prevent development of cancer
you must know causative agent of cancer in order to vaccinate!
currently only 2 approved by FDA
what are therapeutic vaccines?
they treat existing cancer
must know cancer specific antigen!
0 currently approved by FDA
what cancer does HepB cause?
liver cancer
what cancer does HPV cause?
cervical cancer
which vaccine is against HPV?
Gardasil
how do you design a therapeutic vaccine?
- common target vaccine: this would be a vaccine where everybody with this certain cancer would have this same antigen
- patient specific vaccine: this would be a vaccine that’s made from taking the specific patient’s tumor cells and developing a vaccine for it
how do you make a patient specific therapeutic vaccine?
1. remove patients own tumor cells Isolate proteins (antigens)
- couple to a carrier to help make the protein more antigenic
- inject back into patient
what is Provenge?
cancer therapy
- take APC outside the body and inject either tumor RNA into them or tumor antigen
- let the APC mature and produce tumor antigens
- inject the APC back into the patient
- the APC will then present this antigen to T cells and activate T cells to illicit an immune response
this is how you train your APC to attack cancer cells!
how can we engineer CD8 T cells to fight cancer?
we know alot of cancer antigens so we can clone TCR that react with these cancer antigens!
there is a subset of patients that just spontaneously cure themselves of cancer and when we looked at their T cells and cloned their TCR we found that they were antigen specific towards an antigen that was on their tumor!
so if we can figure out a way to clone a TCR and put it onto someone’s T cell we would be engineering CD8 T cells to recognize specific antigens based on their TCR!
so you’re cloning the TCR that reacts with the specific cancer antigen that that patient has – then you take CD8 T cells from that patient and engineer them to express the TCR that would respond to the antigen associated with their tumor – then you inject their CD8 T cells back into them
so freaking cool
what is CAR T-cell therapy?
CAR = chimeric antigen receptor
CAR T-cell therapy is genetically modified t cells
you take the patient’s T cells out of their body and engineer them to recognize CD19 lymphoma
this actually works really well for treating ALL!
what are the common cancer antigens that we know of?
- PSA = prostate cancer
- MART-1 = melanoma
- tyrosinase = melanoma
- CEA = lung, colorectal, breast, pancreatic
- mucin (up-regulated in many cancers)
what is mucin?
makes membranes more sticky
it’s upregulated in many cancers
how is mucin involved in cancer?
normal mucin has a protein core that is blocked and you can’t get to it due to sugars attached to it
but in cancer, the sugars are smaller and the protein backbone gets exposed
so they’re trying to develop a treatment against carbohydrates but this is really hard because literally everything we have done involves proteins
