Immunotherapy Flashcards
passive targeting
relying on leaky vasculature with a drug loaded NP
Innate immunity
basic resistance to disease an individual is born with
rapid protection against microbes
response in place before foreign antigen presents
same response regardless of antigen or previous exposure
adaptive immunity
protection develops more slowly (days)
developed only after exposure to an antigen
effective only against the specific antigen
memory response against recurring antigen
humoral immunity
antigen on bacteria interact with B cell
B-cell gives antigen to helper T cell and releases cytokines
antibodies form from both B cell and helper T cells
cell mediated immunity
antigen presenting immune cell interacts with inactive helper T cell
activated helper T cell triggers cytokine release
helper T cell becomes a cytotoxic T cell and destroys infected cell
checkpoints
lower a stop sign that cancer cells usually present to immune cells
checkpoint inhibitors
work by taking the brakes off the immune system
cytokines
stimulate growth/activity of immune cells
used in recombinant IFNa therapy
–interferons: induce maturation of immune cells
–interleukins: stimulate activity of CD4+ and CD8+ T cells
–granulocyte-macrophage colony-stimulating factors (GM-CSF) promote T cell homeostasis and support dendritic cell differentiation
cytokines in clinical application
used for lymphocyte promotion in various cancers
adoptive T cell transfer
isolate patient own T cells and in vitro engineer T cells
chimeric antigen receptor T cells: genetically engineered T cells specific for antigen on tumor cells
CD29 CAR-T cells first approved for B cell lymphoma treatment
adoptive T cell transfer challenges
cytokine storm/cytokine-release syndrome
tumor lysis syndrome
persistent normal B-cell aplasia
adoptive t cell transfer
binds the antigen
creates gene against protein marker
modifies genes
creates T cell copies with modified gene
attacks tumor cells
activated t cells from patient
t cell isolated form tumor
viral vector encoding tumor specific TCR
human t-cell engineered to express TCR
expand population in culture
genetically engineered activated t cell
clone chimeric receptor into retroviral vector
create human t-cell expressing chimeric antigen receptor
clone human MHC class 1 or 2 genes activated t-cells
immunize mouse with human antigens
isolate mouse human T cell
clone mouse TCR into retroviral vector
human T cell expressing mouse TCR
CART cells
MHC independent
100x more antigens required on target
t cell transduced with tumor specific CAR
CAR: single fusion molecule with antigen specificity plus signaling domain
TCRT cells
MHC dependent
1 antigen required on target
Three types of CAR
based on costimulatory signals
advantages of CAR-T cells
live drug
tumor recognition independent of antigen presentation
multiple selection on antigen
design flexibility
liquid tumors
leukemia, lymphoma
–mutation in hematopoietic progenitor cells
–B cells, T cells and myeloid cells
–chronic or acute leukemia
–recurrence due to residue cells in bone marrow
CD19 CAR-T cells
CD19 is a cell surface protein whose expression is restricted to B cells and B cell precursors
It is not expressed on HSC
It is expressed by most B cell malignancies
CAR-T cells for solid tumor treatment
produce immune suppressing agents such as checkpoint PD-L1
Difficult for CAR-T cells to infiltrate
barriers in solid tumor
physical barrier
metabolic restriction
immunosuppressive microenvironment
immunosuppressive pathways
physical barrier in solid tumor
extracellular matrix
abnormal tumor vasculature
abnormal tumor vasculature
leaky, hypoxic, high interstitial fluid pressure prevents medication from reaching
abnormal tumor vasculature
leaky, hypoxic, high interstitial fluid pressure prevents medication from reaching
Immunosuppressive cells in solid tumor
MDSC, Th17, Treg, TAM
MDSC
suppresses NK and T cells
–deplete essential metabolites
–produce ROS and RNS
–inhibition by direct contact
–inhibition by release soluble factors
Treg cells
suppress T cells by
–inhibitory cytokines
–cytolysis
–metabolic disruption
–targeting dendritic cells
TAMs
immunosuppressive, pro tumorigenic
Immunosuppressive cell depletion
danger signals
tumor-derived antigens
chemotherapeutics
adjuvants
photothermal therapy
photodynamic therapy
radiotherapy
ultrasound
