Cell-Based Therapeutics Flashcards
regulated therapies
cultured cells
sorted cells
cells in 3D scaffolds
engineered cells
non-regulated therapy example
injecting bone cells into bone
criteria to be unregulated
all answers must be YES
1) minimally manipulated
2) homologous use
3) HCT/P combined with device or drug that is sterilizing, preserving, or storage agent?
4) the HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function
types of cell-based therapies
stem cell products
immunotherapies
stem cells and stem cell derived products
do not involve immune cells
stem cell therapy is unspecialized, self-renewal, and pluripotency
example –> stem cell transplantation
immunotherapies
involves immune cells
example –> cancer vaccine and cell-based immune therapies (can be naive or gene based); CAR-T
components of a CAR-T terapy
CAR –> chimeric antigen receptor (gene)
T –> T cells
cells are removed, genetically engineered, expanded and delivered back to the patient (who are pre-conditioned with chemotherapy to restrain immune response)
autologous cell-based therapy
cells from your own body
no graft vs host disease
higher doses feasible
harder to source, immune-compromised
allogenic cell-based therapy
cells from a different donor
easier to source, off the shelf
can induce graft vs host disease and/or immune response
What are some problems you might think could arise when developing drugs that target a single tumor antigen?
on target, off tumor effects (cells target the correct antigen but one expressed on tissues other than the target cancer, results in severe toxicities)
fratricide (cells target an antigen that is expressed on themselves)
What are the main safety issues associated with cell-based gene therapies?
tumor evasion
neurotoxicity due to immune cell activity (potentially fatal)
cytokine release syndrome (CRS)
graft vs host disease
toxicity assocaited with viral genomic DNA (if viral CARs are used)
persist for an extended period and produce a sustained effect –> increases/prolongs ADRs
tumor evasion
escape of cancer cells from recognition and killing by immune cells resulting in clinical resistance to treatment
tumor antigens are not recognized by immune response –> poorly immunogenic
tumors are resistant to or inhibit immune cytotoxic responses
how to prevent cell persisting /sustained effect
engineering of suicide switches
What are two reasons why cell-based therapies have been more successful (and approved by the FDA) for blood cancers, but not solid tumors?
solid tumors –> heterogeneous and have immunosuppressive factors (metabolites, soluble molecules)
immune cells –> infiltration is low, in solid tumors they are dysfunctional
What is one way to clinically mitigate or manage cytokine release syndrome?
avoid steroids (could impact CAR-T cells)
antibodies against toxin and cytokines (IL6)
use cells that induce no or limited CRS (NK cell)
through hemofiltration (to filter out cytokine)
drug substance
gene vector (engineered molecular component)
example –> CAR or gene
drug product
cryopreserved engineered cell (immune cell and gene)
example –> CAR-T/NK cells
ADCC
antibody dependent cell-mediated cytotoxicity
when an antibody interacts with CD16 on NK cells to stimulate activation to kill
potential risk of cell-based therapies
graft vs host disease disease
cytokine release syndrome
graft vs host disease
arise when patients infused with exogenous cells or transplanted with donor tissue recognize these transplants as foreign and react unfavorably
cytokine release syndrome
systemic inflammatory response
results in the release of a high number of pro-inflammatory cytokines that attack the patient’s immune system
lymphodepletion
chemotherapy to prime patient for cell transfer by weakening the immune system to avoid rejection
the process of removing immunosuppressive subsets of immune cells (like Tregs) from the patient
common agent used in lymphodepletion
fludarabine
fludarabine
inhibits DNA polymerase (thus synthesis)
immune cells accumulate F-ara-ATP (the active metabolite) –> makes them sensitivite to lymphodepletion
dosed as > 25-40 mg/m^2
ADME of cell therapy in comparison to small molecule drugs
cells are not secreted but remain in the system
long term –> divide inside recipient
challenges with CAR-T manufacturing
sterilization of final product not possible (aseptic processing key)
patients are very sick (so they need product quickly)
cell variability requirements cannot always be met
donor cells cannot always expand optimally, cells are exhausted
complex logistics –> freeze/thaw necessary mulitiple times
centralized cell therapy manufacturing
PROS –> easier to scale up, central process control and batch records, lower material cost
CONS –> complex logistics, longer time to patient, product must be frozen
decentralized cell therapy manufacturing
PROS –> quicker, closer to consumer; process is ready for infusion and dose not need to be shipped
CONS –> cannot be scaled up; costly
cryopreservation
example agent –> DMSO (most commonly used)
process of freezing of the cell therapy drug product
required as cell therapy products cannot be lyophilized easily
enables shipment and storage of the drug product prior to administration
Tocilizumab (IL6)
drug commonly use to mitigate cytokine release syndrome
extracellular region of CAR
antigen binding domain that binds to cancer cell
naive cell therapies
unmodified immune cells (TILs, hematopoietic stem cell transplants)
just give cell to patient, no engineering
How can immune cells be redirected to attack pathogens?
through engineering synthetic receptors that can recognize antigens present on specific cancers
releasing proteins (cytotoxic granules) that kill target cells
types and sources of cell-based therapies
peripheral blood
core blood
cell lines
induced pluripotent stem cells
peripheral blood characteristics
autologous transfer
patient-specific
10% NK/T cells
core blood characteristics
allogenic
can be cryopreserved
30% NK/T cells
cell lines characteristics
commercially available
allogenic
not like human cells
induced pluripotent stem cells characteristics
allogenic through gene editing
can be cryopreserved
off the shelf
types of adoptive cell-based immunotherapies
donor matching
native immune cells (activated)
TIL (tumor infiltrating lymphocytes)
TCR (T-cell receptors)
CAR-T or CAR-NK
donor matching adoptive cell-based immunotherapies
either haploidentical (half matched so mom, dad, child) or HLA-matched (fully matched so siblings, unrelated, or core blood)
native immune cells (activated)
kill cancer without antigen dependent
natively expanded outside of the body
can be engineered with CARs or infused after expansion without engineering
participate in ADCC, T cells do not
generally do not cause CRS (unlike T cells)
no rejection
TIL (tumor infiltrating lymphocytes)
lymphocytes that have infiltrated a tumor and can recognize specific antigens
mostly CD8+ T cells which can produce cytokines and mediate tumor killing
extracted from the tumor and reinfused back into the patient after expansion
how are genes most commonly engineered into cells?
through viruses because they have highest efficiency, are permanent, and potentially toxic
basic structure of CAR-T cell therapies
extracellular antigen binding domain, transmembrane domain, and intracellular/costimulatory domain
role of extracellular antigen binding domain
bind to cancer cell
role of transmembrane domain
anchor and orientation to facilitate interaction with T cell surface proteins
role of intracellular/co-stimulatory domains
send cytotoxic/killing/activation signals
first two FDA-approved CAR-T cells therapies are targeted against blood cancer
Leukemia
Lymphoma
how is CRS commonly treated?
with IL-6 antibody
