Cell-Based Therapuetics 3 Flashcards
Immunotherapies
-TIL
-CAR-T (also gene)
-cancer vax
Gene-based therapies
-CAR-T (also immuno)
-CRISPR
1 cancer vax for
skin cancer
stem cell therapy approved for
-HSC transplant from cord blood
cell-based therapy approved for
-blood disorders (cancers and sickle cell)
-CAR-T and CRISPR
TIL therapy approved for
melanoma
FDA-approved CAR-T therapies
-Kymriah CD19
-YeSCARTA CD19
-teCARTus CD19
-aBeCMA BCMA
-breyanzi CD19
-Carvykti BCMA
-ex vivo
most common target of CAR-T
-CD19
-then BCMA
co-stimulatory domains of antibodies made by CAR-T
-send killing signals
-CD28 and 4-1BB
BCMA more often a target in
-multiple myeloma cells (plasma cancer)
Cell therapy important points
-effector cells are infused into pt +/- modification
-native (unmodified TIL, HCS) vs cell-based gene therapies (CAR-T/NK, TCR T therapies)
-expanded w cytokine to activate cells (IL-2)
-donor matching and pretreatment of pt needed in all cases
-donor selection must meet cell activation requirements and saftety
Most FDA therapies are
-hematopoetic progenitor transplant for blood disorders
-CER-T is 2nd largest
Cell therapies that are not for blood disorders
-TIL for melanoma
-Provenge prostate cancer vax
All CAR-Ts are for
-blood cancers
-most target CD19
all cell based therapies are done
EX vivo
Adoptive cell therapy: Donor matching
-haploidentical
-HLA-matched
-mathcing is based on HLA
Haploidentical donor
-half-matched
-family member
-always parents
-50% chance of siblings
HLA-matched
-fully matched
-25% chance siblings
Matching is based on
HLA
FDA cell therapies are autologous
-same donor
-same receipient
Before cell therapy infusion
-lymphodepletion
lymphodepletion
-chemo to remove T cells from pt
-7 days
-typically done w combo cyclophosphamide, fludarabine, busulfan
TIL and CAR-T Lymphodepleting regimen
-cyclophosphamide + fludarabine
-sometimes w IL-2 or irradiation for TIL
Adoptive stem cell transfer lymphodepleting regimen
-clofarabine + busulfan
-Fludarabine + Busulfan
Fludarabine
-lymphodepleting agent
-inhibits DNA polymerase
-Fara-ATP metabolite that accumulates in immune cells making them sensitive to lymphodepletion
-25-40mg/m2
Autologous vs allogenic cell therapy manufacture
-autologous does not require pt selection
Cell modification
-Lenti/Retro viral vector
-frozen from 3rd party
-RNA/DNA electroporation
-nanocarriers
CAR-T cell engineering
-lentri/retroviral vectors
-gene delivery tools to engineer T cells
Viral vector manufacturing
-separately using a producer cell line (HEK293)
-formulated and frozen
-shipped to CAR manufacturing
Manufacturing challenges
-sterilization not possible
-aseptic key
-pt need product quickly
-cell viability is not always met
-donor cells fail to expand
-freeze/thaw logistics
Provenge manufacturing lore
-first cell immunotherapy approved in 2010
-went bankrupt 2014 bc shit was too $$ to make
Population for cell therapy studies
-likelihood/magnitude of benefit
-sickest first
-lottery
Cell cryopreservation
-process of freezing cell therapy drug product
-req for all cell products that cant be lyophilized easily =. storaage
-few hours to a few days prior to infusion
Modes of freezing (LN2)
-slow cooling (1C/min) MOST COMMON
-vitrification (-15,000C/min)
-DMSO cryoprotectant (5-7%)
most common mode of cryopreservation
-slow cooling
Cryoinjury of cells
-too slow: solution effect (over-dehydration)
-too fast: intracellular ice crystals
Removal of DMSO
Which type of cell-therapy has had the most FDA approvals so far?
-hematopoeietic (progenitor) cell transplantation
Cancer vax overview
-cell-based
-viral cell-based
-peptide-based
-nucleic acid-based
Cancer vax mech
-NOT gene therapy
-CD54 cells engineered outside
-stimulate T cells OUTSIDE the body w cytokines then put them back in
Prostate cancer vax
-PREVENTATIVE cancer vax
-dont kill directly, stimulate body to kill
Considerations of cancer vax
-longer to manufacture
