Cell-Based Therapuetics 3

Question 1

Immunotherapies

Answer 1

-TIL
-CAR-T (also gene)
-cancer vax

Question 2

Gene-based therapies

Answer 2

-CAR-T (also immuno)
-CRISPR

Question 3

1 cancer vax for

Answer 3

skin cancer

Question 4

stem cell therapy approved for

Answer 4

-HSC transplant from cord blood

Question 5

cell-based therapy approved for

Answer 5

-blood disorders (cancers and sickle cell)
-CAR-T and CRISPR

Question 6

TIL therapy approved for

Answer 6

melanoma

Question 7

FDA-approved CAR-T therapies

Answer 7

-Kymriah CD19
-YeSCARTA CD19
-teCARTus CD19
-aBeCMA BCMA
-breyanzi CD19
-Carvykti BCMA

-ex vivo

Question 8

most common target of CAR-T

Answer 8

-CD19
-then BCMA

Question 9

co-stimulatory domains of antibodies made by CAR-T

Answer 9

-send killing signals
-CD28 and 4-1BB

Question 10

BCMA more often a target in

Answer 10

-multiple myeloma cells (plasma cancer)

Question 11

Cell therapy important points

Answer 11

-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

Question 12

Most FDA therapies are

Answer 12

-hematopoetic progenitor transplant for blood disorders
-CER-T is 2nd largest

Question 13

Cell therapies that are not for blood disorders

Answer 13

-TIL for melanoma
-Provenge prostate cancer vax

Question 14

All CAR-Ts are for

Answer 14

-blood cancers
-most target CD19

Question 15

all cell based therapies are done

Answer 15

EX vivo

Question 16

Adoptive cell therapy: Donor matching

Answer 16

-haploidentical
-HLA-matched

-mathcing is based on HLA

Question 17

Haploidentical donor

Answer 17

-half-matched
-family member
-always parents
-50% chance of siblings

Question 18

HLA-matched

Answer 18

-fully matched
-25% chance siblings

Question 19

Matching is based on

Answer 19

HLA

Question 20

FDA cell therapies are autologous

Answer 20

-same donor
-same receipient

Question 21

Before cell therapy infusion

Answer 21

-lymphodepletion

Question 22

lymphodepletion

Answer 22

-chemo to remove T cells from pt
-7 days
-typically done w combo cyclophosphamide, fludarabine, busulfan

Question 23

TIL and CAR-T Lymphodepleting regimen

Answer 23

-cyclophosphamide + fludarabine
-sometimes w IL-2 or irradiation for TIL

Question 24

Adoptive stem cell transfer lymphodepleting regimen

Answer 24

-clofarabine + busulfan
-Fludarabine + Busulfan

Question 25

Fludarabine

Answer 25

-lymphodepleting agent
-inhibits DNA polymerase
-Fara-ATP metabolite that accumulates in immune cells making them sensitive to lymphodepletion
-25-40mg/m2

Question 26

Autologous vs allogenic cell therapy manufacture

Answer 26

-autologous does not require pt selection

Question 27

Cell modification

Answer 27

-Lenti/Retro viral vector
-frozen from 3rd party
-RNA/DNA electroporation
-nanocarriers

Question 28

CAR-T cell engineering

Answer 28

-lentri/retroviral vectors
-gene delivery tools to engineer T cells

Question 29

Viral vector manufacturing

Answer 29

-separately using a producer cell line (HEK293)
-formulated and frozen
-shipped to CAR manufacturing

Question 30

Manufacturing challenges

Answer 30

-sterilization not possible
-aseptic key
-pt need product quickly
-cell viability is not always met
-donor cells fail to expand
-freeze/thaw logistics

Question 31

Provenge manufacturing lore

Answer 31

-first cell immunotherapy approved in 2010
-went bankrupt 2014 bc shit was too $$ to make

Question 32

Population for cell therapy studies

Answer 32

-likelihood/magnitude of benefit
-sickest first
-lottery

Question 33

Cell cryopreservation

Answer 33

-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

Question 34

Modes of freezing (LN2)

Answer 34

-slow cooling (1C/min) MOST COMMON
-vitrification (-15,000C/min)
-DMSO cryoprotectant (5-7%)

Question 35

most common mode of cryopreservation

Answer 35

-slow cooling

Question 36

Cryoinjury of cells

Answer 36

-too slow: solution effect (over-dehydration)
-too fast: intracellular ice crystals

Question 37

Removal of DMSO

Question 38

Which type of cell-therapy has had the most FDA approvals so far?

Answer 38

-hematopoeietic (progenitor) cell transplantation

Question 39

Cancer vax overview

Answer 39

-cell-based
-viral cell-based
-peptide-based
-nucleic acid-based

Question 40

Cancer vax mech

Answer 40

-NOT gene therapy
-CD54 cells engineered outside
-stimulate T cells OUTSIDE the body w cytokines then put them back in

Question 41

Prostate cancer vax

Answer 41

-PREVENTATIVE cancer vax
-dont kill directly, stimulate body to kill

Question 42

Considerations of cancer vax

Answer 42

-longer to manufacture