Cell-Based Therapuetics 3 Flashcards by Brooke Thornburg

Immunotherapies

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

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Gene-based therapies

-CAR-T (also immuno)
-CRISPR

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1 cancer vax for

skin cancer

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stem cell therapy approved for

-HSC transplant from cord blood

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cell-based therapy approved for

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

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TIL therapy approved for

melanoma

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FDA-approved CAR-T therapies

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

-ex vivo

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most common target of CAR-T

-CD19
-then BCMA

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co-stimulatory domains of antibodies made by CAR-T

-send killing signals
-CD28 and 4-1BB

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BCMA more often a target in

-multiple myeloma cells (plasma cancer)

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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

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Most FDA therapies are

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

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Cell therapies that are not for blood disorders

-TIL for melanoma
-Provenge prostate cancer vax

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All CAR-Ts are for

-blood cancers
-most target CD19

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all cell based therapies are done

EX vivo

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Adoptive cell therapy: Donor matching

-haploidentical
-HLA-matched

-mathcing is based on HLA

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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

-washed off prior to infusion bc toxic -

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