Cell-Based Therapuetics 1 Flashcards by Brooke Thornburg

Biotherapuetics

-living drugs
-larger
-molecular specificities against the target
-activity driven by structure and interaction w cells

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Where do biotherapeutics go?

-DNA therapeutics go to nucleus
-protein therapeutics on membrane
-RNA therapuetics in cytoplasm
-cell-based outside of cell

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Cell-based therapies

-gene therapy when it deilivers or is engineered w a gene
-non-modified cell therapy
-stem cell therapy
-cell-based vax

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Gene therapy

-virus-delivered genes
-gene-edited cells

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Cell therapies can contain

-genes and antibodies
-can start as a gene and grow into antibody
-ex vivo

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Classes of cell-based therapies

-stem-cells and stem cell-derived
-immunotherapies

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stem cells

-cell therapy
-does NOT involve immune cells

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Immunotherapies

-involve immune cells
-cancer vax and cell-based immune therapies
-include native and cell-based gene therapies
-CAR-T and TILs and cancer vax

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Gene therapy

-in vivo or ex vivo engineering
-treat gene defect

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Ex vivo

-gene-therapy that is cell therapy

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Casgevy

-ex vivo CRISPR/Cas9- cell therapy
-NEW! 2023 for sickle cell
-extract stem cells
-infuse CD34 cells w normal gene for hemoglobin
-put stem cells back in patient

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FDA approved cell products

-stem cell (CD34 HSCs)
-TIL
-CAR-T (gene-based)
-CRISPR-edited CD34 HSC (gene-based)
-cancer vax

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Stem cells

-totipotent (whole organism)
-pluripotent (all tissues)
-multipotent (specific cells)

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Which type of stem cells are FDA approved

-multipotent
-fetal tissue, cord blood, adult stem cells

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Sources of stem cells

-bone marrow H and M
-liposuction M
-cord blood H
-specific tissue M

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use of stem cells in cell therapy

-replacement cell therapy (alzheimers, parkinson’s, diabetes, arthritis)
-adult stem cells less versatile than embryonic stem cells
-only 22 embryonic cells lines are eligible for federal funding
-NO FDA approved tissue-regenerative stem cells yet
-FDA has only approved stem cell therapy for cord blood transplantation

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Types of cell therapies that are immunotherapies

-adoptive cell transfer (CAR-T, TILs, NK cells)
-cancer vax (dendritic cells)

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Modification of immune cells

-DC can be vax or TILs
-NK for CAR-NK

Tumor infiltrating lymphocytes (TIL)

-tumor infiltrating lymphocytes
-cells associated w tumor
-tx melanoma

CAR-T or CAR-NK (chimeric antigen receptor)

-synthetic genetic construct targeting a tumor antigen
-CAR-macrophages underdevelopment
-tx blood disorders, cancer, sickle cell disease

When can FDA regulate stem cell therapies

-when more than minimal manipulation and/or it has a systemic effect
-exempt if minimal manipulation and homologous use (taking cells in and out of pt in same procedure w/o altering them)

Hematopoietic stem cell transplantation

-from bone marrow, cord, blood
-FDA regulated unless it meets exemptions

Cell therapy for HIV

-CAR-T
-gene-edited stem cells

cell therapy for covid

-cells can target SARS-COVID

How can immune cells kill cancer cells?

-antibodies or engineered cells recognize tumor antigen

NK cells

-attack pathogen by engineering receptors that can recognize antigens of certain cancers -release cytotoxic stuff that kills target cell

Immune response

-innnate (NK) -adaptive (T and B)

Who is cell-based immunotherapy for?

-pt w advanced cancers (stage 4) -pt who have not responded to primary tx -pt whose cancers returned and spread after initial tx

Autologous vs allogeneic

-autologous: cells from own body -allogeneic: cells from donor

Cells sourced from peripheral blood

-autologous -pt-specific -10% NK/T cells

Cells sourced from cord blood

-allogeneic -can be cryopreserved -30% NK/T cells

Cells sourced from cell lines

-commercially available -allogeneic -not like human cells

Cells sourced from induce pluripotent stem cells

-allogeneic thru gene editing -cryopreserved -off-the-shelf

Donor matching

-sibling best -matched unrelated worst -haploidentical family

Chimeric antigen receptors (CARs)

-engineered receptor expressed on surface of immune cell (like antibody) that recognizes target -can target tumor specific or tumor associated antigens

CAR signaling

-activation = signal to kill target -co-stimulatory domain patheays 4-1BB, CD28, CD8

principles of CAR-T

-cells removed, modified, expanded, put back in pt -pt preconditioned w chemotherapy to restrain immune response

Anatomy of cell-based therapy

-drug product: immune cell + gene) -drug substance (engineered molecular component)

CAR structure

-scFv recognizes tumor antigen -hinge to anchor scFv -sends signal down thru membrane to sotimulatory domain

TIL therapy

-Lifileucel -approved 2024 -for melanoma

TIL principles

-isolate cells from excised tumor -T cells w multiple TCR clonse -memory T cells -T cells that express chemolines -low toxicity! -tumor accessibility could be problem -ability to recover limited number of functional TILs

steps of TIL therapy

1. take cells from tumor 2. isolate TILs 3. expansion 4. back into pt

steps of CAR-T therapy

1. T cell from blood 2. genetic mod w TCR or CAR 3. expansion 4. back to pt

CAR vs TCR

-same thing just using TCR instead of CAR