Cell-Based Therapuetics 1 Flashcards
Biotherapuetics
-living drugs
-larger
-molecular specificities against the target
-activity driven by structure and interaction w cells
Where do biotherapeutics go?
-DNA therapeutics go to nucleus
-protein therapeutics on membrane
-RNA therapuetics in cytoplasm
-cell-based outside of cell
Cell-based therapies
-gene therapy when it deilivers or is engineered w a gene
-non-modified cell therapy
-stem cell therapy
-cell-based vax
Gene therapy
-virus-delivered genes
-gene-edited cells
Cell therapies can contain
-genes and antibodies
-can start as a gene and grow into antibody
-ex vivo
Classes of cell-based therapies
-stem-cells and stem cell-derived
-immunotherapies
stem cells
-cell therapy
-does NOT involve immune cells
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
Gene therapy
-in vivo or ex vivo engineering
-treat gene defect
Ex vivo
-gene-therapy that is cell therapy
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
FDA approved cell products
-stem cell (CD34 HSCs)
-TIL
-CAR-T (gene-based)
-CRISPR-edited CD34 HSC (gene-based)
-cancer vax
Stem cells
-totipotent (whole organism)
-pluripotent (all tissues)
-multipotent (specific cells)
Which type of stem cells are FDA approved
-multipotent
-fetal tissue, cord blood, adult stem cells
Sources of stem cells
-bone marrow H and M
-liposuction M
-cord blood H
-specific tissue M
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
Types of cell therapies that are immunotherapies
-adoptive cell transfer (CAR-T, TILs, NK cells)
-cancer vax (dendritic cells)
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
- take cells from tumor
- isolate TILs
- expansion
- back into pt
steps of CAR-T therapy
- T cell from blood
- genetic mod w TCR or CAR
- expansion
- back to pt
CAR vs TCR
-same thing just using TCR instead of CAR
