Final Exam: New Material Flashcards
(35 cards)
When does the FDA regulate a therapy as a drug?
cell-based therapies must meet all 4 criteria below to be unregulated:
1. minimally manipulated
2. homologous use
3. HCT/P combined with device or drug that is sterilizing, preserving, or storage agent
4. the HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function
What are the different types of cell-based therapies? What is TIL, TCR, and CAR-T?
stem cell therapies
TIL
TCR T cells
CAR-T
CRISPR-edited CD34 HSC
cancer vaccines
non-gene based: stem cell therapies, TIL, cancer vaccines
gene-based: TCR T cells, CAR-T, CRISPR
immunotherapies: TIL, TCR T cells, CAR-T, cancer vaccines
TIL: tumor infiltrating lymphocyte therapy, lymphocytes from a patient’s tumor that are extracted, amplified, and reintroduced to the patient to fight the cancer
TCR: T cell receptors, engineered cells based on cell-specific intracellular receptors
CAR-T: chimeric antigen receptor T cells, synthetic genetic construct targeting a tumor antigen
What are the main components of CAR? What does the extracellular domain represent?
- CARs are engineered proteins expressed on the surface of immune cells that can recognize specific proteins on target cells and deliver an activation signal to the cells
- extracellular domain: antibody binding (binds to antigen on cancer cell)
- intracellular/co-stimulatory domains: send cytotoxic/killing/activation signals
Which immune cell therapies are gene edited?
TCR T cells, and CAR-T are gene-based immunotherapies
What are the basic components of a CAR-T therapy?
- CAR-T therapy is a cell therapy where T cells are engineered to express a CAR molecule (protein) on their surface by delivering the gene (DNA) for that protein
- cells are removed, genetically engineered, expanded, and delivered back to the patient
- patients are pre-conditioned with chemotherapy to restrain immune response
What is the difference between autologous and allogeneic cell-based therapy?
Autologous:
- cells from your own body
- no GvHD, higher doses feasible
- harder to source, immune-compromised
Allogeneic:
- cells from a different donor
- easier to source, “off the shelf”
- can induce GvHD/immune response
What are two problems that could arise when developing immunotherapies that target a single tumor antigen?
- Tumor antigens are not recognized by immune response
- poorly immunogenic
- immunologically ignorant - Tumors are resistant to or inhibit immune cytotoxic responses
- active suppression: either dampen “priming” or avoid/inhibit/resist effector cell function by producing immunosuppressive factors
- ex: antigen escape
What are the main safety issues associated with cell-based gene therapies?
- neurotoxicity due to immune cell activity (can be fatal)
- cytokine release syndrome (CRS) and graft-versus-host disease (GvHD)
- toxicity associated with viral genomic DNA if viral CARs are used (RCR, replication competent retrovirus is a drug product release specification)
- cells might persist for an extended period or produce sustained effect (could increase or prolong adverse reactions, mitigate these through engineering of suicide switches)
What is CRS? What is GvHD?
CRS:
- cytokine release syndrome
- systemic inflammatory response (also called cytokine storm)
- results in the release of a high number of pro-inflammatory cytokines that attack the patient’s immune system
GvHD:
- graft-versus-host disease
- arises when patients infused with exogenous cells or transplanted with donor tissue recognize these transplants as foreign and react unfavorably
- a result of auto-reactive (self-attacking) immune cells
What are two inhibitory receptors expressed on T and tumor cells?
tumor: PD-L1, B7-H3, GD2
T cells: TIGIT, LAG-3, TIM-3
What is a common target antigen for CAR therapy for leukemia?
CD19
What are two reasons why cell-based therapies have been more successful (and approved by the FDA) for blood cancers, but not solid tumors?
Solid tumors are challenging because:
- immune cells cannot penetrate and kill large masses of tumors well
- solid tumors are highly immunosuppressive
- solid tumors are heterogeneous and immune cells are dysfunctional
What is one way to clinically mitigate or manage risks of cell-based therapies, including CRS?
Treating CRS:
- antibodies against toxins and cytokines (IL-6)
- avoid steroids, as they may impact CAR-T cells
- use cells that induce no or limited CRS (NK cells)
- hemofiltration (experimental, “filtering out” cytokines)
Controlling CRS:
- inhibitory CARs (CAR cells engineered to be inhibited when recognizing certain antigen pairs to control activation)
- decoy CARs (CAR cells engineered to be inhibited when bound to decoy peptides
What is an on-target, off-tumor effect?
- cells target the correct antigen, but one expressed on tissues other than the target cancer
- many cancer antigens are also expressed on healthy tissues, albeit and smaller
- can result in severe toxicities
What do Kymriah and Yescarta target? What is the most common antigen for CAR-T?
- both target CD19 expressed on blood cancer cells, the most common antigen for CAR-T
What is a cytokine and what is its main role in cell therapy?
cytokines are proteins which support activation, maturation, and effector functions of immune cells
What is the role of lymphodepletion in cell-based therapy?
Lymphodepletion is a medical process involving the elimination/destruction of lymphocytes and T cells, typically through chemotherapy, to prepare the body for immunotherapy
- chemotherapy to prime patient for cell transfer
Which common agent is commonly used for lymphodepletion in CAR-T therapy?
Fludarabine
- inhibits DNA polymerase, thus inhibiting DNA synthesis
- immune cells accumulate F-ara-ATP, the active metabolite or fludarabine, making them particularly sensitive to lymphodepletion
How are CAR-T cells manufactured? What is commonly used to engineer genes into T cells?
- CAR-T therapy uses lentiviral or retroviral vectors as gene delivery tools- used to genetically engineer T cells
- viral vectors are manufactured separately using a producer cell line
- vectors are formulated and frozen, and shipped to the site of cell therapy product manufacturing
What agent is commonly used for cryopreservation?
DMSO is an agent most commonly used as a cryoprotectant
- minimizes damage
What is immunotherapy and how can immune cells be redirected to attack pathogens?
- immunotherapy is treatment that utilizes a person’s own immune system to fight diseases such as cancer
- adoptive transfer of cells, locally or systemically –> can be engineered or non-engineered, often done with cytokines to enhance cell persistence
- killing occurs by either native killing or by direct targeting of single (or multiple) tumor antigens
What are advantages and disadvantages to nasal drug delivery?
Advantages:
- avoidance of hepatic first-pass elimination and destruction in the GI tract
- rapid absorption of drug molecules across the nasal membrane
- relatively easy and convenient
Disadvantages:
- possible tissue irritation
- rapid removal of the drug from the site of absorption (mucociliary clearance)
- pathologic conditions such as cold or allergies that may alter significantly the nasal bioavailability
- limited area of drug absorption
Identify nasal sections important for systemic drug absorption and potential drug delivery to the CNS.
Respiratory region:
- main site for systemic drug delivery
- relatively large surface area
- epithelium covered with mucus that provides humidification and warming of inhaled air, physical and enzymatic protection against foreign compounds
Olfactory region:
- small surface area
- provides a direct connection between the CNS and the atmosphere
- contains small glands that produce secretions acting as a solvent for odorous substances
What are some features of buccal dosage forms?
- relatively less permeable than sublingual
- slower absorption and onset of action than sublingual
- less influenced by saliva
- suitable for sustained delivery applications
- buccal tablets, patches, semisolids
