Final Flashcards
When does the FDA regulate a therapy as a drug?
The only two approved cell-based therapies are hematopoietic stem cell transplantation and CAR-T (for blood and immune system).
FDA regulates when there was more than minimal manipulation of the cells (can’t do anything to the cell that you would do in a lab).
In order to not be regulated, all of these must be true: Minimally manipulated, homologous use, no excipients or stabilizers or anything, any systemic effect?
What are the different types of cell-based therapies and what are the differences between them?
Stem cells & stem cell-derived products: Don’t involve immune cells. These cells can be differentiated into any type of cell.
- Utilize the property of stem cells (differentiation).
Immunotherapies: Involves immune cells and activation of the immune system.
- Utilizes already mature cells in the body. We use these cells and infuse them back into the patient.
- Adoptive cell transfers, cancer vaccines, etc.
- Not just T cells, there’s also dendritic cells and NK cells.
Cell-based therapy is just cell therapy when it does not involve the immune system (such as stem cell tissue regeneration). Cell-based therapy is immunotherapy when it utilizes immune cells (such as CAR-T).
What are the basic components of a CAR-T therapy?
- Force immune cells to find the genes and stick to them. There are FDA approved drugs. They are very efficacious.
Chimeric Antigen receptor + T cell (or NK, macrophages, or dendritic cells)
Cells are removed, genetically engineered (inject cells with gene), expanded, and delivered back to the patient.
CARs are engineered molecules that are expressed on the surface of immune cells that can recognize specific proteins on the target cells (TSAs and TSAs) and then deliver an activation signal to the cells.
Includes antigen receptor (cancer cell) and co-stimulatory domains that send activation signal to cause cell death.
What is the difference between autologous and allogeneic cell-based therapy?
Autologous - The patient is their own donor. They can only donate to themselves. This is good for rejection. It’s harder to source because it’s hard to rely on your own amount of cells/immune system.
Allogenic - Anyone can donate to anyone (future of stem cell therapy?). Easier to source. Can induce an immune response/rejection because our bloods don’t always match.
What are some problems that may arise when developing drugs that target a single tumor antigen?
The cancer cell is smart. It may down-regulate that antigen that it knows the drug is targeting, leaving that drug pretty useless. For this reason, we want to make drugs that have multiple antigens as the target.
What are the main safety issues that are associated with cell-based gene therapies?
CAR failure - It just doesn’t work. Ex. can’t harvest enough T cells, CAR T cells don’t expand, limited CAR T cell persistence in vivo
Antigen modulation - Antigen loss or down-modulation. Every cancer pt with brain/breast cancer, the cancer expresses different protein (it escapes the CAR T cell target). This is why we may use two different antigens as targets.
CAR toxicities - Ex. Neurotoxicity
Unmet needs - Doesn’t work that well
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 - They are heterogeneous, they have immunosuppressive factors, the immune cell infiltration is low, and the cells in solid tumors are dysfunctional.
- We try to target cytokine networks, immunosuppresive populations, immune checkpoints, and tumor stroma to get around this. (Anything that supports the tumor).
What is one way to clinically mitigate or manage cytokine release syndrome?
Antibodies against toxins and cytokines - block IL-6 (ex. tocilizumab). ***
Avoid steroids (they may impact CAR-T cells)
Use cells that induce no or limited CRS (NK cells)
Hemofiltrition to filter out cytokines
What is the drug substance and the drug product in cell-based therapy?
Drug substance: engineered molecular component (ex. chimeric antigen receptor or gene)
Drug product: Immune cell + gene (ex. CAR-T/NK cell)
What is ADCC? What are multi-specific engagers?
ADCC - antibody-dependent cell-mediated cytotoxicity. When a pt gets Ab therapy, the Ab will not kill the cancer cell, it’ll just block it. The killing is done by the immune system. The Ab interacts with CD16 on NK cells to stimulate the killing.
Multi-specific engagers - Bridge the gap between the cancer cell and the T cell for killing.
What is an on-target, off-tumor effect?
On-target, off-tumor: Cell recognizes the right protein on the wrong place. Ex. CD19 on B cells. This can result in severe toxicities, because you’re killing off healthy cells.
What are some common problems with targeting tumor antigens with cell-based immunotherapies?
Tumor evasion - The shutting down of proteins on the cancer cell that are trying to be targeted. This results in resistance to treatment.
What are the potential risks of cell-based therapies?
Neurotoxicity - Due to immune cell activity, can be fatal
Cytokine release syndrome (CRS) and GvHD - CRS is a systemic inflammatory response (aka cytokine storm) that results in pro-inflammatory cytokines attacking the pts immune system. GvHD is when the donor tissue recognizes the exogenous cells as foreign, and then starts attacking them.
Toxicity associated with viral genomic DNA - Need to make sure the virus is completely dead.
Cells that persist for an extended period - Could increase or prolong adverse reactions. We try to mitigate this with suicide switches.
Is the viral engineering method of cell based therapy permanent or transient?
Permanent. This is the most common type of cell engineering.
What is lymphodepletion and what drugs are commonly used for it?
Lymphodepletion - Donor matching and pre-treatment of patients. This is needed in all cases. It eliminates immune system so that it has no ability to reject the drug.
Cyclophosphamide & Fludarabine - Take these once a day for 7 days.
