Cell-Based Therapuetics 2 Flashcards
Systemic admin
-easier
-suitable for blood cancers/metastatic disease
-risk off-target toxicities
-higher risk of side effects
-potential loss of specificity
Local admin
-more suitable for many solid cancers
-fewer off-target effect
-many tumors harder to get to
Immune cells are infused w
-Cytokines
Cytokines
-support activation, maturation, and effector functions
-IL-2, 7, 15, 21
IL-2
-first immune therapy approved by FDA
-wake up immune cells
-pretty toxic
-when cell is isolated in lab, add cytokines to t cells then freeze them then add back into body (i think less cytokine then?)
Immune cell drug durations
-long lasting
-will stay in pt for years maybe even lifetime
Lymphoma CD-19 immunotherapy
Clinical responses to CAR-T therapy
-lymphoma (CD19 therapy)
-leukemia (CD19 therapy)
anti-CD19 CAR-T therapies
-usually first line
-b-cells also express CD19 tho so all b cells get killed
-loss of b-cells = successful marker of therapy
B-cell aplasia
-CD19 CAR-T side effect (leukemia tx)
-CD19 expressed on B cells
-B cells die
-but this is good it is a sign that it is working
Cell therapies that are not CARs (antibody therapy)
-ADCC
-multi-specific engagers
-antibody therapies via CD16
ADCC
-antibody interacts w CD16 on NK cells
=signal to kill
Multi-specific engagers
-synthetic BiKEs and TriKEs
-killer cell engager
-bridges to bring immune cell and cancer cell closer together
-CD16 or NKp46
Cell therapy responds to
-antibody therapy
NK cell therapy
-NK cells kill cancer without antigen needed
-activate quicker than t cells
-safer
-can expand outside of body
-can engineer like CARs
-ADCC (T cells dont)
-lack of GVHD
-no cytokine release syndrome like T cells
Manufacturing immune cell-based therapies
- Apheresis
- cell activation
- modification
- expansion
- infusion
How can we engineer genes into cells?
-viruses
-mRNA electroporation
-plasmid or nanoparticles
Viruses to get genes into cells
-most common
-dead viruses
-most efficient but most risky
components of cell-based gene therapy
-isolated immune cells
-synthetic (CAR) DNA + viral vector (drug substance)
-cryopreservation media and cytokines if needed
Problems w CAR therapies
-failure (tumor evasion)
-antigen modulation
-toxicities
-unmet needs
Tumor evasion
-prob w cell-based therapies
-cancer cells escaping recognition
=resistance
Tumor antigens are either
-not recognized by immune response (immunologically ignorant)
-resistant to/inhibit immune cytotoxic responses (suppression factors/antigen escape)
Cell therapy indications are limited bc
-immune cells cannot kill tumors well
-heterogenous, immunosuppressive
-low immune cell infiltration
Targets for solid tumor tx
-cytokine networks
-immunosuppressive populatioins
-immune checkpoints
-tumor stroma
Potential risks of cell-based therapies
-neurotoxicity (fatal)
-cytokine release syndrome and GVDH common
-toxicity associated with viral vector of CAR-T therapy
-cells hang out in body for long time
Issues with targeting cancer-associated antigens w cells
-on target, off-tumor effects
=cells target right antigen but one that is also in healthy cells
=toxicities
-fratricide (cells target antigen expressed on themselves = kill each other
Gene-related toxicities associated with
-therapies that use viral vector (CAR)
GVHD
-reaction to transplant
-autoreactive immune cells
-can lead to cytokine release syndrome
Cytokine release syndrome
-systemic inflammatory response
-“cytokine storm”
-release of high number of cytokines that attack pt immune system
-etanercept and tocilizumab to block IL-6
deadliest cytokine
IL-6
CRS symptoms
-fever
severity of CRS
-approx 75% of pt on T cell therapy (CAR-T)
-life threatening in 27-44%
-inc risk w high dose, bad diease, concurrtent infection
Treating CRS
-antibodies against IL-6 (tocilizumab)
-avoid steroids
-use NK cells instead
-hemofiltration (filter out cytokines)
inhibitory/decoys CARs
-suicide gene that can be shut off to prevent CRS
What are some problems that could arise when developing drugs that target a single tumor antigen?
What are the main safety issues associated with cell-based gene therapies?
2 reasons why cell-based therapies are more successful for blood cancers but not solid tumors
One way to clinically mitigate/manage CRS
