L1: Clinical Considerations for immunotherapy (M. Butler) Flashcards
tree requirements for spontaneous therapeutic immune response
immunization
T-cell response
overcome immune suppression
CTLA-4 blockade
ipilimumab
increased T cell activation during priming
increased T cell diversity
inhibition of Treg suppression
lower response rate
PD-1 / PD-L1 Blockade
pembrolizumab, nivolumab
reduction of T cell exhaustion/anergy
blockade of direct tumor-mediated T cell inhibition
pseudo-progression
immune response criteria for clinical trials has nothing to do with the immune response
Pseudo-progression occurs when there is an initial apparent increase in tumor size or progression of disease on radiographic imaging, despite the patient clinically benefiting from the treatment.
immunotherapy
not treating cancer directly
treating the immune system - why there might be a delay in the response (pseudo-progression)
RECIST
Response evaluation criteria in solid tumors
goal: to establish the amount of shrinkage that could not be ascribed to operator error and that would not be found if a placebo was administered
goal was not to decide what would be clinically meaningful but rather what could be measured reliably
immune therapy that is reliant on radiological assessments
iRECIST
newer criteria
immune related adverse event (irAE) mechanisms from immune checkpoint inhibitors for PD-1
more cytotoxicity
hypothyroidism, pneumonitis, myocarditis, arthralgia, autoimmune diabetes
immune related adverse event (irAE) mechanisms from immune checkpoint inhibitors for CTLA-4
hypophysitis, rashes, colitis, enteritis
time course of appearance of irAE in ipilimubab (CTLA-4)
rash and diarrhea ters u earlier
hypophysitis r şeklinde, continues
liver toxicity lower peak ters u later on
colitis
ulcerative and immune checkpoint appear same on endoscopy
ulcerative: increase in IL17+ CD8 T cells
checkpoint colitis: increased expression of IFNgamma T cells
CTLA4 Colitis
colon
between 2nd and 3rd dose
diarrhea
PDL1 colitis
small intestine/upper GI tract
less predicatble
management of irAE
rule out other cause
steroid are first line
anti-TNFalpha
Immune checkpoint inhibitor diabetes
rapid loss of islet function, high glucose, ketoacidosis
40% have autoantibodies
impact of steroid management on survival
use of steroids impact varies between patients
can help address skin adverse events
2 Cell therapies for adoptive T cell therapy
TILs and T cell
TILs (tumor infiltrating lymphocytes)
tumor harvested and T cells are expanded by addition of cytokines
T cell therapy
take blood, selectively expand cells related to tumor
TCR/CAR
CAR T cells are a type of immune cell that has been engineered to recognize and kill cancer cells in a targeted manner
Adoptive cell therapy with gene-engineered T cells
isolate lymphocytes from patient’s blood
antitumor TCR/CAR genes
transduction of peripheral T cells
Redirect the T cells toward tomor cells
expand the genetically engineered T cells
infuse back into patient
gp100
differentiation TAA (tumor assocaited antigen) melanoma
targeted by Tebentafusp
toxicities of CAR therapy
cytokine release syndrome
immune effector cell-associated neurotoxicity syndrome (ICANS) - can be dangerous for brain - seizures
lymphodeptetion
TCR toxicity
Cytokine release syndrome symptoms
inflammatory signs and symptoms associated with exponential T cell proliferation:
fevers, cardiovascular disorder, respirartory disorder, neurological issues (confusion, less consciousness), other organ toxicities
some toxicities can lead to death
what is the grading system for CRS
ASTCT
What is involved in CRS
IL-6, IL-1
monocyte/macrophage lineage and downstream expression of inflammatory cytokines like
IL-6 can result in fever and cardiovascular toxicities
anti-IL-6 receptor antibody can help (Tocilizumab)
