L3: ICIs with Other Approaches (K. Khan) Flashcards
PD-1/ PD-L1 pathway
PD-1 on CD8 T cell
PD-L1 on tumor cell
binding results in T cell inhibition (no antitumor response)
how is PD-1 upregulated/ downregulated
signaling cascade regularly upregulated
with PD-L1 binding - downregulated with SHP2 blocking the cascade
PD-1 upregulation leads to
T cell proliferation, activation, effector function, survival
ICI of PD-1 / PD-L1 pathway
either anti-PD1 or anti-PDL1 antibody to block the interaction
why are combinations with ICIs needed?
increase portions of patients that respond
improve responses in those that do respond - i.e. complete responses
open up ICIs for other more difficult to treat cancer types such as pancreatic cancer
additive combination
just sum of effect
synergistic combination
A futher enhances B
dual synergistic combination
both enhance each other
are all synergistic effects good
no, can also lead to harmful toxicities
what combinations are being used in the clinic
regular FDA approvals with PD-1 or PD-L1 antibody (most chemo) or CTLA-4 antibody
what is VEGF
vascular endothelial growth factor-A
secreted by tumor
VEGF stimulates angiogenesis and vessel movement to tumor
tumor increases blood supply –> tumor can enter vasculature and lead to metastasis
tumor angiogenesis
formation of new blood vessels
(cell survival and proliferation of tumors through VEGF can lead to angiogenesis)
anti-VEGF therapeutics
1- specific inhibition of VEGF with antibodies: Bevacizumab
2- less specific inhibition with tyrosine kinase inhibitors (TKIs) - less specific, may also inhibit others, can increase toxicity
why does VEGF therapies fail
patients can gain resistance
also patients can be intrinsically resistant to angiogenesis inhibition (non-angiogenic tumors - acquire supply by vessel co-option)
what can be done if patient develops resistance?
other angiogenic growth factors can be used: FGF2, HGF
3 main ways angiogenic growth factors or anti-angiogenic molecules have effects on immune system
1 - direct immunosuppressive effects
2- indirect immunosuppressive effects
3 - indirect physical effects
Direct immunosuppressive effects on immune cells of VEGF
increased tumor proliferation and homing
less DC maturation
CD8 T cell: increased IC molecules (exhaustion), less proliferation and function, upregulated TIM-3, PD-1, LAG3
Macrophage: increased PD-L1 expression
Monocyte: increased IL-10 secretion and tumor homing
Indirect immunosuppressive effects on immune cells of VEGF
immunosuppressive properties of tumor endothelium
ICAM1 adhesion molecule reduction = less effector immune cell infiltration
PD-L1 expression by tumor vessels = exhausted T cells
Stabilin 1 = selective recruitment of Tregs
Tumor vessel expression of FasL = CD8 apoptosis
Indirect physical effects on immune cells of VEGF
colorectal carcinoma: leaky, areas of low or no flow, blind ends
this leads to hypoxia and less immune cell infiltration
the impact of VEGF inhibition on various steps in the cancer immunity cycle
during cancer antigen presentation or priming/activation of T cells: helps relieve inhibition of DC maturation and function
also later: vessel normalization and relieving T cell exhaustion
PFS
Progression free survival
duration of time a patient lives with disease but doesn’t get worse
OS
Overall survival
duration of time patient is alive for
Kaplan Meier plots each downward step
death
Hazard Ratio: 1
drug and control same effect
Hazard Ratio: 0.5
favors drug/experimental over control
Hazard Ratio: 2
favors control
MSI-Hi (microsatellite instability) vs MSI-Lo (misrosatelite stable: MSS)
MSI-Hi: mismatch repair deficient, increased mutations, increased chance that CD8 recognizes, leading to cytotoxicity, more neoantigens
MSI-Lo: mismatch repair proficient, tumor cells can repair damage, less reponsive to PD-1 therapy
therefore, anti-PD-1 approved by FDA for MSI-Hi tumors
biosimilar
exact same sequence but different company, has the same function
neoadjuvant therapy
given before surgery to shrink tumor
HCC neoadjuvant VEGFR inhibitor + PD-1 antibody
expansion of T cells, B cells
memory cells in circulation?
Biological rationale for combining ICI’s with anti-angiogenic drugs
VEGF is immunosuppressive
Relieve immunosuppressive vessel barrier
Vascular normalization and increase T-cell infiltration
chemotherapy 4 “poisons”
1- alkylating agents and platinum based
2- anti-microtubule agents (inhibit cell division)
3- anti-metabolites
4- topoisomerase inhibitors
ICD (Immunogenic cell death)
find me signals (dying cells empty cellular content)
eat me signals (pre-apoptotic cell expresses calreticulin)
antibody drug conjugates
a targeted way of delivering effectively a chemotherapy drug
3 main components:
the antibody, linker, payload (drug)
