W8 Immunotherapy (SF) Flashcards
The immune system: “quick re-cap”
What is the difference between the Innate and the Adaptive immune response?
Innate:
*first response “non-specific immunity”
*not discriminate different pathogens
*recognises specific patterns of the foreign organisms
*do not have a memory
*act rapidly (within hours)
* produce cytokines(inflammatory process) and recruitment of other immune cells (eliciting the
adaptive response)
Adaptive:
*when the innate system is not sufficient
*generate a specific immunologic response
to eliminate the target micro-organism and/or
the infected cells
*immunologic memory,→reaction to a second
infection faster and more efficient
T cells need to interact with Antigen Presenting Cells (APCs) to get activated.
What are the steps?
- Antigen Presenting Cells: display the antigen
fragments on the surface bound to its MHC2. - MHC-antigen complex binds to the TCR and
activates the T cell - Activated helper T cells release cytokines influencing the immune response, e.g. modulating B cell activity →multiply and mature into plasma cells secreting antibodies specific for the antigen that activated the B cell→ flags the pathogen for
elimination. Some of the activated B cells differentiate into long-lived memory cells
* Other T-cells may become memory cells
* Cytotoxic T cells (Killer T cells), directly destroy
the infected/damaged cells
Immune cell role in cancer?
- Recognise ‘distressed’ cells
- Identify anomalies in cancer cells (tumor antigens)→trigger an immune response, helping to destroy many pre-cancer or cancer cells
However, cancer cells may bypass immune
responses.
Immune checkpoints:
- Maintenance of immune homeostasis: critical for human survival
- Uncontrolled immune responses to pathogens or overexpressed self-antigens can lead to inflammatory damage and autoimmune diseases
- Immune responses: strongly regulated by different stimulatory and inhibitory
signals →distinguish between self cells and pathogens/abnormal/foreign cells (non-self)→ attack and destroy the non-self only
This tight regulation is enabled by several checkpoints, specific molecules (receptors) on immune cells that require activation, or inactivation, to trigger immune response
Immune checkpoints and cancer
What is the role of activation inhibitory/stimulatory receptors?
Activated cytotoxic T cells express multiple
inhibitory and stimulatory receptors on their surface
Activation inhibitory receptors: suppress immune responses
Activation stimulatory receptors: trigger immune response
Modulate the immune responses of T cells to self-
proteins, pathogens, and tumour cells
A hallmark of cancer cells: avoid detection by the immune system→ by expressing on their cell surface molecules that bind to the checkpoint
inhibitory receptors on T-cells→, suppressing the immune responses directed against them→ cancer cells are able to “hide” from the immune system
Promising strategy in cancer immunotherapy: target these immune checkpoints…
Immune checkpoints inhibitors
Various immune checkpoint inhibitors (ICIs) developed to target co-inhibitory
receptors on T cells, or their ligands on tumour cells, to re-engage the immune
system and restore anti-tumour immune responses
Main targets explored so far: CTLA-4 and the PD-1/PD-L1 interaction
Combination therapies (two agents, e.g.,
ipilimumab + nivolumab), also with chemotherapeutic agents (e.g., carboplatin, paclitaxel) are approved
mAbs as immune checkpoints inhibitors
What is the structure of monoclonal antibodies?
- The currently approved ICIs are all monoclonal antibodies, immune system proteins produced in the lab…
- Their structure is made of two heavy chains and two identical light chains:
- Fc domain
- Hypervariable regions
Types mAbs:
Murine (0 % human)
-omab
Chimeric (65 % human)
-ximab
Humanised (>90 % human)
-zumab
Human (100 % human)
-umab
(In order of inc potential for immunogenicity)
mAbs as immune checkpoints inhibitors
IgG half-life: determined by the Fc region→full-
length IgGs have a half-life of ~ 21 days (few
hours instead for Ab fragments)
Long half-life due to FcRn expression on capillary
vasculature protecting IgG from degradation:
FcRn= neonatal Fc receptor:
o neonatal intestinal transporter for IgGs
o placental maternal-foetal transfer
o IgG homeostasis through serum
o IgG half-life regulation
o mucosal immune surveillance
CTLA-4 Cytotoxic T-Lymphocyte-Associated protein 4
TLA-4: transmembrane INHIBITORY glycoprotein receptor upregulated on the surface of active T cells→ activated→ inhibits immune responses→ prevent over-stimulation of the immune system mediated by the T-cell receptor (TCR)
Competes with CD28, a TCR co-stimulatory receptor, to bind ligands CD80 (B7-1) and CD86 (B7-2) on the surface of APCs, preventing T-cell activation with a key role for the peripheral tolerance to self proteins
Binding of B7-1/B7-2 to CTLA-4 keeps T cells in the inactive state - they do not kill tumour cells
APC Blocking the binding of CTLA-4 to B7-
1/B7-2 with an immune checkpoint inhibitor (anti-CTLA-4 antibody) enables T cells to become active
= tumour cells killed
Approved CTLA-4 examples? (2)
Route of administration?
Ipilimumab, an anti-CTLA-4 monoclonal antibody (IgG1), was the first FDA-approved immune checkpoint inhibitor in 2010
Administered by intravenous infusion; approved in the UK as a monotherapy or in combination:
* monotherapy for melanoma
* combination therapy for melanoma, renal cell carcinoma, colorectal cancer, malignant pleural mesothelioma (+ nivolumab- PD-1 inhibitor), non-small cell lung cancer (+ nivolumab AND
Pt-based drug)
Tremelimumab: new anti-CTLA-4 monoclonal antibody (IgG2), recently approved in the US and EU for the combination treatment of hepatocellular carcinoma (+ durvalumab-PD1-inibitor)
PD-1/PD-L1 interaction
PD-1 (Programmed Cell Death Protein 1): surface receptor expressed on activated T cells, B cells and NK cells. It regulates effector T cells by inactivation: by binding to its ligands, PD-L1 and PD-L2 (Programmed Death-Ligand 1&2) →transmits a co-inhibitory signal, preventing activation
PD-L2:only induced on APCs; PD-L1 is expressed on tumour cells, epithelial and immune cells. Cells in several types of cancer overexpress PD-L1 on their surfaces.
Binding of PD-L1 to PD-1keeps T cells inactive = they do not kill tumour cells.
Blocking the binding of PD-1 to PD-L1 with
an immune checkpoint inhibitor (anti-PD-L1
or anti-PD-1) enables T cells to become active
= tumour cells killed.
Approved PD-1 inhibitors? (3)
Route of administration?
Three PD-1-directed monoclonal antibodies are currently approved in the UK, with additional ones in clinical evaluation:
* nivolumab (IgG4): for melanoma, renal cell carcinoma, non-small cell lung cancer, classical Hodgkin lymphoma, gastrointestinal
cancer, + others;
* pembrolizumab (IgG4): for melanoma, non-small cell lung cancer, classical Hodgkin lymphoma, head and neck squamous
cell carcinoma, renal cell carcinoma, colorectal cancer, breast cancer, cervical cancer, gastric cancer, + others;
* cemiplimab (IgG4): for cutaneous squamous cell carcinoma.
All administered by intravenous infusion.
NB: these mAbs block PD-1 from binding
both PD-L1 and PD-L2
Approved PD-L1 inhibitors?
- atezolizumab (IgG1): for urothelial carcinoma, non-small
cell lung cancer, small cell lung cancer, breast cancer,
hepatocellular carcinoma; - avelumab (IgG1): for Merkel cell carcinoma, renal cell carcinoma, urothelial carcinoma;
- durvalumab (IgG1): for non-small cell lung cancer
All administered by intravenous infusion.NB: as they bind to PD-L1, these mAbs only block the PD-1/PD-L1 interaction, without affecting the PD-1/PD-L2 interaction = potential of more precise
effect and better toxicity profile
Clinical use of mAbs has different disadvantages:
- limited tissue and tumor penetration (poor diffusion due to high MW)
- long half-life
- poor/no oral bioavailability (all i.v. administered)
- immunogenicity
- elevated production costs
