Immunotherapy 2 Flashcards
Dendritic cell
Release cytotoxic cytokines
Antigen presentation to T cells
In cancer:
Suppress T cell functions
Promote tumor growth and progression
T cell
Directly lyse cancer cells
Release cytotoxic cytokines
In cancer:
Release tumor promoting cytokines
Treg
Restore homeostasis to reduce chronic inflammation
In cancer:
Suppress anti cancer immune responses
Stimulate inflammatory cytokine production
Macrophage
Release cytotoxic cytokines
Antigen presentation to T cells
In cancer:
Promote angiogenesis, tumor proliferation, chemotaxis, invasiveness, and metastassi
Myeloid derived depressor cell
Limited
In cancer:
Suppress T cell functions
Recruit immunosuppressive immune cells
NK cell
Release cytotoxic cytokines
Directly cytotoxic to cancer cells
In cancer:
Limited
Cancer immunoediting
Elimination
Equilibrium
Escape
Elimination
Immunity works to destroy developing tumors long before they become clinically apparent
Immunosurveillance
Equilibrium
The process by which the immune system iteratively selects and/or promotes the generation of tumor cell variants with increasing capacities to survive immune attack
Escape
The immunologically sculpted tumor expands in an uncontrolled manner in the immunocompetent host
Why cancer immunotherapy
Improved overall survival as a result of combination with immunotherapy
Immunotherapeutics
Ideally can have prolonged and sustained protection by forming memory
Dogma of Immuno-Oncology
Release of cancer cell antigens
Cancer antigen presentation
Priming and activation
Trafficking of T cells to tumors
infiltration of T cells into tumors
Recognition of cancer cells by T cells
Killing of cancer cells
Types of cancer immunotherapy
Cytokines
Vaccines
CAR-T cells
Checkpoint inhibitors
Molecular agonists
Cytokines
Can directly influence the survival, activation, proliferation and differentiation of T cells as well as indirectly affecting these processes through effects on dendritic cells, macrophages and regulatory T-cells
Types and functions of cytokines
Mediates intracellular signaling to regulate homeostatsis of immune system
Has the ability to act on many different cell types to mediate diverse effects
Multiple have the same functional effects
Clinical applications of cytokines
IFNa: approved by FDA for adjuvant treatment of resected high risk melanoma patients and several refractory malignancies
High dose IL-2: FDA approved for treatment of metastatic renal cell cancer and melanoma
Very limited clinical utility
Cytokine SE
Hypotension, capillary leak syndrome, bleeding problems
Cancer vaccines
Response modifiers working by stimulating or restoring the ability of immune system to fight cancer
Consists of preventative and therapeutic vaccines
Tumor antigen vaccine classes
Tumor associated antigens
Tumor specific antigens
Tumor associated antigens
Over-expressed proteins, differentiation antigens
—variable specificity, high tolerance, high prevalence in multiple patients
Cancers testis antigens
—good specificity, low tolerance, high prevalence in multiple patients
Tumor specific antigens
Oncoviral antigens
Shared neoantigens
Private neoantigens
—ideal specificity, no tolerance, high prevalence in multiple patients (low prevalence in private neoantigens)
Clinical applications of preventative cancer vaccines
Preventative:
-HPV for cervical cancer and head and neck cancer
-HBV for liver cancer caused by hepatitis B virus
Therapeutic
-Sipluleucel-T: for metastatic hormone-refractory prostate cancer
-Most probably be used in the adjuvant or neoadjuvant setting for the treatment of patients with minimal residual disease or more indolent metastatic disease, or those with a high risk of recurrence.
MABs for triggering the immune system
Antibody-dependent cell-mediated cytotoxicity (ADCC)
Attach themselves to cancer cells, making it easier for the immune system to find them
Examples of MABs for triggering the immune system
Rituximab
Cetuximab
Trastuzimab
MABs for inhibiting immune checkpoints
Checkpoint inhibitors block proteins that stop the immune systems attacking cancer cells
MABs for inhibiting immune checkpoints
Ipilimumab
Atezolizumab
Pembrolizumab
CD28
Interacts with CD80 or CD86 which are upregulated on activated antigen presenting cells
Amplifies TCR signaling to activate T-cells
CTLA-4
Interact with CD80 or CD86
Dampens the expression of T-cells by sending inhibitory signals to it
Anti-CTLA-4
Promotes T cell priming by APCs in lymph nodes
Tregs and CTLA-4
Treg constitutively expresses CTLA-4
Anti-CTLA-4 functions partially due to depleting and suppressing Tregs
PD-1/PD-L1
Induced by TCR/CD28-mediated activation signaling
PD-L1: expressed in infected cells and tumor cells as well as antigen presenting cells
PD-L2: generally expressed in antigen presenting cells
CTLA-4 vs. PD-1 in T cells
CTLA-4 is an on off switch
PD-1 is dynamic, milder response to blocking
PD-1/PD-L1 mechanism
Inhibits T-lymphocyte proliferation, survival and effector functions inducing apoptosis of tumor specific T-cells
Anti PD-1
Promote effector functions in T cells
Rescue T cells from adaptive resistance
Anti-PD-1 v. Anti PD-L1
In principle may work differently due to diverse ligand-receptor interactions
In practice, they shoe similar response levels of efficacy and cytotoxicity
Combined Immune Checkpoint Blockade
Improved efficacy by combining anti-CTLA-4 and anti PD-1
Increased toxicity by the combination
TIL therapy
Tumor infiltrated lymphocyte
Tumor resection
Isolation of TIL and initial outgrowth ex vivo
Rapid expansion of TIL
Returned to patient
Adoptive cell transfer (ACT)
Giving prepared T cells to the patient
T cell receptor therapy
Isolation of peripheral T cells via leukapheresis
Introduction of a retrovirus
Transduction of viral vector
(CAR therapy)
Specific TCR
ACT
Specific TCR types
Melanoma differentiation antigen recognition
Overexpressed antigen recognition
C/T antigen recognition
Viral antigen recognition
Chimeric antigen receptor (CAR) therapy
1st gen: extracellular, transmembrane and Intracellular activating domain
2nd gen: 1 customatory domain often CD28 or 4-1BB
3rd gen: 2 customatory domains (CD28+4-1BB or OX-40)
4th gen: CAR “truck” NFAT, Inducible cytokine
