| What is goal and approach of cancer immunotherapy? | Goal:
Achieve better defense against tumor by the effectors of the immune system
Reduce side effects on healthy tissue
Two approaches:
Passive immunotherapy: monoclonal naked or conjugated
antibodies
Active immunotherapy: activation of tumor antigen-specific CTL of the pt |
| How is passive cancer immunotherapy w/monoclonal Abs? | Mab can target :
Tumor Ag on hematological tumors
Tumor Ag on solid tumors
Receptors of immune cells infiltrating a tumor
Blood vessels irrigating a tumor
Objective: Define the tumor surface-ome for a more
comprehensive approach
Applications:
First line treatment
Combined therapy, mainly in resistant tumors
Large expansion over the last 15-20 yrs |
| What are the two types of tumor antigens? | Tumor specific antigens (TSA): excellent targets
Viral antigens: ex HBV antigens in liver carcinoma
Neoantigens: derive from mutated genes (oncogenes, tumor suppressor genes or others): ex: ras, p53
Tumor associated antigens (TAA):
less immunogenic, more challenging to target
Over- or aberrantly expressed proteins. Ex: VEGF
Cell type-specific differentiation antigens: normal cell proteins characteristic of a given maturation stage of a cell type. Ex: CD20, CALLA (CD10)
Oncofetal antigens: fetal proteins normally silenced in adult cells, but reexpressed after epigenetic alterations
Cancer-testis antigens: Ags present in normal germ cells of testis and ovary, and in fetus but not adults reappear in cancer. |
| What are different characteristics of TAA and TSA? | . |
| What are various monoclonal Abs in cancer therapy? | Origin:
Chimeric
Humanized
Human
Structure:
Complete Ig molecules: maintain the effector function
Fab or Fab’2 : smaller, better tumor penetration
scFv: single chain variable fragment (fusion of VH-VL)
Chemical composition:
Purified naked antibody (alone)
Conjugated antibody: radioactive, immunotoxin, ADEPT |
| What are monoclonal Ab terminology? | . |
| What are mechanisms of action of naked Abs? | Effector functions :
Complement activation (CDC)
NK cell activation (ADCC)
Ex: Rituximab (Rituxan) : anti-CD20 approved in 1997 for NonHodgkin lymphoma
Modulation of Ligand-Receptor interaction:
Agonist or antagonist effect on a receptor of cytokine, growth factor, hormone….
Ex: Trastuzumab (Herceptin) anti-ErbB2 (or HER-2), approved in 1998 for treatment of breast cancer
Ex: Bavacizumab (avastin): anti-VEGF (vascular endothelial growth factor, treatment of colon cancer) approved in 2018 |
| What are examples of antitumor abs action on cancer? | HER2: Human Epithelial Growth Factor Receptor 2
Herceptin: anti-HER-2:
- Effector function: ADCC
- EGF antagonist: inhibits cell proliferation
Tumor cells secrete VEGF to induce angiogenesis.
Anti-VEGF antibodies:
- Block VEGF-VEGFR interaction
- Inhibit angiogenesis
- Induce tumor hypoxia |
| Why is use of radioactive Abs conjugates? | Radiolabeled monoclonal antibodies
Entire Ig molecule or Fab or (Fab’)2: binds Ag
Radioisotope responsible for cell toxicity (high intensity, low action radius)
Ex: radiolabeled anti-CD20 (Zevalin) for treating Non-Hodgkin lymphoma (NHL) cases that are resistant to purified anti-CD20
May be used in “multistep targeting”: Ab- streptavidin then biotinylated radioactive ligand (clinical trials) |
| Why is use of Abs-drug conjugates? | ADC= MAb+ cytotoxic payload (drug) + linker
mAb targets a receptor
Drug is delivered in target cell via R-mediated endocytosis
Allows use of up to 1000x more toxic drugs, mainly tubulin inhibitors and DNA-damaging drugs
To date, 10 ADCs have been approved by the FDA for cancer treatment. Example: Adcetris is an anti-CD30 used for treatment of Non-Hodgkin lymphoma, in combination with chemotherapy |
| What is use of bispecific Abs? | Genetically engineered antibodies that bind simultaneousl to 2 different antigen epitopes:
Both on tumor cell: higher specificity
One on the tumor cell + One on an immune cell (Ex: CD3): potentiation of cellular immunity
Atumaxomab (Removab®) was the first approved T cellengaging BsAb for the treatment of malignant ascites; it was approved initially in 2009 and is currently used worldwide |
| What are some examples of Abs indications in cancer immunotherapy? | Haematological tumors
Non-Hodgkin B cell lymphomas (CD20)
Myeloid acute leukemia (CD33)
Chronic lymphocytic leukemia (CD52)
Solid tumors:
breast cancer (Her 2 = ErbB2)
Melanoma, colorectal cancer
Non-small cell lung cancer (NSCLC): VEGF
Squamous cell carcinoma of the head and neck (SCCHN)
Less than 15 monoclonal antibodies approved by the FDA for cancer therapy in 2012
A tremendous increase in the use of monoclonal antibodies for cancer therapy in recent years |
| How is increase in use of monoclonal Abs in cancer? | Increase in numbers: (≃ 100 mAbs, all indications included)
Increase in indications : more cancer types
Increase in options: naked versus labeled
Better targeting : epitope refining
Protocols of cancer immunotherapy with mAb
In first line immunotherapy or for refractory tumors
Alone or in combination with chemotherapy or radiation therapy
As a complement to surgery for removal of subclinical microscopic tumors |
| What is active cancer immunotherapy? | Intended to inhibit immunosuppressive mechanisms and
amplify antigen-specific T cell responses
Three approaches used :
Checkpoint inhibitors: mAbs antagonists of inhibitory signals
CAR-T cell therapy: Patient treatment with modified autologous T cells
Therapeutic cancer vaccines: Tumor antigens or genes encoding for these Ags, that either activate pre-existing host antitumor immune cells or induce the differentiation of new ones |
| How are tumor evasion mechanisms by cancer cells? | . |
| How is cumulative mutations overtime after tumor evasion? | . |
| How is tumor resistance through checkpoints? | Immune checkpoint proteins belong to the B7 family ligands and the CD28 family receptors. They act as co-inhibitory molecules between APC and T cells
In physiological conditions, they ensure that the immune system is activated only when needed, in order to avoid chronic inflammation or autoimmunity
The most important are:
CTLA4
PD-1 and PD1-L |
| Describe the two pathways of resistance to checkpoints of tumors? | Resistance through CTLA4:
CTLA4 or CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152, is an analog of CD28 expressed on activated T cells and on Treg
It binds B7-1 or B7-2 and blocks signaling through C
Resistance through PD1-PD1L:
The PD-1 (programmed cell death-1) receptor and its ligands, PDL1/PD-L2, are members of the family of immune checkpoint proteins:
PD-L1 and PD-L2 are commonly expressed by dendritic cells and macrophages
Normally, PD-1 is increasingly expressed on activated T cells to halt or inhibit immune responses
The PD-1/PD-L1 pathway is a resistance mechanism of tumor cells:
PD-L1 is overexpressed on tumor cells or on non-transformed cells in the tumor microenvironment
Its binding to PD-1 receptors on activated T cells leads to persistent CTL inhibition in the tumor microenvironment |
| How is immunotherapy w/immune checkpoints inhibitors? | Based on mAb that inhibit checkpoint molecules: PD-1 /PD-L1 and CTLA4
Reactivates T cells in the tumor microenvironment
Is one of the most successful cancer therapies in recent years
Anti-PD1 and antiPD-L1 mAb revert tumor tolerance by CTL
Anti-CTLA4 mAb reverse inhibition of T cell activation |
| What are some checkpoint inhibitors in clinics? | Three FDA approved mAbs, all are anti-PD-L1
Atezolizumab (Tecentriq):
Humanized IgG1
Approved in March 2019. Used in combination with
chemotherapy for the treatment of Non-small cell lung
carcinoma (NSCLC) and explored for many cancers including prostate, colon, pancreas, gastric,…
Durvalumab (Keytruda) : human IgG1 indicated mainly for advanced melanoma
Avelumab (Bavencio) : human IgG1 indicated mainly for NSCLC |
| How is CAR-T cell therapy for cancer? | Autologous live reprogrammed T cell therapy
Patients are treated with their own T cells transfected with CAR
CAR: Chimeric Antigen Receptor. Generations 1 to 3 consist of:
A tumor antigen-binding domain (scFv fragment of a tumor-specific Ab: VH+VL) + a trans-membrane region anchoring scFv to the cell
One or more intra-cellular signaling domains containing ITAM, that activate the T cell upon Ag binding |
| How is principle of CAR-T cell therapy in cancer? | Blood is collected from the cancer patient by leukapheresis
T cells are selected by purification on Ab coated beads. Most suitable are T-memory stem cells
T cells are transfected virally or non-virally with a CAR molecule and expanded in vitro
Modified T-cells are reinfused to the patient with or without combined chemotherapy. T cells bind to antigen-expressing tumor cells and kill them
Advantage:
Ag binding by Ab-binding site, not TCR: no need for APC, no MHC restriction
Higher number of specific T cells
Intracellular signaling domains overcome suppressive microenvironment |
| What are the two FDA approved CAR-T cell therapy? | Tisagenlecleucel: CD19-targeted T cells. Trade Name: Kymriah
Approved in August 2017 for the treatment of acute lymphocytic leukemia (ALL) of pro-B cells in pediatric and young adult patients
Survival rate after 3 months : 83% in relapsed ALL patients
Axicabtagene: CD19-targeted T cells. Trade name: Yescarta
Approved by the FDA in October 2017 for the treatment of Diffuse Large B cell Lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma
Indicated in adults who failed 2 previous therapies
Side effects: cytokine release syndrome and neurologic events, potential fatal |
| How are cancer vaccines? (with tumor Ags) | . |
| How are cancer vaccines with modified tumor cells? | . |
| How are cancer vaccines w/tumor DNA? | . |
| How are vaccines based on pulsed Dcs? | . |
| How are vector based vaccines of cancer? | . |
| What are 2 FDA approved vaccines of cancer? | Provenge (Sipuleucel-T):
Customized treatment of metastatic prostate cancer
Approved in 2010
Life expectation prolonged for 4 months
Imlygic (talimogen laherparepvec: T-VEC)
Treatment of recurrent melanoma after surgery
Approved in October 2015
Oncolytic virus therapy |
