NOVEL CANCER THERAPIES; IMMUNOTHERAPY Flashcards
IMMUNOTHERAPY APPROACHES FOR CANCER TERATMENT
- ADOPTIVE CELLULAR THERAPY (TUMOUR INFILTRATING LYMPHOCYTES, T CELL RECEPTORS, TUMOUR-INFILTRATING T CELLS, PERIPHERAL T CELLS, CAR T CELLS)
- VACCINE THERAPY (DENDRITIC CELL VACCINES, PEPTIDE VACCINES, DNA VACCINES, MODIFIED TUMOR CELL VACCINES, TUMOUR-ASSOCIATED ANTIGENS, ONCOLYTIC VIRUSES)
- IMMUNOMODULATORS (CYTOKINES, INTERFERONS)
- TARGETED ANTIBODIES (MONOCLONAL ANTIBODIES, ANTIBODY-DRUG CONJUGATES)
- IMMUNE CHECKPOINT INHIBITORS (TAKING THE BREAKS OFF THE IMMUNE SYSTEM, STIMULATION)
COLEY’S TOXIN?
- SOMETIMES REFEREED TO AS MBV (MIXED BACTERIAL VACCINE)
- THE 1ST ATTEMPT TO USE IMMUNOTHERAPY AND HYPERTHERMIA AGAINST CANCER
- BY SURGEON WILLIAM B. COLEY (LATE 19TH, EARLY 20TH CENTURY); TO TREAT INOPERABLE SARCOMA ON A YOUNG GIRL
- MADE A BACTERIAL TOXIN MIX AND INTRODUCED IT INTO A TUMOUR, WITH THE IDEA THTA THE INFLAMMATORY RESPONSE THAT WOULD CAUSE WOULD ATTACK CANCER AS WELL
WHO IS CONSIDERED THE FATHER OF IMMUNOTHERAPY?
WILLIAM B COLEY (LATE 19TH/EARLY 20TH CENTURY)
- FRST DEMONSTRATION OF A ‘CANCER VACCINE’
CLASSIFICATION OF TUMOUR ASSOCIATED ANTIGENS
1) CANCER-GERMLINE (EXPRESSED ONLY BY TUMOR CELLS AND ADULT REPRODUCTIVE TISSUES) E.G. MAGE, BAGE, GAGE, NY-ESO-1
2) DIFFERENTIATION (EXPRESSED BY TUMOURS AND A LIMITED RANGE OF NORMAL TISSUES) E.G. TYROSINASE, Melan-A, gp100, CEA, MART-1
3) OVEREXPRESSED (EXPRESSED BY BOTH NORMAL AND TUMOR CELLS, BUT MUCH MORE HIGHLY EXPRESSED IN TUMOR CELLS) E.G. HER2, WIT1, MUC1, ppCT
4) VIRAL (EXPRESSED ONLY BY TUMOR CELLS AS A RESULT OF VIRAL INFECTION) E.G. HPV, HBV, EBV, HTLV
WHAT TYPE OF CELLS ARE TYPICALLY USED IN ANTITUMOR VACCINES?
DENDRITIC CELLS
GENERATED FROM PERIPHERAL BLOOD MONOCYTES
EXAMPLE OF A CANCER WHERE DENDRITIC CELL THERAPY CAN BE USSED?
PROSTATE CANCER
USING CYTOKINES IN IMMUNOTHERAPY, OPPORTUNITIES AND PROBLEMS?
DO NOT WORK WELL AS SINGLE AGENTS (MONOTHERAPIE)!!!!, NEED TO BE USED IN COMBINATION THERAPIES
AS KEY MEDIATORS OF CELL COMMUNICATION IN THE TUMOR MICROENVIRONMENT, CYTOKINES CAN HAVE BOTH ANTI AND PRO TUMOR EFFECT 9PRODUCTION AND FUNCTION OF MANY CYTOKINES IS DYSREGULATED IN CANCER)
ANTI:
- DIRECT GROWTH INHIBITION
- ENHANCED CYTOTOXIC ACTIVITY OF LYMPHOCYTES
- ENHANCED CYTOTOXIC ACTIVITY OF MYELOID CELLS
PRO:
- PROMOTION OF TUMOUR CELL SURVIVAL, STEMNESS AND PROLIFERATION
- IMMUNOSUPPRESSION
- DYSREGULATED CYTOKINE NETWORK AND TUMOUR-PROMOTING INFLAMMATION
- PROMOTE EMT AND INVASIVENESS OF TUMOUR CELLS
- PROMOTE ABNORMAL ECM PRODUCTION AND IMMUNOSUPPRESSION BY CANCER ASSOCIATED FIBROBLASTS
- NEOANGIOGENESIS
- USE OF BOTH CYTOKINES AND CYTOKINE ANTAGONISTS IN CANCER THERAPY?
WHAT ARE MONOCLONAL ANTIBODIES?
Monoclonal antibodies are laboratory-produced molecules engineered to serve as substitute antibodies that can restore, enhance, modify or mimic the immune system’s attack on cells that aren’t wanted, such as cancer cells.
- can kill cancer cells but also destroy normal B cells
ADOPTIVE T CELL THERAPY FOR CANCER?
1) TREATMENT MODALITY
2) SOURCE OF T CELLS (CELLS ISOLATED FROM A PATIENT’S TUMOUR)
3) ANTIGEN-SPECIFIC T-CELL ENRICHMENT (CAN BE GENETICALLY MODIFIED)
4) T CELL EXPANSION AND INFUSION (CELLS EXPANSION IN VITRO, THEN RE-INFUSED INTO THE LYMPHODEPLETED PATIENT)
DESCRIBE THE TREATMENT OF PATIENTS WITH T CELLS RECOGNISING TUMOUR-SPECIFIC MUTATIONS
- TAKE A TUMOUR SAMPLE
- EXTRACT DNA FROM NORMAL AND MALIGNANT TISSUE
- GATHER KNOWLEDGE OF THE MUTATIONS IN A PATIENT’S TUMOUR, WHICH CAN BE USED TO SYNTHESISE PEPTIDES
- PEPTIDES ARE INCUBATED WITH THE PATIENT’S OWN APC (ANTIGEN PRESENTING CELLS)
- THESE APCs ARE THEN COCULTURED WITH PATIENT’S T CELLS, THUS ACTIVATING TUMOUR-SPECIFIC T CELLS
- SPECIFIC T CELLS ARE THE SELECTED, EXPNDED AND RE-INFUSED INTO THE TUMOUR-BEARING PATIENT
How does Chimeric Antigen Receptor T-Cell Therapy (CART) work/
CART CELLS ARE GENE-MODIFIED T CELLS
T cells are collected from a patient. T cells are collected via apheresis, a procedure during which blood is withdrawn from the body and one or more blood components (such as plasma, platelets or white blood cells) are removed. The remaining blood is then returned to the body.
T cells are reengineered in a laboratory. The T cells are sent to a laboratory or a drug manufacturing facility where they are genetically engineered, by introducing DNA into them, to produce chimeric antigen receptors (CARs) on the surface of the cells.
After this reengineering, the T cells are known as “chimeric antigen receptor (CAR) T cells.” CARs are proteins that allow the T cells to recognize an antigen on targeted tumor cells.
The reengineered CAR T cells are then multiplied. The number of the patient’s genetically modified T cells is “expanded” by growing cells in the laboratory. When there are enough of them, these CAR T cells are frozen and sent to the hospital or center where the patient is being treated.
At the hospital or treatment center, the CAR T cells are thawed and then infused into the patient. Many patients are given a brief course of one or more chemotherapy agents, called “lymphodepletion,” before they receive the infusion of CAR T cells. CAR T cells that have been returned to the patient’s bloodstream multiply in number. These are the “attacker” cells that will recognize, and attack, cells that have the targeted antigen on their surface.
The CAR T cells may help guard against recurrence. CAR T cells may eradicate all of the cancer cells and may remain in the body months after the infusion has been completed. The therapy has resulted in long-term remissions for some types of blood cancer.
PARTICULARLY RELEVANT TREATMENT IN CONTEXT OF LEUKEMIA AND LYMPHOMA + MELANOMA
CART CELLS ARE ABLE TO REMAIN IN PATIENT FOR:
10 OR MORE YEARS
CASE OF DOUG OLSON, WHO HAS A DECADE-LONG LEUKAEMIA REMISSION WITH PERSISTANCE OF CD4+ CART CELLS
Using PD-1/PD-L1 and immunotherapy
What is the PD-1/PD-L1 pathway?
The PD-1 (programmed cell death-1) receptor is expressed on the surface of activated T cells. Its ligands, PD-L1 and PD-L2, are expressed on the surface of dendritic cells or macrophages. PD-1 and PD-L1/PD-L2 belong to the family of immune checkpoint proteins that act as co-inhibitory factors that can halt or limit the development of the T cell response. The PD-1/PD-L1 interaction ensures that the immune system is activated only at the appropriate time in order to minimize the possibility of chronic autoimmune inflammation.
The role of PD-1/PD-L1 in cancer
Under normal conditions, the immune system performs a series of steps which lead to an anticancer immune response and cancer cell death, known as the cancer immunity cycle1:
- Tumor cells produce mutated antigens that are captured by dendritic cells
- The dendritic cells prime T cell with tumor antigen and stimulate the activation of cytotoxic T cells
- Activated T cells then travel to the tumor and infiltrate the tumor environment
- The activated T cells recognize and bind to the cancer cells
- The bound effector T cells release cytotoxins, which induce apoptosis in their target cancer cells
The PD-1/PD-L1 pathway represents an adaptive immune resistance mechanism exerted by tumor cells in response to endogenous immune anti-tumor activity. PD-L1 is overexpressed on tumor cells or on non-transformed cells in the tumor microenvironment2. PD-L1 expressed on the tumor cells binds to PD-1 receptors on the activated T cells, which leads to the inhibition of the cytotoxic T cells. These deactivated T cells remain inhibited in the tumor microenvironment.
Using PD-1/PD-L1 and immunotherapy
Monoclonal antibody therapies against PD-1 and PD-L1 are being routinely used including:
Nivolumab, an anti-PD-1 drug developed by Bristol-Myers Squibb, which is approved for previously treated metastatic melanoma and squamous non-small cell lung cancer.
Pembrolizumab, developed by Merck is approved for previously treated metastatic melanoma.
There are several other immunotherapy options being used or in development.
CANCER RESPONDING THE BEST TO ANTI-PD-1 AND ANTI PD-L1 THERAPIES?
HODGKIN’S LYMPHOMA
‘HOT TUMOURS’?
Describes a tumor that is likely to trigger a strong immune response. Hot tumors often have many molecules on their surface that allow T cells (a type of immune cell) to attack and kill the tumor cells. Hot tumors usually respond to immunotherapy.
- ‘Hot’ tumors are characterized by the accumulation of proinflammatory cytokines and T cell infiltration (T cells able to reach the tumour core)
