Immunotherapy Flashcards
what is imunotherapy
the use of the patient’s own immune system to fight disease (cancers/chronic viral infections)
what therapies give a a significant advance in cancer treatment beyond traditional treatment (chemotherapy, radiotherapy and surgery)
Immuno-oncology therapies
why should patients be treated as early as possible with immunotherapy
as this will be before the immune system has selected for highly-resistant variants as over time, tumours become resistant to the immune system
what do immunotherapies recognise - unlike in autoimmune disease where IS can attack own cells
recognises an antigen that is dissimilar to the host
what response do Immunotherapies induce when engaging and recruiting the immune system to combat disease
an antibody generation response against a specific antigen (foreign entity) typically present on the cell surface of a virus or cancer cell.
what are immunotherapies directed at
A specific antigen/cluster of antigens that compose the unique signature of a virus or cancer cell that is dissimilar to its host thus recognizing self from non-self.
2 reasons immunotherapy success is dependent on tumour load first being reduced
Immune system cannot cope with large tumours
Lots of antigen shedding would stimulate the regulatory T-cells (stop immune response against tumour)
what is the most promising area of immunotherapy (targetting cell-surface component s of tumour cells)
Humanized monoclonal antibodies
how do antibodies reacting with antigens on the surface of tumour cells protect the host
by complement mediated opsonization and lysis and also through recruitment of macrophage and NK ADCC
what do The FcR cells act as and do
act as cytoxic effectors
cause crosslinking of antibody coated cells which leads to apoptosis or exit from the cell cycle, and makes the cells sensitized to irradiation and DNA damaging chemotherapy
3 things unmodified naked antibodies to
inhibit functions of signalling receptors so stop tumour growth (like neutralisation during infection)
Promote opsonisation of tumour cells and their phagocytosis (complement mediated lysis recruitment of macrophage)
Opsonisation of tumour cells also causes their destruction by NK ADCC, apoptosis and sensitization (chemo and radio)
what are modified antibodies called
immunoconjugates (a tumour targeting antibody linked with a toxic effector component) - such as radioisotope, toxin or small drug molecule
How many humanized or fully human monoclonal antibodies and immunotoxins were approved by the US Food and Drug Administration by the end of 2019 for use in cancer
e.g.
More than 20
e.g. MAb approved for HER2 in breast cancer, CD20 in lymphoma, EGF in colorectal cancer
what do Therapeutic antibodies do to tumour cells to activate the NK cell to kill tumour cell (antibody-mediated cell-mediated cytotoxicity)
coat a tumor cell with their Fc regions pointing away from the cell.
These engage the FcγRIII receptors on an NK cell.
Signals from the receptors activate the NK cell to kill the tumor cell
what were monoclonal antibodies originally produced using - makes them very useful for treating a broad range of clinical conditions.
mouse hybridomas-
Specificity of mouse monoclonal antibodies
problem when mouse monoclonal antibodies are introduced into humans
Recognised as foreign, and evoke an immune response known as the HAMA response. human anti-mouse antibody quickly clears the mouse monoclonal antibodies. This reduces efficiency of the treatment
2 other complications from introducing mouse monoclonal abs into humans
allergic reactions
the accumulation of mouse and human ab complexes in organs such as the kidneys which can cause life threatening problems.
2 main ways of making mouse monoclonal abs more like those from humans
Design and construct genes to clone the promoter, leader and variable region from a mouse ab gene, and constant region exons from a human ab gene (a mouse human chimera - chimeric ab) -
is partially humanised.
e.g of a chimeric ab that is used for treatment in non-Hodgkin’s lymphoma.
rituximab - targets CD20 of the B cells in non-Hodgkin’s lymphoma. A human anti-chimeric antibody response (HACA) is observed.
CDR grafting and what does it involve
now possible to engineer abs in which all of the sequence is human except the CDRs
involves the substitution of non-human cdr domains from a mouse ab into the most closely related human ab sequence available, so that only the cdr domains are non-human.-this is a fully humanized ab
2 advantages of humanized abs due to CDR grafting
retain the biological effector functions of human antibody and are more effective than mouse abs in triggering complement activation and fc receptor mediated processes such as phagocytosis in humans.
Less immunogenic in human than mouse-human chimeric abs
what is mouse abs half-life compared with the half lives of their human or humanized counterparts - this is another advantage to humanising abs
very short half-life of a few hours compared to 3 weeks of human/humanised counterparts
why have technological developments been undertaken so that fully human antibodies are produced by engineering the Ig loci, rather than components within the Ig molecule.
as chimerization and humanization of abs are labour intensive procedures, involving sequence analysis, engineering approaches, analysis and optimization of binding affinity, and evaluation of immunogenicity for each ab.
how are fully human Ig produced in mice by antibody engineering
Mice Ig H and L loci removed (Knockout mice)
Embryonic stem cells from KO - from blastocyst and
HAC (human artificial chromosome) containing human Ig H and L loci - transfected into ES cells.
Transgenic mice that produced human Ig
Can make hybridomas that produce human Ig from mice
after Human artificial chromosome gets transfected into ES cells what happens to the modified ES cells
they get put back into a blastocyst and transplanted into surrogate mothers. The B cells of the offspring produced human abs in response to antigen.
whats the transgenic mice response useful for
producing large quantities of human abs
2 drugs produced using human Ig in mice production
Panitumab - approved for tx of metastatic colorectal cancer
Zanolimumab (lymphoma) - in phase III trials for t-cell lymphoma
how many deathscausedbyskin cancer does melanoma account for
75%
what did James Allison study
a known protein that functions as a brake on the immune system. He realized the potential of releasing the brake, unleashing our immune cells to attack tumours. He then developed this concept into a brand new approach for treating patients
what did James Allison study
a known protein (CTLA-4) that functions as a brake on the immune system. He realized the potential of releasing the brake, unleashing our immune cells to attack tumours. He then developed this concept into a brand new approach for treating patients
what did Tasuku Honjo discover
a protein expressed in dying T cels (PD-1) which is also a brake, but with a different mechanism of action. Therapies based on his discovery proved to be strikingly effective in the fight against cancer.
what did KEYTRUDA (PD-1 inhibitor) result in with melanoma
3 year survival of metastatic melanoma patients 40%, whereas previously survival was measured in months
what was KEYTRUDA approved as first line treatment for (whose tumours express PD-L1 at >50%, and other cancers)
advanced non small cell lung cancer (NSCLC)
when was KEYTRUDA FDA approved as the first cancer treatment for any solid tumour
May 2017
5 cancers keytruda (pembrolizumab) is approved to treat
melanoma
non-small cell lung cancer
colon/rectal cancer
cervical cancer
renal cell carcinoma
what do monoclonal antibodies as Immune Agonists drugs target
specific cell surface proteins on T cells, causing stimulation of T cell activity
where is the target for therapeutic antibodies CD30 found
on the surface of anaplastic large cell lymphoma tumour cells (T cell lymphoma) or Hodgkins lymphoma
What does the anti-CD30 antibody brentuximab coupled to the cytotoxic drug auristatin (brentuximab–vedotin) help prevent and do
Prevents mitosis and induces the tumour cell to die by apoptosis - after ab has attached the conjugate to the surface of the tumor cell, the conjugate is internalized into endosomes, where cathepsin cleaves the linker and releases the auristatin. This drug passes to the nucleus and binds to microtubules which prevents them from forming a mitotic spindle.
One advantage ofimmunotoxinsoverconventional
chemotherapy
thetoxin’sdestructive
powerisspecifically
targetedatthetumourandawayfromhealthyproliferatingtissues.
why must Auristatinonlybeadministeredwhenconjugatedtoanantibody
as its so toxic
what are Bispecific T cell engager (BiTE®) Antibodies designed to do to cancer cells
bridge cancer cells to CTLs
what does Adoptive T cell transfer involve doing outside of the body (ex vivo)
generating large numbers of T cells, outside the body
What are the isolated T cells genetically engineered to do in adoptive t cell transfer
to produce cytokines such as IL-2, which will boost their activity.
how are the t cells expanded in vitro in adoptive t cell transfer, before being put back into the patient
in vitro stimulation with antigen-presenting cells
what are CAR—chimeric antigen receptors
genetically engineered protein constructs which can be incorporated into a patients own cytotoxic T cells to try to help them recognise and fight cancer cells
how is CAR T cell therapy provided
by removing/harvesting T cells from a patient with cancer
Transfecting cells with CAR genes which are directed against patient’s tumour type to expand the modified T cell population
reinfusing cells back into patients
what was one CAR T-cell therapy approved to treat in 2017
children with acute lymphoblastic leukemia (ALL)
what type of cell are dendritic cells
type of antigen presenting cells
how do dendritic cells induce an adaptive immune response
they take up antigen and present it on MHC class II to T cells
dendritic cell vaccine process
Peripheral Blood mononuclear cells (Monocytes, NK cells and lymphocytes) are isolated from patient’s blood
Dendritic cell progenitors are negatively selected using magnetic beads (CD3, CD11b, CD16)
These cells are cultured in the presence of the growth factors GM-CSF and TNFa for 9 days.
Tumour cells from the patient or tumour specific antigens are added to the cells and they are re-infused back into patient (stimulates adaptive IR)
E.g of a cancer subunit vaccine given in USA since 1982 to healthcare professionals
Hep B subunit vaccine - prevents liver cancer (hepatic carcinoma)
how many deaths from cervical cancer does HPV cause worldwide per year prior to vaccination
250,000 deaths
what 2 types of HPV are responsible for 70% cases
HPV-16, HPV-18
whats the HPV vaccine called in the NHS programme
Gardasil
4 types of HPV gardasil protects against
HPV6
HPV11
HPV16
HPV18
What is research being undertaken to develop a vaccine for
exploit the ability of CTLs to target EBV-related antigens on the cells of all Burkitt lymphomas
advantage of immunization with whole tumour cells
do not need to have identified the tumour antigen
disadvantage of immunisation with whole tumour cells
most tumours are weakly immunogenic, and do not present antigen effectively and so cannot overcome the barrier to activation of resting T cells
what does Antigen independent cytokine therapy use cytokines such as IL-2, interferon and TNF to do
boost the immune system non-specifically (ie not in an antigen dependent manner).
what patients has interleukin treatment been used on (high doses of IL-2)
patients with metastatic melanoma or kidney cancer
what was observed in 15-20% of patients who had interleukin treatment
at least partial tumour regression in 15-20%. Some patients displayed complete regression - maybe due to stimulation of pre-existing t cells/due to NK activation
what is the only drug so far which has generated long-term responses in metastatic melanoma and metastatic renal cell carcinoma
Proleukin (high dose recombinant IL-2)
What treatment has generated good clinical trial responses with a massive response rate of 80-90% in hairy cell leukemia
interferon alpha and beta treatment
What do colony-stimulating factors do that has worked in mice e.g granulocyte-macrophage colony-stimulating factor (GM-CSF)
induce tumour cell differentiation and suppress tumour growth
why may in vivo expansion and transfer of large numbers of activated NK cells be beneficial
as NK cells are important in tumour surveillance and killing
what have trials shown, regarding NK cell numbers and drug administration
daily administration of low-dose IL-2 after high-dose chemotherapy expanded NK cell numbers
why were NK cells from related haploidentical donors given to acute myeloid leukaemia patients in a trial
to achieve a partial mismatch between donor NKs and recipient that could provoke NK activation and more tumour kill (5/19 patients went into complete remission)
targetting what should deprive the tumour of oxygen and nutrients, causing regression.
target the antigens expressed in the blood vessels
what are leukaemias treated by which is classed as immunotherapy
bone marrow transplantation (bone marrow removal and replacement)
5 e.gs of diseases BMTs can treat people with
acute leukaemia
aplastic anaemia
chronic leukaemia
hemoglobinopathies
hodgkin’s lymphoma
immune deficiencies
what does allogeneic BMT involve
transplantation of bone marrow from a reasonably compatible MHC donor - results in graft versus leukaemia effect
what is graft versus host disease (complication of allogeneic BMT)
graft also launches an attack on the recipient
