Immunotherapy in Haematological cancers Flashcards
What is the indirect evidence that there is cancer immunosurveillance?
primary immunodeficiency results in high risk of cancer; acquired immunodeficieny-organ transplants and HIV increases risk; tumour infiltration by immune cells correlates with outcome; antibodies and T cells have been foudn specific for cancer somatic mutations; cancers accumulate mutations to evade immune response and secrete immunosuppressor cytokines
Which primary immunodeficiencies are linked to high risk of cancer?S
CVID; SCID-mice
Give examples of increased cancer risk in organ transplants?
10-30x risk of non-melanoma skin cancer; x12 lymphoma
Give examples of HIV-1 influencing cancer risk?
oncogenic viruses- Kaposi’s sarcoma; lung cancer incidence doubles with low CD4 coutn
Give an example of the adaptive system being specific for cancer neo-antigens?
autologous IgG have been foudn for >2000 neoantigens; CD8 cells against BCR-ABL1 protein in CML
What mutations do cancer cells accumulate to evade the immune response?
downregulation or mutation of MHC-I; mutations in beta-2 macroglobulin; downregulation of CD1d
What is the function of CD1d?
presentation of lipid antigens to NKTs
What immunosuppressive cytokines do cancers secrete?
IL-10 and TGFb
What receptor do NK and T cells express to eliminate premalignant cells?
NKG2D
When is NKG2D upregulated?
UV and oncogene, polymorphism in it relates to high cancer rates
What are the steps of cancer immunoediting?
Elimination; equilibrium and escape
How does allogenic stem cell transplantation work in cancer therapy?
give chemotherapy to reduce tumour and immune cells than give donor cells which recognise malignancy as target
What immune effect does alloSCT harness?
graft vs leukaemia effect
What is the evidence that there is graft vs leukaemia effect?
T cell depletion increases relapses rates; donor lymphocyte infusion can eliminate minimal residual disease or treat relapse- as can reducing immunsuppression
What are the different types of immunotherapy for haematological cancers?
vaccines; monoclonal antibodies; CAR T cells; checkpoint inhibition; alloSCT
What determines that clinical efficacy of monoclonal antibodies?
target specificity and humanised Mabs
What cells express CD52?
all lymphocytes
What are the mechanisms of action of anti-CD20 mAbs?
ADCC; complement dependent cytotoxicity; direct cytotoxicity; adaptive cellular immunity
How does anti-CD20 cause direct cytotoxicity?
induction of programmed cell death via a lysosomal pathway after homotypic adhesion
How does anti-CD20 cause adaptive cellular immunity?
debris from increased dead cancer cells is taken up by APCs and presented to effectors- ?vaccination effect
What cells express FcR and are involved in ADCC?
macrophages and NK cells
What is the effect of rituximab in B cell lymphomas?
adding rituximab to CHOP therapy increases overall suvival by 13% at 5 years
Aside from use as chemoimmunotherapy , how else is rituximab used in haem cancers?
maintenance therapy- longer remission and deeper repsonses over time
What is rituximab used for in haematology generally?
ITP and AHA
What AI diseases is rituximab used for?
RA; vasculitis; renal disease; EBV infection and post transplant lymphoproliferative disease
What is the fully humanised version of anti-CD20?
ofatumumab and obinutuzumab
What is the anti-CD52 agent?
alemtuzumab
When is alemtuzumab efficacious and what paradigm does this present?
effective in chemotherapy CLL with certain mutations adn demonstrates the use of immunotherapy in chemo-resistant disease; graft T cell depletion in SCT
What are the benefits and disadvantages of using alemtuzumab in conditioning for SCT?
minimises risk of GvHD but increases infections and risk of relapse
What marker is strongly expressed in plasma cells?
CD38
What mAb is used for multiple myeloma?
daratumumab
What is the efficacy of daratumumab in multiple myeloma?
36% patients with refractory disease respond; in combination with chemo improves progression free survival at 1 year from 60 to 83%
How is elotuzumab thought to work?
ant-SLAM7 which may prime NK cells to attack myeloma ; ADCC
Give an example of a toxin conjugate mAb?
brentuximab vedotin
What does brentuximab target?
anti-CD30 with a microtubule disrupting agent attached
What is brentuximab used for?
relapsed lymphoma- CD30+ T cell lymphoma and relapsed HL
What are bispecific T cell engager antibodies?
have 2 specificities e.g anti-CD3 and anti-CD19- one part will stick to tumour cell and then also bind to T cells and activate them
What is the name for anti-CD3-anti-CD19 bispecific antibody?
bilatumomab
What is bilatumomab used for?
acute lymphoblastic leuakaemia
What is the benefit of CAR-T cells?
they aren’t dependent on MHC
What is a disadvantage of CAR T cells?
only target cell surface antigens ; requires patient to have enough lymphocytes; cytokine storm; neurotoxicity; myelosuppression
What is found in the endodomain of CARs?
activator molecules from the TCR e.g the xeta chain as well as co-stimualtory molecules
What is found on the extracellular domain of CARs?
Fab portion of hte antibody
What is usually the vector for creating CAR T cells?
lentiviruses
Why does there need to be host conditioning before CAR-T cell therapy?
to reduce the immunoreaction against the CAR T cells as they cause strong immune reaction
When have CAR T cells been shown to be effective?
anti-CD19 CAR-T cells have induced complete remission in 70-85% of patients with relapsed/refractory B cell acute lymphoblastic leukaemia; durable response in refractorydiffuse large B cell lymphoma in 40%
What antigen have CAR T cells been targeted against for multiple myeloma?
B cell maturing antigen - specific for plasma cells
Give an example of a malignancy where there are CTLA-4 polymorphisms?
myeloma
What malignancies over express PD-L1?
solid tumours; myeloma; HL
Give an example of an anti-PD1 mAb?
nivolumab
What cancers is nivolumab used in ?
melanoma; squamous non-small cell lung cancer ; renal cell carcinoma; HL
Is there not a problem with rituximab reducing B cell function?
doesn’t appear to cause clinically significant normal B cell and antibody depletion (CD20 not expressed on plasma cells)- only if repeated courses is there a risk of recurrent infection
Why are yd T cells effective in anti-tumour effects?
potently cytotoxic and produce IFNy
What do the non-redundant role of yd T cells in host protective responses result from?
combination of unique antigen specifities; high clonal frequencies and a pre-activated differentiation status that allows for very rapid repsonses
What are the 2 subsets of yd T cells made in the mouse thymus?
IFNy producing and IL-17 producing
What have recent reports suggested about the role of IL-17 producing yd T cells in cancer?
tumour-promoting in both mouse and humans
What are hte main determinants of yd T cell tumour recognition?
yd TCR; NK cell receptor- NKG2D
How does IFNy production enhance tumour cell clearance?
induces upregualtion of MHC-I and enhances CD8 reposnes; inhibits angiogenesis
What is the function of IL17 in tumour promotion?
recruits immunsuppressive cells e.g MDSCs or small macropahges which can rpomote angiogenesis, tumour cell grwoth and iTreg differentation
How are yd T cells generally split?
according to the Vy chain they use
How was the role of yd T cells during tumour development inferred?
comparing tumour progression in yd T cell-deficient mice and wild type mice
From mouse KO studies of yd T cells, what was foudn about their role in tumour development?
yd T cell prevented the chmical induced development of papillomas and their progression into squamous cell carinomas; protective against spon B cell lymphoma nad prostate whilst ab T cells promoted tumour progression
What does the antitumour cytoxocity of skin resident yd T cells rely on?
both TCR and NKG2D expression
What demonstrates the importance of NKG2D in tumours?
high cancer susceptbility in NKG2D deficient mice
What is the function of NKg2d?
senses molecular stress signatures that are upegulated on transformed cells
How do yd T cells carry out effector functions ?
release perforin and granzymes; express CD95L and TRAIL that engage death receptors; secrete IFNy
What surface marker correlates with either IFNy or IL17 production in yd T cells?
CD27+ secrete IFNy whilst CD27- secrete IL17
Although some studies have suggested a dentrimental effect to IL-17 producing yd T cells, when have they been shown anti-tumour?
cooperate with BCG vaccination to mediate bladder cancer regression (recruited antitumour neutrophils to the bladder)- which didn’t happen in yd defieint and IL-17 deficient mice
What cancers have been domsonatrated to show reduced grwoth in yd T cell deficient mice and IL-17 deficient mice?
breast cacner mets and pancreatic intraepithelial neoplasia - correlates with increased angiogenesis due to increased VEGF
Give examples of how MDSCs act in a protumour way?
inhibit IFNy and CD8 T cell cytotoxicity
Where are yd T cells found in humans?
intestine and dermis
What do IL-17 producing yd T cells secrete that recruit MDSCs ?
IL-8; TNF and GM-CSF
How is IL-17 yd t cells related to human colorectal cancer?
major sourceo f IL-17 invovledi n chronic inflammation; IL-17 producing yd T cell infiltration positively correlated with clinical stage
What causes human yd T cells to produce IL-17?
reqruire a highly inflammatory milieu
Why is the concept of boosting type 1 cytotoxic yd T cells in patietns with cancer appealing?
indendent of MHC (tackles a common immune evasion mechanism) and of mutated epitopes (ideal effectors against tumours with low mutation loads)
Why are bisphosphonates given before yd T cell therapy?
interfere with phosphoantigen processing enzymes so increase the intracellular levels of them
What may limit the clinical performance of yd T cells in cancer therapeutics?
susceptibility to T cell exhaustion and activation induced cell death
What may the cause of increased IL-17 yd T cell in human colon cancer?
tumour-induced disruption of the piethlail barrier may induce release of commensal bacterial products leading to activation of DCs, production of IL-23 and differenation into IL_17 yd T cells
What is the name for the CTLA-4 mAb ?
ipilumumab (licensed for melanoma)
What was the problem with the early vaccine formulation using short peptides?
minimal clinical effectivenness- poor pharmacokinetics leading to rpaid lcearance before DCloading; didn’t have an effective DC activating adjuvant- just as likely to induce tolerance as immunity
What are the ideal tumour antigens for vaccination?
expressed in the target tumour population in a high number of patients with a cancer; expressed at low levels in normal tissues and should be essential for cancer survival to mimised immune escpe
How does onclytic virus therapy work?
employs native or engineered viruses that selectively replicate in and kills cancer cells
What are the mechanisms by whch oncolytic viruses function?
acute tumour debulking due to tumour cell infection and lysis, induction/initiation of systemic anti-tumour immunity- can be modified to express specific cytokines that favour immune cell recruitment or produce T cell costimuatlry moelcules on infected tumour cells
How can the oncolytic viruses avoid immune killing before they can replicate and infect tumour cells?
PEGylation of the viral coat and polymer coating-preventing antibody binding and neutralisation
What oncolytic virus has been approved by the FDC?
T-VEC- modified HSV-1 for advanced melonoma
What are the downsides with oncolytic therapy?
immunocompromised patients may not be good candidates as OV-mediated antitumour immunity could be compromised; efficacy in advnaced
What is the theory behind adoptive cell therapy?
circumvent the duty of breaking tolerance to tumour antigens and produce a large amount of high avidity effector T cells
When ahve autologous TIL infeusions been successful?
melanoma
Why is host lymphodepletion thought to improve ACT with TILs?
elimiates immunosuppressive cells- Tregs; MDSCs in tumour microenvironemnt and increasing IL-7 and IL-15
Why is there a high immunogenicity of melanoma compared with otehr malignancies?
high frequency of mutational events in the cancer
What are hte problems with TIL ACT?
cost; time; lymphodepletion can be life-threatening; only been efficacious in melanoma
