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biology of cancer > Immunotherapy and cancer II > Flashcards

Immunotherapy and cancer II Flashcards

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1
Q

what are some cell based therapies for cancer?

A
  • LAK; lymphokine activated killer
    -NK-T CELLS
  • yd T cells
  • DC
  • TIL: tumor infiltrating lymphocyte
  • CAR: chimeric antigen receptors
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2
Q

LAK cells features

A
  • PBMC taken from patients and cultures with IL2 invitro
  • Heterogenous population
  • NK, NKT & Tcells (CD25+)
  • predominantly NK cells
  • higher than normal anti-tumor activity
  • can target NK resistant tumor cells
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3
Q

natural killer cells

A
  • recognise lack of MHC1
  • about 5-10% of human peripheral blood lymphocytes
  • majority are CD3- CD56+
  • primarily found in blood, BM, spleen and liver
  • main cell type in LAK population
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4
Q

LAK cells and cancer

A
  • relatively easy to produce in large numbers
  • simple activation of a cell subset
  • limited specificity
  • localise to tumor sites
  • many need additional IL2 to maintain activation
  • toxicity, capillary leak syndrome
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5
Q

what was the Rosenberg Trial of 1993?

A
  • used LAK cells and IL2
  • 181 patients with advanced (metastatic) cancer (97 renal and 54 melanoma)
  • 10 complete responses in LAK+IL-2 group compared with 4 in the IL2 alone group
  • overall result was a trend towards increased survival with LAK
  • many toxic effects due to vascular permeability
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6
Q

NK-T cells

A
  • subpopulation of T cells
  • found in thymus, liver and BM, few found in spleen or lymph nodes
  • some inhibitory and activation receptors shared with NK cells
  • can kill tumor target cells in vitro; mainly through TCR and CD16
  • ability to produce cytokines to direct immune response
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7
Q

NK-T recognition

A
  • MHC independent
  • NKT cell TCR recognises the MHC-I like molecule , CD1d
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8
Q

CD1d

A

-relatively nonpolymorphic
- restricted distribution on cells of the haematopoietic lineage
- present glycolipids
- synthetic a-GalCer used to study NKT cells
- unknown whether tumors express glycolipid ligands that stimulate NKT cell activity

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9
Q

NKT immunotherapy

A
  • a-galactosyl ceramide
  • used for invitro expanded NKT based vaccines
  • used a-galcer pulsed DCs
  • well tolerated
  • induce expansions of NKTs in vivo
  • some stable disease in a variety of cancers
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10
Q

role of NKT

A
  • MOA; unknown but may be linked to yIFN production
  • study in lung cancer = treatment with a-GalCer loaded DCs = increase NKT TILs
  • resected tumor 1 week after APC injection
  • showed increased y-IFN in response to a-GalCer exvivo
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11
Q

the yd T cell features; structural

A
  • TCR structurally similar to ab
  • may not need normal AP mechanism
  • may not recognise peptides and therefore no need for protein processing
  • may detect stress or small organic molecules which signify infection
  • can respond to MICA and MICb expressed on stressed cells
  • can recognise small organic molecules secreted by bacteria
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11
Q

yd Tcell; association with cancer

A
  • primitive T cell in the mucosa
  • can directly target a range of tumor cells but also been identified in TIL
  • suggested to target cancer stem cells
  • can directly target bacteria
  • thought to recognise endogenous pyrophophonates
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12
Q

what is zometa (zoledronic acid)?

A
  • amino bisphosphate used in osteoporosis
  • blocks mevalonic acid pathway (HMG-CoA to cholestrol)
  • allows build up of isopentenyl pyrophosphate
  • zometa has been used in prostate and breast cancer
  • look at effector cells
  • reduced yd T cells in PB of patient receiving treatment
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13
Q

yd T cell therapy

A
  • ex vivo activation trialled in RCC in combination with low dose IL2 =stable disease
  • also trialled in NSCLC
  • in vivo activation use of zometa or lymphostimulatory regimes.
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14
Q

what is therapeutic vaccination?

A
  • to induce long lasting reponse against tumor
  • stimulate adaptive arm of the immune response
  • use professional APC such as DCs
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15
Q

explain priniciple of DC vaccination

A
  • vaccination of patient with mature APC DCs
  • isolation of monocytes from peripheral blood
  • generation of immature DCs
  • loading of DCs with whole cell tumor-lysate
    process repeats
16
Q

what is antigen loading?

A
  • defined tumor antigens; at least 4 different peptide targets needed
  • undefined tumor antigens; DC-tumor cell hybrids, tumor cell lysates, nectrotic/apoptotic tumor cells, tumor RNA
17
Q

targetting DC in vivo

A
  • use chimeric proteins to deliver antigens to DC specific molecules
  • Ag linked to CD205. MHC1 and MHC2 presentation
  • need to understand consequences of ligating these surface molecules
18
Q

endogenous vaccination

A
  • immunogenic chemotherapy
  • radiotherapy
  • anti-tumor antibodies
  • T cell immune checkpoint blockade
19
Q

Ex vivo generated cytokine-driven DCs

A

ex vivo instruction to generate and maintain cytotoxic effector and helper T cells

20
Q

reprogramming inflammation

A
  • targetting DCs with TLR ligands
  • cytokine blockade
21
Q

targeting antigens to DC subsets in vivo

A

DC antibody linked to pathogen and/or cancer specific antigens and DC activators

22
Q

why is manipulaiton of TILs important?

A

presence of lymphocytes has prognostic significance

23
Q

why does the presence of lymphocytes have prognostic significance?

A
  • large numbers of TILs in many tumors
  • high number of CD8+ cells has prognostic significance
  • high CD8+/Treg ratio
  • pre exisiting antigen specificity of TILs has been correlated with outcome in immunotherapy of melanoma
24
Q

methods of adaptive cellular therapy with TILs

A

assumes that TILS already have knowledge of transferred T-cells:
- tumor biopsy
- in vitro polyclonal stimulation (IL2 and anti CD3 antibody)
- lymphodepletion of patient (enhances persistence of transferred T cells)
- stimulated T cells reintroduced into the patient

25
Q

results of adaptive cellular therapy with TILs

A
  • cytotoxcitiy against tumor cells in culture
  • homing of transferred T cells to tumor in vivo
  • > 50% objective response rate
  • best results when patients are pre-treated with peripheral lymphodepletion regimen of total body irradiation (improved survival benefit)
25
Q

disadvantages of adaptive cellular therapy (ACT) with TILs

A
  • need enough tumor to generate sufficient CTLs
  • TILs may be refractory to stimulation
  • time consuming and labor intensive; requires infrastructure
  • culture time may be too long
  • culture time MAY influence quality of T cells
  • high failure rate of culture
26
Q

ACT using peripheral blood derived T cells

A

results in clonal expansion against a known antigen
- advantage of easy availibility of large numbers of T cells
- peripheral blood contains many precursors with TAA reactivity

27
Q

method of ACT using peripheral blood derived T cells

A
  • isolte peripheral blood
  • stimulate in vitro with autologous DC + antigen
  • grow out tumor reactive clones/ polyclonal pool
  • used extensively for treatment of post-transplant lymphoprolifrative diseases
  • used in haematological malignancies; some success
  • cloning and culture take time
28
Q

what is high affinity TCR

A

ability of T-cells to detect antigens at low densities

29
Q

high affinity TCR reduction

A
  • TCRs reactive to TAAs characterised and cloned
  • a and b chains to TCR are engineered into retroviral vector
  • patients CD8+ T cells from peripheral blood are removed and transduced with TCR virus
  • adoptive transfer back into patients
30
Q

problems with high affinity TCR reduction

A
  • initial results 2/15 patients with clinical response
  • T cells remain in peripheral blood for up to 1 yr
  • epitopes need to be characterised and matched to HLA
  • must be present in tumor
  • becomes patient specific therapy
31
Q

what are CARs?

A

chimeric antigen receptors
- similar in nature to TCR transgenics but not MHC restricted

31
Q

what are CARs composed of?

A
  • antibody recognition domains
  • cytoplasmic tail with multiple signalling domains that activate T cells
32
Q

disastrous case study using CARs

A
  • patient with colon carcinoma
  • CAR against Erb-B2
  • patient developed acute autoimmune response
  • possible due to low levels of antigen on lung epithelium
33
Q

lymphodepletion

A

a treatment to reduce the population of circulating lymphocytes, prior to infusion of TCR-T cells

34
Q

how is lymphodepletion achieved?

A

drugs such as Fludarabine and cyclophosphamide.
- TRI; total body irradiation

35
Q

what does lymphodepletion do?

A

removes T cells that compete for homeostatic cytokines and =
- increased prolif. & acquisition of effector functions for infused cells
- increased expression of serum IL7 and IL15
- may enhance APC function
- reduces number of circulatory regulatory cells

36
Q

what is the best phenotype for a T cell in ACT?

A
  • CD4 or CD8
  • naive

biology of cancer (13 decks)

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