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Paper 1: Specialist Themes > H3 - cancer immunotherapy > Flashcards

H3 - cancer immunotherapy Flashcards

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1
Q

what are some examples of CAR-T cell success stories?

A
  • CD-19-targeted CAR-Ts induce prolonged remission in R/R B cell lymphomas and B-ALL, some patients potentially cured
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2
Q

why does relapse occur in CAR-T therapy?

A

tumour cell intrinsic factors
* tumour heterogeneity + adaptability
* resistance to cell death

CAR-T cell factors:
* functional deficits + exhaustion
* limited persistance

TME factors:
* immunosuppresive milieu
* metabolic environment
* poor trafficking/infiltration

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3
Q

what are some broad strategies to overcome T cell relapse?

A
  • improve CAR design: dual or multi-targeted CARs
  • enhance CAR-T cell product: optimise manufacturing
  • modulate TME: combination therapies (ICIs)
  • novel constructs + combinations
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4
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A
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5
Q

what are CAR-T cells?

A

engingeered T cells which are designed to target specific antigens on cancer cells
* particualrly successful agaisnt haematological malignancies

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6
Q

how have cancer treatment strategies progressed?

A

from surgical resection -> radiotherapy -> chemo -> targeted therapies

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7
Q
A
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8
Q

what is an example of remarkable outcomes achieved in B cell malignancies?

A

CD19-targeted CAR-T cells induce prolonged remission in R/R B cell lymphomas and B-ALL [Larson 2021]

though 40-60% of patients relapse

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9
Q

wwhy does CAR-T cell relapse occur?

A

complex cross-interactions among CAR-T cells, tumour cells and the TME

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10
Q

what is an example of alternative splicing contributing to antigen-negative relapse?

A

Sotilo et al 2015
* alternative splicing of CD19 mRNA, specifically SRSF3-mediated exon 2 skipping, produced truncated CD19 variants that evade CAR-T recognition
* account for nearly half of CD19-negative relapses in study group
* the isoforms existed pre-treatment, reflect exisiting heterogeneity
* shows limitations of single-target therapy when multiple variants exist: can use multi-targeting to target heterogeneity

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11
Q

how does antigen escape/loss contribute to CAR-T relapse?

A

malignant cells lose expression of target antigen: major mechanism

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12
Q

with what frequency does antigen escape occur in some common cancers?

A
  • B cell lymphoma: 20-28% patients
  • B-ALL: 16-68%
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13
Q

what are some antigens proposed as options for dual antigen targeting with CD19?

A
  • CD20 and CD22, both expressed in malignant cells
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14
Q

what are trial results for CD19/CD20 dual antigen therapies?

A
  • data from 2 studies CD19/CD20 w R/R B cell lymphoma: 1 demonstrated no relapses owing to antigen loss, 1 out of 12 in the other study with biopsy sample available had antigen loss
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15
Q

what are trial results for CD19/CD22 dual antigen therapies?

A
  • 2 trials w R/R B-ALL
  • post-relapse biopsy smapling, reported loss of one or both antigens in 25-33% patients w relapse
  • one identified CD19 loss in 50% of patients w B-ALL

therefore this may not circumvent problem of antigen escape

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16
Q

How do genetic mutations cause antigen loss? studies?

A
  • under cytotoxic pressure from CAR-T cells, some tumour cells undergo 2ry gene mutations, can lead to functional antigen loss or inability of CAR-Ts to recognise antigen
  • e.g. antigenic epitope transformation, e.g. point mutations in CD19 exon 3 can affect epitope recognosed by CD19 CAR-Ts (like FMC63)
  • e.g. disturbance of antigen translocation
  • e.g. antigen endocytosis
  • e.g. truncation or loss of antigen expression via deletion
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17
Q

what do mutations in CD19 exons 2 and 4 lead to?

A

CD19 protein loss
Sotillo 2015

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18
Q

what do mutations in CD19 exons 2-5 lead to?

Study These Flashcards
A

induce loss of heterozygosity
* truncated protein that lacks functional transmembrane domain
* leads to irreversible CD19 surface antigen loss

Orlando 2018

CD19 exon 2 is confirmed to be essential for CD19 transcript integrity, frameshift mutation -> retention of intron 2 w nonsense codon

19
Q

what do mutations in CD19 exons 2 lead to?

Study These Flashcards
A

disrupt CD19 transcript integrity -> truncated variant

20
Q

what is a risk factor for relapse in multiple myeloma patients?

Study These Flashcards
A

deletion of BCMA gene
(in CAR-T anti-BCMA therapy)
da Via 2021

21
Q

what do mutations in exon 3 lead to?

Study These Flashcards
A

point mutation alters epitope recognised by CD19 CAR-T (FMC63) in high grade B cell lymphoma -> CD-19 +ve relapse
can be killed by CAR targeting alternative epitope 21d4
Zhang 2020

22
Q

why do genetic mechs of immune escape like loss of HLA alleles not affect CAR-T therapies?

Study These Flashcards
A

CAR-Ts act in MHC independent manner for antigen recognition

23
Q

why is CD-19 commonly targeted for CAR-T therapy?

Study These Flashcards
A
  • has lineage-specific expression (this is why B cell malignancies are easier to treat), expressed on all B cells including malignant ones, so does lead to B cell depletion
  • high and uniform expression on malignant B cells: close to 100% in malignant cells in B-ALL, a single CAR-T can potentially target the large proportion of tumour cells
  • CD19 not shed as soluble molecule, cannot ‘clog up’ the CAR-Ts in the bloodstream and cause off target effects
  • proven clinical efficacy: success in early phase clinical trials over a decade ago
24
Q

what does B-ALL stand for?

Study These Flashcards
A

B-cell precursor acute lymphoblastic leukaemia

25
what are shortfalls of exon deletion studies of CD19? what are alternatives?
* demonstrate power of sequencing to identify specific resistance mutations * tracking complexity across all tumour cells = challenging * alternative = circulating tumour DNA (ctDNA) to track multiple somatic mutations + monitor genomic evolution [**Scherer 2016**]
26
how can tumour cells switch phenotypes?
* **clonal evolution**: inherent heterogeneity of tumours from abberant differentitation: Darwinian evolution leads to shifts in predominant phenotype * **differentiation plasticity**: some cancer cells (w cancer stem cell properties) can dedifferentiate, leading to changes in surface antigen expression * **lineage switch**: convert to different lineage to initial diagnosis, specifically in leukemias, become CD-19-ve via leveraging inherent plasticity of haematopoietic cells * **adaptive immune resistance**: immune cells in TME release inflammatory cytokines which can trigger this * **genetic + epigenetic alterations**: cause loss/downregulation of tumour antigens, suppress/reactivate genes, alter immunogenicity * **alterations in ICs**: incr expression of PD-L1 to evade T cell attack * **metabolic reprogramming**: can create nutrient-deprived TME to inhibit immune cells + support survival of tumour cells w certain phenotypes
27
what can TNFa do to cause melanoma cells to adapt?
decrease expression of differentiation antigens e.g. gp100 * causes switching to less differentiated phenotype, akin to EMT seen in epithelial cancers
28
how can lineage switching be overcome to avoid CAR-T cell relapse?
target markers assocaited with alternative lineage e.g. CD70 or CD123 combined with CD19 [Ruella 2016, Yan 2020]
29
what did a genome-wide CRISPR screen by Singh 2020 identify?
impaired death receptor signalling in leukemia cells decided caused antigen-independent resistance by inducing CAR-T cell dysfunction
30
what did Yan 2022 report re apoptosis deficiency?
* apoptosis deficiency via NOXA loss contributes to resistance * pharmacological augmentation of NOXA with HDAC inhibitors sensitised tumour cells to CAR-T killing
31
what are intrinsic T cell factors that limit their efficacy?
* exhaustion, can come from chronic antigen exposure or tonic signalling * limited persistence
32
what are some studies linking T cell characteristics to CAR-T outcome?
* **Fraietta 2018**: epigenetic programs + chromatin accessibility alterations are linked to CAR-T exhaustion in ex vivo expansion * **Prinzing 2021**: seletion of DNMT3A in CAR-Ts prevented exhaustion in CLL (chronic lymphocytic leukemia) models * **Shao 2022**: inhibiting overactivated Ca signalling made CAR-Ts resistant to exhaustion provides molecular insights to exhaustion, but translating findings into superior clinical products = challenging
33
what are alternative strategies for optimised CAR-T cell design to avoid exhaustion?
* optimise CAR w costimulatory domains (OX40, ICOS, CD27) or cytokine expression (IL-15, IL-7 + CCL19) to enhance persistance [**Chen 2019, Sun 2021**] * optimise manufacturing protocols to shorten culture times or select less-differentiated phenotypes [**Gennert 2021**]
34
what is the percentage of CD19+ relapses which are due to short in vivo CAR-T persistance?
33-78% B cell recovery within 6 months is a marker for poor persistance and increased relapse risk
35
break down **Myers et al 2024** wrt CAR-T reinfusion, to combat limited CAR-T persistance
* reinfusion of CAR-T in R/R/ B-ALL patients receiving inital CD19 CAR-T * CARTr investigated for relapse prevention, relapse, or nonresponse * responses seen in 52% for relapse prevention, 50% for relapse and 0% in group with initial nonresponse * CARTr = well tolerated and did not preclude subsequent therapies * potentially clinically meaningful reduction in incidence of relapse/death in responders * **limitations**: though is retrospective study, could use allogenic cells from healthy donors have also been studies with suboptimal outcomes in adult lymphoma [**Gauthier 2021**]
36
what is a common CD19 CAR-T?
* CTL019/tisagenlecleucel * huCART19
37
how does the TME inhibit CAR-T function?
* inhibitory cells (Tregs, MDSCs (myeloid-derived suppressor cell), TAMs (tumour assoc macrophages)) * soluble factors (TGFb) * checkpoint ligands (PD-L1) cold tumours lacking T cell infiltration are resistant to immunotherapy
38
what are strategies to counteract immunosuppression?
**Liu 2021** engineered CD19 CAR-T expressing PD-1/CD28 chimeric switch receptor * converted PD-1 signalling (inhibitory) into activating CD28 signal -> superior T cell function against PD-L1+ B cell lymphoma in vitro + vivo switch receptors need large-scale validation, this small study had some toxicities other strats: * combine CAR-T w ICIs like anti-PD-1 * engineer CAR-Ts to secrete ICI blocking antibodies * could make TME hotter by increasing infiltration
39
how does hostile metabolic TME compromise CAR-T function?
**Fultang 2020**: T cells suceptibel to low arginine TME as have low arginine resynthesis enzymes. metabolic engineering enhanced CAR-T proliferation * small molecule drugs could be used to modify environment or reverse exhaustion * single-cell omics used to map metabolic landscape of TME [**Artyomov 2020**]
40
how might we be able to improve T cell infiltration to cold tumours?
* **Biondi et al 2021**: overexpressing CXCR4 in CD33 CAR-Ts improved homing to bone marrow in preclinical model * highlights that chemokine axes influence trafficking * CAR-Ts will need to be engineered to express specific chemokine receptors to target tumour sites, remodel TME and enhance infiltration
41
how can we improve CAR-T design?
* develop dual or multi-targted CARs to prevent antigen escape * novel costim domains or cytokine expression to enhance persistance * counteract TME suppresion via switch receptors, or intrinsic inhib receptor KO *
42
how to enhance CAR-T cell product?
* optimise manufacturing, select phenotypes assocaited with better persistence * explore allogenic CAR-Ts as a more robust effector
43
how can we engineer CAR-Ts to modulate TME?
* employ combination therapies. CAR-T w ICIs, or small mols * use conventional radio or chemo, or oncolytic viruses to remodel cold tumours and enhance immunogenicity before CAR-T infusion
44
what possible nvoel constructs are there for CAR-Ts?
develop CAR-Ts which can secrete BiTEs [Choi 2019] investigate combinations to activate endogenous IR alongside CAR-T therapy

Paper 1: Specialist Themes (14 decks)

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