MGY378 27: oncolytic viruses (OV)

first OV approved for head and neck cancers

adenovirus, 1960s China

OV principles

• target and destroy tumour cells w/o damaging healthy cells

  • direct lysing

  • activation of imm sys against tumour

• unarmed: virus without added genes

• armed: with added genes

  • engineered to deliver cytokines, antibodies, or other factors that are antitumour/ affect immunosuppressive tumour env

• target tumour independent of TAA expression patterns - target tumour directly

antitumour effects

• enhancing immunogenic cancer cell death

  • thru mutation of key genes in virus to make it replicate better in cancer cell

• enhancing TC effector activity

  • for presentation of TAAs so imm sys can recognise it

• enhancing APC functions

  • So TC come and destroy virus-infected cancer cell

• reversing TC exhaustion

  • production of anti-TC exhaustion cytokines

immune response against cancer

• ROS

  • from ER/ genotoxic stress

• TAA uptake

• CTL

• NK cell

antiviral vs antitumour immunity

why is antitumour immunity slower than antiviral immunity?

cancer progresses slower

problems with imm resp and OVs

• the virus is still a virus - imm sys can mount a response and get rid of it -- challenge

  • cannot repeat the dose - limits efficacy

• delivery: trying to deliver tumour in a specific area

  • ex: gliablastoma. BBB poses a challenge to viral delivery there

• u want a virus that can induce an imm response and kill tumour cells but it has to be attenuated

H101

• adenoV OV

• nasopharyngeal carcinoma

• combo w/ chemo

ECHO-7

• echovirus OV

• unresectable stage IIIB-IV melanoma

teserpaturev

• HSV1 OV

• glioblastoma

• following radiotherapy and temozolomide

nadofaragene firadenovec

• adenoV OV

• non-muscle invasive bladder cancer

T-Vec

• HSV1 OV

• recurrent melanoma

  • unresectable cutaneous & subcutaneous nodal lesions

• local treatment

• deleted y34.5 virulence gene → loss of ICP34.5

• deleted US12 gene

• eng to expr GM-CSF

Loss of ICP34.5 in T-vec

• In HSV infection, the host cell response w antivirals to shut off translation (p-lates eIF2a)

• ICP34 can overcome this by activating the phosphatase to remove the P from eIF2a so the virus can keep translating

• solution = get rid of ICP34

  • Cannot replicate in healthy cells, which have intact eIF2α pathways.

  • Can replicate in tumour cells, which often lack proper antiviral signaling (e.g., dysfunctional PKR pathway).

Loss of US12 in T-vec

• gene that blocks peptide presentation to MHC I so the virus doesn't show itself to imm sys

• knock it out so viral ag and TAAs are both shown better to the imm sys > viral-infected tumour cells get killed

GM-CSF in T-vec

recruits antitumour immune cells

T-vec stats

• if body has seen oncolytic virus before it will mount a response

  • works for both sero-ve and +ve, but sero+ve = more side effects

• 58% reduction compared to GM-CSF only (standard care)

• melanoma makes it so u can inject virus directly into site of tumour

• combo w/ PDL-1 inhibitor = checkpoint blockade → antitumour

RNA OVs

• RNA viruses kill tumours faster

  • replicate in cytoplasm

• but less tumour selective

• immune sys must clear in healthy cells

enveloped viruses as OVs

• less oncolytic

• more likely to be cleared by imm resp before showing activity

virus size for OV

• smaller viruses can diffuse thru tumour better

• but larger viruses have more transgene carrying capacity

ONYX-015 OV

• adenoV OV

• deleted E1B55kd gene

  • cannot degrade p53 → replicates better in p53-deficient cells (tumour cells)

• for head and neck cancers

added genes for cytokine delivery

• GM-CSF

• IFN

• IL12

• IL2

added genes for TAA presentation to imm sys

• CEA

• PSA

added immune checkpoint inhibitors

• PDL-1

• CTLA-4

added tumour suppressor genes

p53

added anti-angiogenesis component

anti-VEGF antibody

VSV & Newcastle Disease virus as OVs

• animal viruses, rare pre-existing immunity

• inducer of IFNs

• safe

• apoptosis/ necrosis of infected (tumour) cells release TAAs → antitumour TC activations

ARV-PB1

• avian orthoreovirus

• non-enveloped, dsRNA

• 10 segment genome

• low pre-existing immunity (distinct from human orthoreoviruses)

• syncytia formation (CPE) in infected (tumour) cells

ARV-PB1 gene segments:

• S1

• M1

• L1

from avian orthoreoviruses:

• S1: strain 128

• M1: GX110058

• L1: strain AVS-B

ARV-PB1 stats

• lot of replication in cancer cell lines → spreads to other cells

• expression of ISGs

• causes apoptosis of infected (tumour) cells

• injection didn’t kill healthy mice

• no pathology in healthy hepatocytes

limitations of OVs

• poor efficacy against solid tumours

  • physical barriers

• poor vascular/ lymphatic access may limit delivery

• pre-existing immunity

• solid tumours secrete immunosuppressive TGF-beta and IL10 → reduce immune cell recruitment

solutions to limitations

• prime-boost with different OVs to avoid nAbs against virus

• combo with radiation/ chemo → solid tumour becomes more permeable to OV

  • can combo with surgical resection too

• local delivery to solid tumours

combo T-vec & anti-PD1

• for surgically unresectable stage IIIB and IV melanoma

• response rate 68%

• no dose-limiting toxicity

combo T-vec & anti-CTLA4

• for stage IIIB and IV melanoma

• combo therapy = 39% response rate

  • OV alone = 18%