Science - USA (2021-12-10)

SCIENCE science.org

By Alan Melcher^1 , Kevin Harrington^1 ,

Richard Vile^2

O

ncolytic virus (OV) therapy is now

something of a misnomer. The initial

paradigm was that naturally occur-

ring or genetically engineered viruses

would preferentially infect, replicate

in, and lyse cancer cells relative to

normal cells, leading to selective direct cy-

totoxicity. The immune system used to be

considered detrimental, given its potential to

recognize and respond to the virus, prevent

its replication, and limit viral spread and tu-

mor cell killing ( 1 ). This view has now been

largely replaced by a model in which infec-

tion of the tumor by the virus makes it more

visible to the immune system for recognition

and attack. Tumor cell killing by the virus

and/or immune effector cells effectively gen-

erates an in situ vaccine, with tumor antigens

released into a microenvironment modified

by viral infection to reverse tumor-induced

immune suppression.

By 2020, there were ~100 reported clini-

cal trials using OVs, treating more than 3000

cancer patients. Approvals were granted in

different countries for picorna-, adeno-, and

herpes viruses, although only one agent

was approved by the US Food and Drug

Administration (FDA). The growing rec-

ognition of the immune basis of oncolytic

virotherapy coincided with the success of

immunotherapy in the clinic, particularly

immune checkpoint inhibitors (ICIs), which

block negative regulatory elements that

control immune tolerance, specifically the

programmed cell death protein 1 (PD-1) axis

and cytotoxic T lymphocyte–associated an-

tigen 4 ( CTLA-4). These drugs revealed that

the immune system can and does respond

to cancer, but tumors evolve to escape im-

mune detection through immunoediting ( 2 ).

However, if the immune system can be reen-

ergized and reactivated, immune control of

the tumor can be reestablished.

The number of OVs being tested in pre-

clinical models, with a particular focus on

their immunogenicity, has since increased.

However, in some ways the field has been

struggling with an embarrassment of (po-

tential) riches. It has been unclear how to

prioritize the most promising preclinical

agents to take forward to clinical testing.

Additionally, how to accurately measure

the immunogenicity of tumor cell death

after OV infection—particularly for viruses

that do not readily infect mouse cells (e.g.,

coxsackie virus, adenovirus, and measles vi-

rus) and so cannot be tested reliably in pre-

clinical models—has been a challenge. The

variety of OVs covers DNA, single-stranded

RNA (ssRNA), and double-stranded RNA

(dsRNA) viruses, and the immunobiologi-

cal consequences after infection of tumor

and/or other cells varies, including the sig-

naling pathways activated, such as retinoic

acid–inducible gene I (RIG-I)–like recep-

tors for viral RNA and the cyclic GMP–AMP

synthase (cGAS)–stimulator of interferon

genes (STING) pathway for cytosolic DNA.

The degree to which these pathways remain

intact within cancer cells, and the relative

contribution of the response to infection of

nonmalignant cells in the tumor microen-

vironment (such as cancer-associated fibro-

blasts, endothelial cells, macrophages, and

other immune cell subtypes), adds further

complexity to understanding how tumor

immunogenicity is generated by OVs.

Much current work is focused on the abil-

ity to genetically modify OVs to encode trans-

genes, such as cytokines, ICIs, tumor-associ-

ated antigens, bispecific T cell engagers, and

microRNAs, as payloads to boost the antitu-

mor immune response. However, the choice

of these encoded transgenes has often been

based on limited mechanistic understand-

ing. For example, granulocyte-macrophage

colony-stimulating factor (GM-CSF) is ex-

pressed in many OVs being clinically tested,

even though the evidence supporting the

benefit of virally encoded GM-CSF is limited.

A further challenge is the inevitable antiviral

(alongside antitumor) immune response acti-

vated by treatment. Even if viruses to which

patients have not been previously exposed

are used, neutralizing antiviral antibodies

(NAbs) will increase with treatment, poten-

tially compromising repeat administrations,

particularly if the route of administration is

systemic. Even though intravenously deliv-

ered OVs (e.g., adenovirus and vaccinia virus)

can infect tumors in patients ( 3 , 4 ), despite

the presence of NAbs in the case of reovirus

( 5 ), concerns about sufficient delivery to tu-

mors have led to the administration of many

OVs—including talimogene laherparepvec

(T-Vec), a clinically approved OV for the

treatment of advanced melanoma—being re-

stricted to direct intratumoral injection.

The rapid expansion of ICIs into the clinic

has affected the development of OVs and

other immunotherapeutics in unexpected

ways. Usually, advances in the clinic lag years

behind the laboratory discoveries that under-

pin them, but this has reversed. To improve

on the benefit from ICIs, which remains lim-

ited to an overall response rate of only 10 to

15% of all cancer patients (although this is

higher in certain tumor types and some pa-

tient groups), combination strategies have

been empirically tested without sufficient

understanding of the immunobiology of why

they might (or might not) work. Trials of ICI

combinations with chemotherapy or radio-

therapy are relatively easy to design because

the ICI is added to current standard-of-care

regimens, and such trials have met with con-

siderable success ( 6 , 7 ). However, immuno-

therapy-OV combinations have so far been

disappointing. In almost all such studies, the

collection and analysis of patient samples

has been inadequate and/or unreported, so

it remains generally unknown why combina-

tions, which showed promise in preclinical

models, have failed to translate into patient

benefit. This lack of correlative, translational

data particularly applies to negative trials

(which are at least as important, in terms of

mechanistic understanding, as positive stud-

ies), leaving the immune changes that occur

in patients after treatment unknown.

There have been few large, randomized con-

trolled trials including OVs so far, and those

that have been reported have been discour-

aging. A study of vocimagene amiretrorepvec

(TOCA 511), a replicating retrovirus encoding

cytosine deaminase, which converts the pro-

drug 5-fluorocytosine into 5-fluorouracil,

failed in a phase 2/3 study of direct injection

into the surgical cavity on first or second re-

section of high-grade glioma, randomized

against standard of care ( 8 ). A second phase

2b study involving pexastimogene devacire-

pvec (Pexa-Vec), a vaccinia virus encoding

GM-CSF, was also unsuccessful when tested

in sorafenib-refractory hepatocellular carci-

noma (HCC) ( 9 ). Both studies have plausible

explanations for their lack of success. In the

TOCA 511 study, patients had fewer treat-

ment cycles than in earlier phase trials, and

for Pexa-Vec, the poor responses of advanced

HCC are notoriously difficult to reverse.

CANCER

Oncolytic virotherapy as immunotherapy

Recognizing immune responses to oncolytic virotherapy opens the way for new combinations

(^1) The Institute of Cancer Research, London, UK. (^2) Mayo
Clinic, Rochester, MN, USA. Email: [email protected];
[email protected]; [email protected]
10 DECEMBER 2021 • VOL 374 ISSUE 6573 1325