Science - USA (2021-12-10)

INSIGHTS | PERSPECTIVES

GRAPHIC: KELLIE HOLOSKI/

SCIENCE

science.org SCIENCE

However, the trial that best illustrates
both the promise and challenges of im-
munovirotherapy is the testing of T-Vec
with the anti-PD1 ICI pembrolizumab
(MASTERKEY-265, NCT02263508). T-Vec
is a genetically modified type I herpes sim-
plex OV with viral ICP34.5 and ICP47 genes
deleted, to enhance tumor tropism and
reduce neurovirulence, and encoding GM-
CSF. Despite T-Vec being clinically approved,
the phase 3 study in advanced melanoma
on which its approval was based pre-dated
widespread use of ICIs (and BRAF inhibi-
tors) in this disease and had subcutaneous
GM-CSF as its control arm. Nevertheless, a
randomized study of T-Vec with ipilimumab
(an anti-CTLA4 ICI) was promising ( 10 ), and
clinical analysis of the phase 1b lead-in stage
of the randomized pembrolizumab 6 T-Vec
study was also encouraging, with impressive
clinical responses ( 11 ).

Alongside clinical data from this early
stage of MASTERKEY-265, translational
readouts from 21 patients addressed the hy-
pothesis suggested by preclinical data (of
this and other ICI-OV combinations) that
the virus would turn the immunologically
“cold” tumor “hot” and thus prime for ICI
efficacy. “Heat” illustrates the variable level
of immune activation within a tumor and is
described using parameters such as PD-L1
expression, T cell infiltration, and interferon
gene signature. However, heat can denote dif-
ferent things, and there remains huge uncer-
tainty around its meaning and importance.
Heat could be of the wrong sort, reflecting
immune activation directed against the virus
rather than immunogenically weaker tumor
antigens. Heat also needs to be generated at
the right time as well as in the right place.
Measuring heat and how its different immu-
nological forms influence antiviral and anti-

tumor immune effectors is a critical area of

research that offers the potential to unleash

the real value of OV as an immunotherapy

(see the figure). However, as a biomarker,

immunological heat is currently of limited

practical use, with PD-L1 expression being

the only manifestation routinely tested and

used for clinical decision-making.

In the early stages of the MASTERKEY-265

trial, detailed patient sample analysis

showed that OV injection turned cold tum-

ors hotter ( 11 ). Unfortunately, however, the

later randomized phase 3 trial was stopped

because of clinical futility. Given the encour-

aging early clinical data, this setback re-

quires explanation. It may, again, be down to

the clinical context, in that a larger group of

melanoma patients, with limited metastatic

disease, did too well with single-agent pem-

brolizumab (with an expected 5-year survival

rate approaching 50%) for the addition of

T-Vec to make a significant difference. More

provocatively, there were subtle differences

in the protocols between the phase 1b and

3 stages of the trial, with T-Vec injections

starting 5 weeks earlier in phase 1b, before

pembrolizumab, whereas the two treatments

began at the same time in phase 3. Hence, in

the phase 3 component, the virus may not

have had time to heat up the tumor before

ICI treatment began. Whatever the reason,

this study illustrates, for OVs in particular

and immunotherapy more generally, how in-

formative immune analysis can be and that

the testing of a sufficient number of patients

within a consistent, clinically appropriate

trial setting is crucial.

Looking at immunotherapy more broadly,

the mechanistic basis of successful treat-

ments is incompletely understood and tar-

gets only a small fraction of the pathways

that are increasingly studied. For example,

stimulatory antibodies targeting positive im-

mune checkpoints, such as CD40 and 4-1BB,

have yet to show substantial clinical activity

despite preclinical promise, and this is also

true for small molecules targeting other

inhibitory immune targets, such as indole-

amine 2,3-dioxygenase (IDO) ( 12 ). Hence,

OVs are not alone in struggling to make the

transition from early- to late-stage trial suc-

cess and clinical adoption, although encour-

aging single-agent phase 1 studies of OVs

have recently been reported ( 13 , 14 ). These

trials involved clinically challenging meth-

ods of delivery, namely of a herpes simplex

OV through intratumoral catheters ( 13 ) and

neural stem cell delivery of an adenovirus in-

jected into the surgical resection cavity ( 14 ),

both in high-grade glioma. Limited, correl-

ative immune data were included in these

studies, but the challenge of therapy and

immune analyses in larger trials (in terms of

practicality and outcome) remains.

The progression of a drug from promis-

ing early-phase clinical and translational

data to more widespread application in pa-

tients is always challenging. For immuno-

therapy, this has been achieved for ICI and

chimeric antigen receptor (CAR)–T cells but

not yet for OVs, where the need for combina-

tion strategies to improve outcomes brings

complications. What is required is an imag-

inative and collaborative approach to ear-

ly-then-late–phase trials, perhaps focusing

on less immunotherapy-responsive diseases

than melanoma, such as microsatellite sta-

ble colorectal and ovarian cancer, or brain

tumors. Studies should maximize transla-

tional immune analysis to improve scientific

insights, which can then support larger tri-

als to determine true efficacy as well as re-

verse translation back to the laboratory for

truly iterative basic and clinical research.

Multiarm trials, which combine experimen-

tal arms in the same study, may be one way

to cover more ground faster, to fully realize

the potential of OVs as powerful and adapt-

able candidates to turn cold tumors hot, thus

improving the benefits of current immuno-

therapy for more cancer patients. j

REFERENCES AND NOTES

1. A. C. Filley, M. Dey, Front. Oncol. 7 , 106 (2017).


2. G. P. Dunn et al., Annu. Rev. Immunol. 22 , 329 (2004).


3. R. Garcia-Carbonero et al., J. Immunother. Cancer 5 , 71
   (2017).


4. C. J. Breitbach et al., Nature 477 , 99 (2011).


5. A. Samson et al., Sci. Transl. Med. 10 , 422 (2018).


6. L. Paz-Ares et al. N. Engl. J. Med. 379 , 2040 (2018).


7. S. J. Antonia et al., N. Engl. J. Med. 379 , 2342 (2018).


8. T. F. Cloughesy et al., JAMA Oncol. 6 , 1939 (2020).


9. M. Moehler et al., OncoImmunology 8 , 1615817 (2019).


10. J. Chesney et al., J. Clin. Oncol. 36 , 1658 (2018).


11. A. Ribas et al., Cell 170 , 1109 (2017).


12. G. V. Long et al., Lancet Oncol. 20 , 1083 (2019).


13. G. K. Friedman et al., N. Engl. J. Med. 384 , 1613 (2021).


14. J. Fa re s et al., Lancet Oncol. 22 , 1103 (2021).

10.1126/science.abk3436

Oncolytic viral infection
kills tumor cells, releasing
antigens and recruiting
innate eector cells.

At the lymph node, viral, self, and

tumor antigens are presented to naïve

and memory T cells, which, primed

and expanded, travel to the tumor.

Activated T cells inltrate the tumor, where

they recognize antigens and kill tumor cells.

This antitumor response can be boosted by

immune checkpoint inhibitors.

Dendritic

cell

Antigen

Memory

T cell

Naïve

T cell

Oncolytic

virus

Innate eector
cell

Tu m o r

cell

Immune

checkpoint

inhibitor

Oncolytic virus infection Immune checkpoint inhibition

Oncolytic viruses are multifaceted tumor killers
Oncolytic viruses delivered to the tumor not only kill tumor cells directly, but also potentiate antitumor
immune responses by releasing antigens and activating inflammatory responses. This may allow immuno-
logically “cold” tumors to become “hot.”

1326 10 DECEMBER 2021 • VOL 374 ISSUE 6573