REVIEW SUMMARY
◥CANCER IMMUNOTHERAPY
Neoadjuvant checkpoint blockade for
cancer immunotherapy
Suzanne L. Topalian*, Janis M. Taube, Drew M. Pardoll
BACKGROUND:Immunotherapies that target
the interaction of programmed death 1 (PD-1)
with its ligands, PD-L1 and PD-L2, have ushered
in the modern oncology era. The PD-1 pathway
is a key mediator of local immunosuppression
in the tumor microenvironment (TME) but can
also modulate T cell priming against tumor
antigens in secondary lymphoid tissues. In
advanced inoperable cancers refractory to other
treatments, drugs that block the PD-1 receptor
on lymphocytes or the PD-L1 ligand on tumor
and/or immune cells [anti–PD-(L)1] can mediate
tumor regression. Although anti–PD-(L)1 treat-
ment is broadly active and is regarded as a
“common denominator”for cancer therapy,
many tumors demonstrate de novo or acquired
resistance. Using anti–PD-(L)1 therapies in the
neoadjuvant (presurgical) setting, when the tumor
is potentially“resectable for cure,”presents a
potential solution. There is ample oncologic
precedent for this approach with presurgical
chemotherapies in breast and lung cancer, as-
sociating pathologic response with improved
long-term clinical outcomes. Our Review focuses
on the development of neoadjuvant immuno-
therapies in the era of PD-1 pathway blockade,
highlighting particular considerations for im-
munological mechanisms, clinical development,
and pathologic response assessments.ADVANCES:The immunologic effects of the
PD-1 pathway on T cell priming, effector func-
tion, and exhaustion suggest distinct mecha-
nisms underlying neoadjuvant immunotherapy
versus chemotherapy. Whereas neoadjuvant
chemotherapy can“debulk”tumors preoper-
atively, neoadjuvant immunotherapy aims to
enhance systemic immunity against tumor
antigens, eliminating micrometastatic tumor
deposits that would otherwise be the source of
postsurgical relapse. Furthermore, neoadjuvant
PD-(L)1 blockade while the primary tumor is in
place, as opposed to adjuvant therapy directed
only against micrometastatic disease after re-section, leverages higher levels of endogenous
tumor antigen present in the primary tumor
to enhance T cell priming.
We discuss scientific evidence that supports
two different but not mutually exclusive mod-
els by which neoadjuvant
PD-(L)1 blockade may pro-
mote systemic antitumor
immunity.First,anti–PD-
(L)1 rejuvenates tumor-
specific cytotoxic T cells
that already reside in the
TME, causing their activation, proliferation,
and trafficking to micrometastatic deposits.
Second, tumor-draining lymph nodes (TDLN)
appear to be the focal point for anti–PD-(L)
1 activity, where dendritic cell presentation
of tumor antigens to T cells is enhanced; these
tumor-specific T cells then enter the bloodstream
and migrate to tumor sites. The destruction
of micrometastases is central to the notion that
neoadjuvant PD-1 blockade should result in
enhanced relapse-free and overall survival in
operable patients who would otherwise relapse
after surgery alone.
There is a strong rationale for evaluating
neoadjuvant immunotherapy across tumor
types. Presurgical drug administration provides
abundant on-therapy tissue for in-depth mech-
anistic and biomarker studies. We discuss data
from recent clinical trials of neoadjuvant anti–
PD-(L)1 that show that pathologic tumor re-
gression can outpace radiographic regression
and demonstrate the involvement of diverse
cellular subsets in this process.OUTLOOK:At present, more than 100 clinical
trials of neoadjuvant anti–PD-(L)1 blockade,
as monotherapy or combination therapy, are
ongoing or planned. Combining anti–PD-1 with
anti–CTLA-4 (cytotoxic T lymphocyte–associated
protein 4), or with multidrug chemotherapies
for triple-negative breast and lung cancer, has
yielded substantial pathologic response rates that
are encouraging but require longer follow-up.
Next-generation trials may help assign patients
to postsurgical observation or intervention de-
pending on the degree of pathologic response,
similar to the precedent established with non-
immunologic neoadjuvant therapies in breast
cancer. Tumors resected after neoadjuvant
immunotherapy provide sufficient materials
for in-depth scientific interrogations that are
expected to further illuminate mechanisms of
response and resistance, revealing pathways
and molecules that can be cotargeted in new
treatment combinations to increase the effi-
cacy of anti–PD-(L)1 therapy.▪RESEARCH
Topalianet al.,Science 367 , 525 (2020) 31 January 2020 1of1
The list of author affiliations is available in the full article online.
*Corresponding author. Email: [email protected]
Cite this article as S. L. Topalianet al.,Science 367 ,
eaax0182 (2020). DOI: 10.1126/science.aax0182Primary
tumorTumor
cellKillingAnti-PD-(L)1 Dendritic
cellT cellAfferent
lymphaticAnti-PD-(L)1Tumor
draining
lymph nodeEfferent
lymphaticBloodstreamMicrometastases
in tissuesTwo potential mechanisms for the enhancement of systemic antitumor T cell immunity after neoadjuvant
PD-(L)1 blockade.PD-(L)1 blockade could result in the“in situ”expansion of tumor-specific T cell clones already
within the tumor microenvironment. This expansion and activation is largely driven by PD-L1–and PD-L2–expressing
dendritic cells in the tumor. Tumor-specific tumor-infiltrating lymphocytes may represent naïve T cells or T cells that
have already been“primed”to tumor antigen before PD-1 pathway blockade. In addition, tumor antigen–containing
dendritic cells that originate in the tumor pick up tumorantigens and traffic to the tumor-draining lymph nodes,
where they present antigens either ineffectively or in a tolerogenic fashion to tumor-specific T cells. PD-(L)1 blockade
could act at this point, enhancing productive stimulation of tumor-specific T cells or partially reversing tolerance
induction. Activated T cells enter the circulation by way of efferent lymphatics and then egress into tissues.
ON OUR WEBSITE◥Read the full article
at http://dx.doi.
org/10.1126/
science.aax0182
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