inmunoterapia

1. REVIEW ARTICLE – TRANSLATIONAL RESEARCH AND BIOMARKERS
An Update on Immunotherapy for Solid Tumors: A Review
Toan Pham, MBBS, BMedSc, PGDipSurgAnat, FRACS1,2,3,4
, Sara Roth, BSc, MSc, PhD1
,
Joseph Kong, MBChB, MS, PhD, FRACS1,2,3,4
, Glen Guerra, MBBS, PGDipSurgAnat, FRACS1,2,3,4
,
Vignesh Narasimhan, MBChB, FRACS1,2,3,4
, Lloyd Pereira, BSc (Hons), PhD1
, Jayesh Desai, MBBS, FRACP3
,
Alexander Heriot, MB, BChir, MA, MD, MBA, FRACS, FRCS (Gen.), FRCSEd, FACS, GAICD1,2,3,4
,
and Robert Ramsay, BSc (Hons), PhD1,5
1
Divisions of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; 2
Cancer Surgery, Melbourne,
VIC, Australia; 3
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia;
4
Department of Surgery, University of Melbourne, Melbourne, VIC, Australia; 5
Department of Pathology, University of
Melbourne, Melbourne, VIC, Australia
ABSTRACT In recent years, it has been demonstrated
that immunotherapy is an effective strategy for the man-
agement of solid tumors. The origins of immunotherapy
can be traced back to the work of William Coley, who
elicited an immune response against sarcoma by injecting
patients with a mixture of dead bacteria. Significant pro-
gress has been made since, with immune markers within
the tumor now being used as predictors of cancer prognosis
and manipulated to improve patient survival. While surgery
remains central to the management of most patients with
solid malignancies, it is important that surgeons consider
the different immunotherapy strategies that can be
employed to manage disease. Here, we highlight how the
immune system influences tumorigenesis and bring atten-
tion to how current and future immunotherapies can serve
as an adjunct to surgery.
Cancer is the leading cause of mortality worldwide,
being responsible for 8.8 million deaths in 2015.1
Despite
advances in prevention, screening, and diagnosis of cancer,
the landscape of cancer treatment has been altered by the
advent of immunotherapy, offering improved survival in
several solid cancers and establishing itself as a new
therapeutic modality.2
The concept of exploiting the host immune system to
eradicate cancer was first conceived by William Coley. In
pioneering work, a mixture of attenuated bacteria was
injected into patients in order to elicit an immune-mediated
response against sarcoma.3,4
However, significant advances
in cancer immunology have only been achieved in recent
years, with immunotherapy demonstrating clear efficacy in
clinical trials, and a synergistic effect when used in
combination.5,6
In this review, we delineate the relationship between
cancer and the immune response and discuss how this has
been used as a basis for immunotherapy. As personalized
medicine begins to enter the domain of all oncology spe-
cialties, an awareness of available therapies is important,
allowing surgeons to provide the most up-to-date care for
their patients.
THE IMMUNE SYSTEM AND PROGNOSIS:
A NOVEL STAGING SYSTEM
Our immune system continuously protects us against
environmental pathogens and malignant cells (Fig. 1).
However, malignant cells can acquire the capacity to evade
the action of the immune system and form cancer7
.
A seminal publication by Galon et al.8
demonstrated that
low infiltrating cytotoxic (CD8?
) and memory (CD45RO?
)
lymphocytes predict early relapse in colon cancer (CC). This
led to a new scoring system called Immunoscore (IS),9–11
which has been evaluated in 1336 stage I–III CC patients
and further validated in 2681 patients by an international
Toan Pham and Sara Roth have contributed equally to this study and
are co-first authors.
Ó Society of Surgical Oncology 2018
First Received: 27 February 2018
T. Pham, MBBS, BMedSc, PGDipSurgAnat, FRACS
e-mail: toan.pham@petermac.org
Ann Surg Oncol
https://doi.org/10.1245/s10434-018-6658-4

2. consortium. Both studies concluded that high IS is associ-
ated with longer recurrence-free survival.11,12
Moreover, IS
was able to identify high-risk patients (low IS) within
American Joint Committee on Cancer (AJCC) stage II CC,
thus making IS a powerful biomarker tool to stratify patients
to adjuvant chemotherapy. IS was translated to other tumor
types including gastric cancer13,14
and melanoma,15
in
which patients within the same tumor–node–metastasis
(TNM) stage could be stratified with enhanced accuracy to
predict long-term outcomes. Hence, IS is expected to
become a new component of the AJCC TNM system.
CANCER IMMUNOTHERAPY STRATEGIES
In cancer immunotherapy, the host immune system is
used to target and eradicate cancer cells.3,16
Tumors
express neoantigens that can be recognized as foreign by
the immune system and increase the level of T-lympho-
cytes infiltrating the tumor (TILs). This relationship can be
further described by the concept of immunoediting, which
forms the basis of modern cancer immunology research.17
In this paradigm, elimination, equilibrium, and escape are
key components. Elimination is the recognition and
destruction of tumor cells by the immune system. Subse-
quently, through immunoediting [e.g., expression of
immune checkpoints, loss of major histocompatibility
complex (MHC) expression, and/or upregulation of
T-regulatory cells], tumors create a sanctuary against the
immune system, thereby establishing an equilibrium
between tumor growth and immune destruction. In this
context, tumors escape immune control when the degree of
immunoediting allows for unchecked proliferation. This
model is underpinned by the close interaction between the
immune system and cancer cells, thus our understanding of
this relationship is an important component in the devel-
opment and considered use of immunotherapy. An outline
of the main classes of immunotherapy is shown in Fig. 2
and further described under each subheading below.
Immune Checkpoint Inhibitors: Reactivation of Tumor-
Infiltrating T-Cells
Immune checkpoints are the body’s natural brakes to
dampen the immune response and prevent autoimmunity.
Tumor cells can exploit this avenue to escape the immune
system by expressing complementary molecules that
interact with T-cells, rendering them incapable of killing.
Hence, these immune checkpoints [e.g., programmed cell
death (PD)-1, PD-L1, cytotoxic T lymphocyte-associated
antigen (CTLA)-4] form therapeutic targets.
The first immune checkpoint inhibitor (ICI) discovered
was ipilimumab (Bristol-Myers Squibb), an anti-CTLA-4
Innate Immune System
Microbes
Complement
system
Dendritic cell B cells Antibodies
T cells
Effector T cells
Blood vessel
NK cell
Infected/
transformed cell
Infected/
transformed cell
Granulocytes Monocytes/
Macrophages
Skin barrier
Hours Days
Adaptive Immune System
FIG. 1 Overview of the immune system: the immune system is
divided into the innate and adaptive arms. The innate system responds
rapidly to a conserved repertoire of pathogenic antigens, whereas the
adaptive system mounts a specific and memory response that initially
requires 4–7 days to develop
T. Pham et al.

3. antibody.18
It was first approved for the treatment of
unresectable metastatic melanoma, and the results were
encouraging with median overall survival of 10.1 months
versus 6.4 months in the control group.18
This equated to
improved 1- and 2-year survival rates of 46 versus 25 %
and 24 versus 14 %, respectively.18
Despite its promising
therapeutic efficacy, there were significant side effects,
including diarrhea (41.4%), colitis (15.9%), and endocrine
disorders (37.6%), and five on-trial mortalities.19
As such,
ipilimumab is now used as second-line therapy or in
combination with another ICI.
Pembrolizumab (Merck & Co.) and nivolumab (Bristol-
Myers Squibb) are the first two Food and Drug Adminis-
tration (FDA)-approved ICIs that block the interaction
between PD-1 (expressed by T-cells) and its ligands PD-L1
and PD-L2 (expressed by tumor and myeloid cells).20
These therapies have similar efficacy and long-term out-
comes to anti-CTLA-4 therapy but without significant side
effects,21
thus gaining FDA approval following landmark
clinical trials for melanoma (KEYNOTE-002),22
non-small
cell lung cancer (KEYNOTE-010),23
microsatellite unsta-
ble/mismatch repair gene deficient colorectal cancer,24
and
gastric cancer (KEYNOTE-059).25
Recently, combination anti-PD-1 and anti-CTLA-4
therapies in treatment-naı̈ve metastatic melanoma
(CHECKMATE-067)5
have demonstrated a synergistic
survival advantage over either monotherapy.5
Conse-
quently, pembrolizumab is now being tested with a variety
of other drugs, including molecular targeted therapies, such
as dabrafenib and trametinib, in BRAF-mutant advanced
melanoma (KEYNOTE-022).26
Expanding an Existing Immune Response: Adoptive
Cellular Therapy
Another emerging immunotherapy is adoptive cellular
therapy (ACT), where tumor-specific lymphocytes are
extracted from peripheral blood or resected tumors and
expanded ex vivo. These lymphocytes are then reintroduced
into the patient with or without systemic lymphodepletion
therapy. The Surgery Branch of the National Cancer Insti-
tute, led by Steven Rosenberg, has been at the forefront of
this therapy, with first successes in melanoma27,28
and cur-
rent clinical trials targeting other malignancies including
head and neck,29,30
renal cell,31
and gynecological can-
cers.32,33
Recent trials have explored the combination of
ACT with BRAF inhibitor34
and PD-1 ICI.35
ACT has even
led to an additional indication for metastasectomy which was
once considered futile, now a potential source for tumor-
specific lymphocytes used in ACT.36
a b
Dying
tumor cell
Granzyme
& perforin
Cytotoxic
T-cell
Cytotoxic
T-cell
Cytotoxic
T-cell
Cytotoxic
T-cell
Cytotoxic
T-cell
NK cell
CAR T -cell
CAR T -cell
Antigen
presenting cell
Oncolytic
virus
Radiation
Neoantigen induced
cytotoxic T-cell
Cytotoxic
T-cell
MDSC
Treg
MHC class I
presentation
Resistant
tumor cell
Tumor
surface protein
Immune
checkpoint
receptor/
ligand
interaction
Immune
checkpoint
inhibitor
Vaccine induced
cytotoxic T-cell
Recognition and Elimination
Of Malignant Cell
Radiation or Oncolytic Virus
induced Tumor Neoantigen
Adoptive CAR T-cell therapy
or Cancer Vaccination
Administration of Immune
Checkpoint Blockers
Adoptive CAR T-cell or NK cell
therapy
Depletion or Suppression of
MDSC and Tregs
Low Immunogenicity of
presented Antigen
Expression of Immune
Checkpoints
Downregulation of MHC
Class I Expression
Suppression by MDSC or
Tregs
c
NORMAL
IMMUNOSUPPRESION
THERAPY
OPTONS
FIG. 2 Tumor ‘‘escape’’ mechanisms (pink) and associated
immunotherapy counterstrategies (green): a normal recognition of
transformed cells by MHC class I presentation of tumor-associated
antigen and subsequent destruction by specific cytotoxic T-cells
(blue); b malignant cells escape immune recognition by low
immunogenicity of the presented antigen, expression of immune
checkpoints, downregulation of MHC class I, and generation of an
immunosuppressive microenvironment; c current immunotherapies
counteracting these evasion mechanisms via increasing the tumor-
specific antigens (radiation, vaccination, oncolytic viruses), immune
checkpoint blockade, CAR T-cells, and NK cell therapies, and
elimination of immunosuppressive microenvironment
Immunotherapy for Solid Tumors: A Review

4. Enhancing the Immunological Profile of Solid Tumors
Tumors with sparse TILs typically have low mutational
burden and consequently low neoantigen load. In order to
address this subset of challenging cancers, immune-based
strategies such as radiotherapy, oncolytic viruses, and
cancer vaccines have been developed to enhance the
immune recognition of these tumors.
Radiotherapy Radiotherapy can induce antigen expression
through tumor cell death and upregulation of MHC class I on
surviving tumor cells, both increasing their susceptibility to
cytotoxic T-cell killing.37
Single high-dose (5–10 Gy) or
hypofractionated (3 9 8 Gy) radiotherapy induces a
proinflammatory response that may result in an abscopal
effect,38
which is most pronounced in immunogenic tumors
including renal cell carcinoma (RCC), melanoma, and
hepatocellular carcinoma (HCC).39
Several clinical trials
are now investigating the combination of radiotherapy and
immune checkpoint inhibitors,40
because radiation has been
associated with PD-L1 upregulation.41
Oncolytic Viruses Oncolytic viruses (OV) are genetically
engineered or naturally occurring viruses that selectively
replicate in and kill cancer cells without collateral damage
to normal tissues. The release of antigens from the lysed
cancer cell enhances immune recognition and triggers
further immune-mediated destruction.42
The tumor
specificity of OV can be attributed to multiple factors
including the virus’s tropism for specific tissue type,
downregulation of the antiviral response of cancer cells,
and/or engineered enhancements to the virus to exploit the
different intracellular milieu of cancer cells.43
OV can also
be ‘‘armed’’ with genes encoding for immunodulators such
as granulocyte-macrophage colony-stimulating factor
(GM-CSF) or tumor-associated antigens to further
enhance their function.43
The first OV approved by the FDA was T-Vec, an
oncolytic herpes simplex virus type 1 armed with GM-
CSF, for the treatment of advanced melanoma.44
Further
oncolytic viruses such as Pexa-Vec against hepatocellular
carcinoma, G47D against glioblastoma and prostate cancer,
and CG0070 against bladder cancer show promising
results.43,45
The main disadvantage of OV is the acquired specific
immunity against the virus that effectively neutralizes any
repeat therapy. However, even partial responses leading to
downstaging may facilitate surgical resection and ICI
therapy.
Cancer Vaccines Cancer vaccines represent a different
approach of generating tumor-specific T-cells in poorly
immunogenic tumors, against either neoantigens or
differentially overexpressed self-antigens. Most cancer
vaccines to date have demonstrated limited clinical
benefit,46
which can be attributed to immune-suppressive
mechanisms within the tumor microenvironment (TME) if
administered as monotherapy. The success of ICI has led to
a renaissance of combination therapy cancer vaccine
clinical trials, with promising results.47,48
A few
encouraging examples include the FDA-approved
Sipuleucel-T (dendritic cell vaccine) for castrate-resistant
prostate cancer,49
TG01 (mutant K-ras peptide vaccine) for
pancreatic cancer,50
and two personalized neoantigen
vaccines for melanoma.47,48
The TetMYB vaccine, a
DNA plasmid encoding a modified MYB oncoprotein
fused with tetanus antigen to break self-tolerance, is being
tested against advanced colorectal and adenoid cystic
carcinoma (NCT03287427).51
NK Cell and CAR T-Cell Therapy: Lifting the Cloak
of Invisibility
Another immune evasion technique employed by tumor
cells is downregulation of MHC class I molecules, thus
rendering the tumor invisible to cytotoxic T-cells.52,53
This
adaptation has been observed in patients treated with ICI
and cancer vaccines,48,54
and may be countered by natural
killer (NK) and chimeric antigen receptor (CAR) T-cell
therapies, as these two immune cells do not rely on MHC
class I presentation for tumor recognition.
In early-phase clinical trials, NK cell therapy has proven
to be safe and well tolerated, albeit with limited success, in
non-small cell lung,55,56
gastrointestinal,57
breast, ovar-
ian,58
and renal cell cancers, and melanoma.59
The intrinsic
lack of tumor infiltration by NK cells is often attributed to
suppressive TME. This can be mitigated by nanoparticles
that attract and expand NK cells within the tumor60
or
genetically modified NK cells.61
CAR T-cells are autologous T-cells that have undergone
ex vivo genetic modification to express a tumor-specific
hybrid receptor. Prominent successes have been achieved
in hematological malignancies, including the use of anti-
CD19 CAR T-cells in non-Hodgkin’s B cell lymphoma and
lymphoblastic leukemia, which gained FDA approval in
2017.62–64
Current target antigens include epidermal
growth factor receptor (EGFR), human epidermal growth
factor receptor 2 (HER-2), mesothelin, and carcinoembry-
onic antigen (CEA)65
on solid tumors.
Early-phase trials have shown CAR T-cells to be safe
and feasible in a variety of solid tumors, including non-
small cell lung cancer,66
neurological malignancies,67–69
breast,70
pancreatic,71,72
and metastatic colon cancer,73
and
sarcoma.74,75
Furthermore, enhanced efficacy in combina-
tion with ICI has been observed against melanoma,
Hodgkin’s lymphoma, and non-small cell lung cancers.76
T. Pham et al.

5. T-Regulatory and Myeloid-Derived Suppressor Cells:
Antisuppressor Therapy
T-regulatory (Treg) and myeloid-derived suppressor
cells (MDSCs) are partly responsible for the immunosup-
pressive TME,77
thus representing a potential avenue in
cancer immunotherapy.
FoxP3-expressing Treg cells induce self-tolerance and
prevent autoimmunity. Tumors can exploit Tregs to their
advantage, and current therapeutic strategies are focusing
on depleting these cells.78
Two such therapies are dacli-
zumab (IL-2 receptor blocking antibody) and denileukin
diftitox (IL-2:diptheria toxin fusion peptide), which have
demonstrated robust clinical outcomes79
in metastatic
breast cancer80,81
and chemo/immuno-naı̈ve stage IV
melanoma.82
Additionally, the checkpoint inhibitor ipili-
mumab has been reported to deplete tumor-infiltrating
Tregs via antibody-dependent cell-mediated cytotoxicity
(ADCC) in melanoma patients.83
MDSCs are immature myeloid cells that suppress
cytotoxic T-cell function and modulate the activation and
expansion of Tregs by immunosuppressive cytokines,
arginase-1, and reactive oxygen species (ROS) and nitric
oxide (NO).77
Treatments targeting MDSCs were
serendipitously discovered as a by-effect of other cancer
treatments.84
Ipilimumab and vemurafenib (BRAF inhibitor) have
been shown to reverse the immunosuppressive effect of
MDSCs in melanoma.85,86
Sunitinib (tyrosine kinase inhi-
bitor) decreases MDSC levels by reducing the expansion of
monocytic MDSCs and inducing apoptosis of granulocytic
MDSCs,87
being the first-line therapy for metastatic RCC.
All-trans retinoic acid (ATRA) and vitamin D3 promote
differentiation of MDSCs into mature nonsuppressive cells
and have shown benefit in metastatic RCC88
and head and
neck squamous cell carcinoma (SCC),89
respectively.
Sildenafil, tadalafil, and vardenafil (PDE5 inhibitors) have
been shown to inhibit arginase-1 and NO expression and
significantly reduce disease burden in myeloma patients90
and circulating MDSCs in head and neck SCC.91
Addi-
tionally, conventional chemotherapeutic drugs, namely
gemcitabine and 5-fluorouracil, have been found to
decrease MDSC and to improve antitumor immune
responses.92,93
Other Barriers Against Immunotherapy
In addition to the immune-evasive mechanism men-
tioned above, further parts of the TME can adversely affect
immune cell function.
Some tumors create a hostile TME for TILs by depleting
nutrients and oxygen and releasing acidic94
and toxic
metabolites.95
Others promote an immunosuppressive cell
infiltrate by altering the inflammatory cytokine milieu.96
Lastly, modifications of the tumor vasculature such as
downregulation of intercellular adhesion molecule 1
(ICAM-1)97
and altering the tumor stroma98,99
to retard
T-cell migration have been described.
Research into counteracting some of these mechanisms
is currently being done, however there are no clinical trials
to date.
THE RISE OF IMMUNOTHERAPY CLINICAL
TRIALS
An enquiry of the ClinicalTrials.gov database revealed
that, of the 60,903 cancer trials in the entire database, the
search string ‘‘Cancer AND Immunotherapy’’ returned
1994 (* 3%) interventional studies, and of these, 313
(* 16%) have been completed (Table 1). Recent years
have seen a rapid increase in the number of immunotherapy
trials (Fig. 3). Although earlier trials were disappointing,
more recent trials featuring combination therapies have
shown promising results. Thus, there is a need for further
evaluation of upcoming therapies as well as the potential
synergistic effects of existing therapies.
INTEGRATION WITH SURGICAL PRACTICE
Local/Regional Control
The success of treating primary solid malignancies is
highly dependent on the disease stage. Surgery has tradi-
tionally played a role in this setting, with early-stage
disease often cured with a margin-negative resection. In
contrast, in many locally advanced solid tumors, neoadju-
vant therapies such as radiotherapy and/or chemotherapy
have shown benefit in downstaging cancers to enable
resection. This is exemplified in breast cancer, where
5-year survival for stage III patients was similar between
mastectomy (96.3%) and chemoradiotherapy combined
with breast-conserving surgery (90.9%, p = 0.669).100
More recently, chemoimmunotherapy has been used suc-
cessfully to downstage prostate cancer.101
Distant/Metastatic Disease
The presence of metastatic disease has classically
implied an incurable state for patients. Surgery has tradi-
tionally had a limited role, often reserved for control of
symptoms. Chemotherapy and radiotherapy can extend
overall survival in this cohort; however, this requires bal-
anced consideration given the impact on quality of life and
treatment-related morbidity.
Harnessing what immunotherapy promises to offer, we
have the potential to turn advanced cancer into a chronic
Immunotherapy for Solid Tumors: A Review

6. disease, or state of equilibrium.17
This has been demon-
strated in subgroups of the CheckMate-066 and -067
melanoma trials, where clinical benefit from nivolumab is
seen beyond disease progression for advanced mela-
noma.102
Furthermore, improvement in survival has been
achieved with dual checkpoint inhibition.5
TABLE 1 Phase and modality of completed immunotherapy clinical trials against solid malignancies (compiled from ClinicalTrials.gov;
5/15/2018)
Solid cancer
type
Phase of
clinical trial
(number of
trials*)
Immunotherapy modality (number of trials*)
I II III Cancer
vaccine
Checkpoint
inhibition
Adoptive
cellular
therapy
CAR
T-cell
Oncolytic virus,
gene therapy
Anti-Treg,
anti-MDSC
Cytokine,
targeted therapy
Prostate 17 27 7 39 4 2 3 3
Melanoma 39 41 5 40 6 19 1 2 1 16
Lung 18 30 3 35 5 1 10
Head and neck 11 8 10 2 1 1 5
Neurological 26 20 3 24 1 8 4 3 9
Gynecological 12 15 1 16 3 1 8
Anal 3 2 1 1 1 2
Penile 3 1 1 1 2
Sarcoma 10 8 8 1 4 1 4
Urothelial 7 14 4 9 1 4 1 1 9
Breast 18 18 23 1 6 6
Hepatobiliary 9 4 2 6 4 2 3
Colorectal 10 13 1 17 1 2 1 3
Esophagogastric 6 4 5 1 4
Pancreas 13 11 2 20 1 1 1 3
Total 202 216 28 254 21 58 12 10 4 87
*Where a trial involves more than one therapy, it is counted in duplicate according to the number of immunotherapy modalities used
0
5
10
15
20
25
30
1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015
Number
of
Trials
Year of Trial Commencement
The Rise of Cancer Immunotherapy Trials
FIG. 3 Trend showing the rapid
increase in number of started
cancer immunotherapy trials from
1995–2015 (compiled from
ClinicalTrials.gov; 5/15/2018)
T. Pham et al.

7. When examining published data, there is a changing role
for surgery. Current immunotherapeutic agents are most
effective when there is low to moderate tumor burden given
the limited immunosuppressive factors. Therefore, surgery’s
role is still foremost to achieve cure in early-stage disease,
however what was once considered futile/palliative surgery
now has the potential to offer cure when combined with
immunotherapy. This not only includes resecting tumors
after downstaging, but also removing tumors in some can-
cers, including metastatic deposits, in order to understand the
immune profile of the resistant clone, and for the expansion
of TILs. Both of these methods allow a personalized treat-
ment algorithm to be developed and modified throughout the
patient’s journey, so that the best outcomes can be achieved.
CONCLUSIONS
Immunotherapy is a promising therapeutic avenue that is
rapidly shifting the paradigm of cancer management. This
review is intended to raise awareness about the current
immunotherapeutic strategies. Immunotherapy can provide
an important adjunct to current available therapies to
improve long-term outcomes in previously resistant or
incurable cancers. With its growing use, it is important for
surgeons and surgical oncologists to embrace it, thereby
providing immunotherapy as a treatment options for their
patients.
ACKNOWLEDGMENT Not applicable.
DISCLOSURE All authors are involved in the MYPHISMO clin-
ical trial (NCT03287427).
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