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ME64CH06-Hwu ARI 12 December 2012 17:37
Harnessing the Power
of the Immune System
to Target Cancer
Gregory Liz´
ee,1Willem W. Overwijk,1
Laszlo Radvanyi,1Jianjun Gao,2Padmanee Sharma,2
and Patrick Hwu1
1Department of Melanoma Medical Oncology, The Center for Cancer Immunology
Research and 2Department of Genitourinary Medical Oncology; The University of Texas
M. D. Anderson Cancer Center, Houston, Texas 77030; email: phwu@mdanderson.org
Annu. Rev. Med. 2013. 64:71–90
First published online as a Review in Advance on
October 22, 2012
The Annual Review of Medicine is online at
med.annualreviews.org
This article’s doi:
10.1146/annurev-med-112311-083918
Copyright c
2013 by Annual Reviews.
All rights reserved
Keywords
immunotherapy, vaccines, T cells, adoptive transfer, immune
checkpoint blockade
Abstract
For many years, immunotherapeutic approaches for cancer held more
promise than actual clinical benefit for the majority of patients. How-
ever, several recent key advances in tumor immunology have now turned
the tide in favor of immunotherapy for the treatment of many different
cancer types. In this review, we describe four of the most effective
immunotherapeutic approaches currently used in the clinic: cancer vac-
cines, immunostimulatory agents, adoptive T cell therapy, and immune
checkpoint blockade. In addition, we discuss some of the most promis-
ing future strategies that aim to utilize multiple immunotherapies or
combine them with other approaches to more effectively target cancer.
71
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Further
ANNUAL
REVIEWS
ME64CH06-Hwu ARI 12 December 2012 17:37
BCG: Bacillus
Calmette–Gu´
erin
CTL: cytotoxic T
lymphocyte
INTRODUCTION
For most of the twentieth century, the ability
of the immune system to recognize and
eradicate cancer was doubted by the vast
majority of medical oncologists. Prevailing
wisdom postulated that tumorigenesis and
disease progression could not occur in the
face of an immune response; thus, a diagnosis
of cancer meant a priori that such antitumor
responses had failed. Furthermore, the notion
that immune responses may in fact prevent
the occurrence of clinically manifested disease
could not be proven unequivocally, as still
remains the case today. However, several
anecdotal case studies documented evidence of
unexplained spontaneous tumor regressions in
cancer patients, providing support for the idea
that antitumor immune responses may play
a critical role in some patients. Furthermore,
a strong connection between infection and
tumor regressions was observed and docu-
mented as early as 1884 by Anton Chekhov (1).
Following up on these observations, surgical
oncologist William Coley utilized a mixture of
killed bacteria to treat patients with different
types of cancer. These so-called Coley’s toxins
demonstrated some degree of clinical efficacy
and were used clinically from 1893 to 1963,
usually with mixed results (2).
More recently, evidence for the connection
between infections and tumor regressions has
come from Bacillus Calmette–Gu´
erin (BCG),
a tuberculosis vaccine preparation consisting
of attenuated Mycobacterium, which can be
used to effectively prevent recurrences in the
majority of superficial bladder cancer patients,
presumably by activating an antitumor immune
response (3). But perhaps the most convinc-
ing evidence for the existence of antitumor
immunity came from clinical trials performed
in the late 1980s. These trials showed that
some metastatic melanoma and renal cell car-
cinoma patients experienced dramatic tumor
regressions in response to treatment with the
cytokine interleukin (IL)-2, which was known
to have no direct tumoricidal capacity but
instead was a potent activator of an immune
cell subset known as cytotoxic T lymphocytes
(CTLs) (4). Although most patients progressed
on IL-2 therapy, ∼15% of patients had ob-
jective responses, and half of these went on to
be completely cured (5, 6). These results led
the US Food and Drug Administration (FDA)
to approve IL-2 in the late 1990s as the first
bona fide immunotherapy for the treatment
of cancer patients. They also inspired several
research studies over the past two decades
to develop alternative immunotherapies with
better safety and efficacy and to improve
understanding of IL-2’s mechanism of action.
Today, there remains little doubt that the
immune system has the inherent capacity
to recognize and eradicate cancer. The past
25 years of immunological research has led to a
vastly improved understanding of the molecular
mechanisms of the immune system, and this in
turn has allowed the design and development of
new drugs and methods to induce and manip-
ulate the antitumor immune response ex vivo
and in vivo.
This review focuses on four of the most
important and effective T cell–based im-
munotherapeutic approaches for treating can-
cer patients: cancer vaccines, immunostimu-
latory agents, adoptive T cell therapy, and
immune checkpoint blockade. Because it is
rapidly becoming apparent that combination
treatments are likely to be the most effective
approaches for inducing long-term tumor re-
gressions, we also discuss some of the more
promising combination therapies being tested
in cutting-edge clinical trials that are either
planned or under way.
CANCER VACCINES
A successful therapeutic cancer vaccine ac-
tivates a cancer patient’s immune system,
resulting in eradication or long-term control
of disease. Such a vaccine typically consists of a
tumor antigen in an immunogenic formulation
and activates tumor antigen–specific helper
cells and/or CTLs and B cells. B cells secrete
their specific antibody receptors to cause
72 Liz´
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Naïve T cell
Proliferation
Activation
Tumor cell
Cytotoxic
T lymphocyte
Tracking
TCR
CD28 CD86
CD27 CD70
+
CD40
+
Immunostimulatory
agents
Tumor cell lysis
Cytokine release
TLR
ligands Anti-CD40
TLR
Direct binding
Antigenic
peptides
Vaccine formulations
Whole protein
antigens
Tumor cell
lysates
Nucleic acid
Dendritic cell
Processing and
presentation
Tumor antigens
MHC
class I
Phagocytic
uptake
Activation,
expression of
costimulatory
molecules
Antigen
processing and
presentation
MHC
class I
Figure 1
Generation of antitumor T cell responses using cancer vaccines and immunostimulatory agents. Tumor-associated antigens (TAA, red )
expressed in the context of surface MHC class I (HLA) molecules on the surface of tumor cells can activate TAA-specific CD8+T cells
to perform cytolytic functions and/or release inflammatory cytokines to further amplify the adaptive immune response (right).
Generation of such tumor-reactive T cells de novo requires stimulation of na¨
ıve T cells by activated dendritic cells (DCs) expressing
both the appropriate TAAs and costimulatory molecules such as CD86 and CD70. This combination of signals leads to the activation,
proliferation, and trafficking of TAA-specific T cells to the tumor site, where they can cause tumor regressions. Cancer vaccine
formulations can be used to introduce TAAs to DCs in several ways, including nucleic acids coding for TAAs, tumor cell lysates, whole
TAA proteins, or TAA-derived peptides. DCs can then process and present these TAAs to na¨
ıve T cells in the context of MHC class I
molecules (lower left). However, optimal CD8+T cell activation requires the expression by DCs of costimulatory ligands for CD27 and
CD28, which are known to be upregulated by the combination of Toll-like receptor (TLR) stimulation and ligation of the CD40
receptor (upper left). Thus, the generation of an optimal antitumor T cell response requires a combination of TAA-specific vaccination
with DC activation signals provided by TLR ligands and CD40-specific antibody. MHC, major histocompatibility complex.
TCR: T cell receptor
the lysis or phagocytosis of cells that display
antigens they recognize. CTLs use their T cell
receptor (TCR) to specifically recognize small
cell-derived peptides presented on a cell’s
surface bound to major histocompatibility
complex (MHC) class I molecules. If the T
cell is activated and its TCR binds a particular
MHC/peptide complex, it will release cytotoxic
molecules and cytokines that will kill the cell
and stimulate activation of nearby immune
cells (Figure 1). CD4+helper T cells promote
the activation of both B cells and CTLs. Can-
cer vaccines cause the selective activation and
proliferation of B and T cells that can recognize
tumor cells, thus preparing them for their
cancer-killing action. The most successful
cancer vaccine approach to date is preventative
vaccination against human papilloma virus
(HPV) (7). Through antibody formation it
prevents viral infection and, by extension, also
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APC:
antigen-presenting cell
virus-induced cervical cancer. However, most
cancers are not thought to be virus-induced,
and therapies are needed for patients with
established disease. Most recent cancer vac-
cines have focused on the induction of CTLs,
although antibodies contribute to antitumor
responses in some settings.
Although therapeutic cancer vaccines have
impressive antitumor activity in numerous
animal models, their clinical benefit in cancer
patients has tended to be minimal (8) until
recently (see Table 1 for a selection of recent
cancer vaccine clinical trials). Foremost, in 2010
the FDA approved Dendreon’s Provenge R
,a
dendritic cell (DC)–based cancer vaccine for
the treatment of metastatic prostate cancer (9).
This approach takes advantage of the fact that
DCs are the most potent antigen-presenting
cells (APCs) for priming CTL responses
(Figure 1). Provenge (sipuleucel-T) is a prepa-
ration of the patient’s own peripheral blood
cells, which are loaded with a fusion protein of
granulocyte-macrophage colony-stimulating
factor (GM-CSF) and prostatic acid phos-
phatase (PAP), a normal prostate-specific anti-
gen. Upon injection, the GM-CSF-activated
APCs in the preparation presumably present
the PAP to the patient’s T cells, which become
activated, proliferate, and attack the patient’s
tumor. Although Provenge’s extension of
median survival time by 4.1 months compared
to placebo leaves much room for improvement,
it provides an important proof-of-principle for
other cancer vaccine strategies. Indeed, a differ-
ent prostate cancer vaccine based on poxviruses
encoding prostate-specific antigen (PSA) and
three immunostimulatory molecules and mixed
with GM-CSF significantly improved median
overall survival by 8.5 months (10).
In melanoma, a recent randomized prospec-
tive phase III trial of a modified gp100 peptide
vaccine combined with IL-2 showed signif-
icant increases in overall response rate and
progression-free survival compared to IL-2
alone, with a trend toward improved overall
survival (11). Another peptide vaccine, based
on long peptides spanning two oncoproteins
from HPV16, had even more dramatic benefit
in patients with vulvar intraepithelial neoplasia,
curing 9 of 19 patients (12). A double-blind
controlled clinical trial of a personalized B
cell idiotype protein vaccine for follicular
B cell lymphoma patients in remission after
chemotherapy increased disease-free survival
from 31 to 44 months (13). Thus, randomized
controlled clinical trials are beginning to reveal
cancer vaccine approaches with true clinical
benefit.
The aforementioned vaccines are based on
specific, known tumor antigens, manipulated to
increase their immunogenicity before injection:
GM-CSF+PAP fusion protein loaded onto
APCs, PSA encoded in an immunogenically
enhanced poxvirus, gp100 or HPV peptides
emulsified in incomplete Freund’s adjuvant,
and purified idiotype protein mixed with GM-
CSF. However, a different approach, not based
on identifying the tumor antigen, is also show-
ing clinical impact. Specific modifications of
the tumor microenvironment could entice the
patient’s immune system to mount a productive
immune response against the antigens present
in the patient’s tumor. For example, two stud-
ies of external beam radiation combined with
intratumoral injection of the APC-activating
Toll-like receptor 9 (TLR9) agonist CpG re-
sulted in shrinkage of both injected and distant,
uninjected tumor deposits in patients with B
cell lymphoma and T cell lymphoma (mycosis
fungoides) (14, 15). This suggests, as demon-
strated in mouse models, that tumor antigen
released after irradiation into a CpG-activated
tumor microenvironment induced an effective
antitumor immune response. In effect, the
tumor is turned into its own vaccine, obviating
the need for the identification of specific tumor
antigens and their often cumbersome and
costly formulation into vaccines.
It appears likely that immune responses
induced in this manner are mostly directed
against unique proteins that are recognized as
“foreign” by the immune system. In animal
studies, carcinogen-induced tumors elicited
spontaneous, curative immune responses
specifically against proteins encoded by
mutated genes (16). It remains to be seen
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Table 1 Selected cancer immunotherapy clinical trials
Therapy Formulation Description
Tumor antigens or
target
Status of clinical
development
Dendritic cell Autologous PBMC loaded with
GM-CSF+PAP fusion protein
Prostate: PAP FDA-approved (9)
Viral Vaccinia and fowlpox virus
encoding PSA and CD86,
ICAM-1 and LFA3
Prostate: PSA Phase II (10)
Cancer vaccine
Protein Autologous tumor Ig idiotype
conjugated to KLH, given with
GM-CSF
Follicular B cell
lymphoma:
idiotype
Phase III (13)
Peptide Overlapping long peptides of
HPV E6/E7 proteins emulsified
in IFA
gp100.209-217(210M) peptide
emulsified in IFA
Vulvar neoplasia:
HPV16 E6/E7
Melanoma: gp100
Phase III (11, 12)
Intratumoral
immune activation
External beam irradiation +CpG B cell lymphoma
Mycosis fungoides
Phase III (14, 15)
Tumor infiltrating
lymphocytes
(TILs)
Isolation of T lymphocytes from
primary or secondary tumors
followed by in vitro expansion
with IL-2
Polyclonal tumor
antigens
Clinical (phase II)
(61–64)
Antigen-expanded
T cells
In vitro reactivation and
expansion of T lymphocytes
recognizing specific
tumor-associated antigens
(TAAs)
MART-1,
tyrosinase, gp100,
NY-ESO-1, or
polyclonal
Clinical (phase I/II)
(53, 54, 55)
Adoptive T cell
transfer
Engineered TCR
expression
Genetic modification of T cells to
express a T cell receptor (TCR)
recognizing known TAAs
MART-1, gp100,
p53, and
NY-ESO-1
Clinical (phase I/II)
(56, 57, 65)
Engineered CAR
expression
Genetic modification of T cells to
express a chimeric antigen
receptor (CAR) consisting of
TAA-specific antibody fused to
CD3/costimulatory molecule
transmembrane and cytoplasmic
domains
Ganglioside GD2,
GD3, and
HMW-MAA
(MCSP-1)
Preclinical (58, 59, 66)
Anti-CTLA-4 mAb Assessment of safety, toxicity and
survival in metastatic melanoma
patients treated with
anti-CTLA-4 antibody
CTLA-4 Phase I–III (83, 85, 86,
104, 105)
Immune checkpoint
blockade
Anti-PD-1 mAb Assessment of safety, activity, and
immune correlates of anti-PD-1
antibody in cancer patients
PD-1 Phase I (94)
Anti-PD-L1 mAb Safety and activity of anti-PD-L1
antibody in patients with
advanced cancer
PD-L1 Phase I (95)
Abbreviations: PBMC, peripheral blood mononuclear cell; GM-CSF, granulocyte macrophage colony stimulating factor; PAP, prostatic acid
phosphatase; PSA, prostate-specific antigen.
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whether therapies based on directly increasing
tumor immunogenicity are most effective in
tumor types with large numbers of genomic
mutations, such as colorectal cancer, smoking-
related lung cancer, and cutaneous melanoma
(16).
A host of small, early clinical trials are ex-
ploring multiple vaccine platforms, including
whole tumor cells, viruses, bacteria, peptides,
proteins, and DNA, in addition to TLR ago-
nists, immunostimulatory synthetic adjuvants,
and antibodies, some of which will be discussed
in more detail in the next sections. It appears
that cancer vaccines are finally beginning to
deliver on their decades-old promise owing to
our deeper understanding of the complexities
of the vertebrate immune system, empirical
data on what works clinically from a host of
earlier trials, and increased availability of new
immunostimulatory agents and procedures.
With the recent commercial success of other
cancer immunotherapies, some of these agents
are now being backed by large pharmaceutical
companies, inspiring hope that they may
one day be added to the standard anticancer
armamentarium.
IMMUNOSTIMULATORY
AGENTS
Toll-like Receptor Ligands
Because activated DCs are the most potent cell
type known to stimulate and prime de novo T
cell responses, much effort has been devoted
to understanding the mechanisms that activate
these cells. Some 50 years after clinical use of
Coley’s toxins was halted, we now know that the
most active antitumor component of the vac-
cine was likely to be lipopolysaccharide (LPS),
a major component of bacterial cell walls. This
is because DCs express a receptor, TLR4, that
can specifically recognize LPS, leading to po-
tent DC activation and presumably inducing
tumor-specific immunity in some patients. The
BCG vaccine may utilize a similar mechanism
to prevent recurrence of bladder cancer. It is
now known that DCs express a stunning array
of such activating receptors, each of which can
recognize and respond to a different pathogen-
derived signal (17). There are currently 13
known Toll-like receptors, which can recognize
viral or bacterial nucleic acids (TLR3, TLR7,
TLR8, and TLR9), bacterial cell wall compo-
nents or flagellin (TLR4 and TLR5), bacterial-
derived lipoproteins or glycolipids (TLR1 and
TLR2), parasite-derived profilin (TLR11), etc.
All of these are known to lead to the activation of
DCs, inducing the expression of type I interfer-
ons, cytokines (e.g., IL-12), and costimulatory
molecules (e.g., CD80, CD86, and CD40) that
are critical for activating T cell responses (18).
Knowledge of this array of DC-activating re-
ceptors has provided a strong impetus to utilize
some of these pathogen-derived ligands clini-
cally in the induction of tumor antigen–specific
responses in cancer patients (Figure 1).
The first clinical trials analyzing the effec-
tiveness of TLR ligand treatment of cancer
patients were initiated ∼10 years ago and tested
two compounds: the TLR7 agonist imiquimod
and unmethylated CpG DNA, recognized by
TLR9. Imiquimod applied as a topical cream is
considered one of the great successes in TLR
ligand therapy, as its application has resulted in
an 80%–90% clearance rate for superficial basal
cell carcinoma in multiple clinical trials (19,
20). The recurrence rate is also remarkably low
(<20%), and imiquimod has been used to treat
a variety of dermatological conditions, includ-
ing actinic keratoses, lentigo maligna, common
warts, and molluscum contagiosum (21, 22).
Unfortunately, topical or systemic administra-
tion of TLR7 agonists in patients with more
advanced cancers has not resulted in the same
degree of success. Although clinical trials eval-
uating the TLR7 agonist 852A have reported
strong systemic upregulation of interferon-α
and other markers of immune activation and
transient disease stabilization in some patients,
objective response rates have remained low
(23, 24). Similar results have been observed
with the systemic administration of TLR9
agonists as a monotherapy: although a strong
propensity to activate innate immune responses
in melanoma and renal cell carcinoma patients
was observed, objective clinical responses have
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ME64CH06-Hwu ARI 12 December 2012 17:37
been comparatively rare (25, 26). Route of
administration has been demonstrated to be an
important factor in the induction of antitumor
responses; intralesional and in situ delivery of
TLR9 agonists have shown some promise in
more recent studies (14, 27, 28).
TLR4 agonists such as Salmonella-derived
endotoxin (LPS) were first used in experimental
trials for cancer patients more than two decades
ago (29, 30). Effects on the immune system
were dramatic, leading to major increases in in-
flammatory cytokines TNF-αand IL-6, as well
as dose-limiting toxicities that included fever
and chills. Despite these immune effects, anti-
tumor responses were modest, and severe side
effects that included hepatic toxicity and un-
expected hematological changes led eventually
to the cessation of the clinical use of TLR4
agonists. The TLR3 agonist polyriboinosinic-
polyribocytidylic acid (poly I:C) was first em-
ployed in clinical trials for cancer patients some
30 years ago because of its propensity to in-
duce type I interferons (31, 32). Although this
compound showed no toxic side effects, it also
showed only modest antitumor activity (33).
Much more recently, poly I:C has been used
as an experimental treatment for patients with
recurrent anaplastic gliomas. Although poly I:C
monotherapy was well tolerated, it had no sig-
nificant effect on disease progression or survival
(34); however, the combination of poly I:C with
radiation therapy suggested some clinical ben-
efit in this patient population (35).
Although TLR ligands have had limited
clinical success as monotherapies, their abil-
ity to activate DCs and boost T cell prim-
ing makes them highly effective adjuvants in
combination with peptide or protein vaccines.
Vaccination using melanoma antigen-specific
peptides has been augmented with both CpG
and imiquimod (36, 37). These two compounds
also induced increased levels of tumor antigen-
specific T cells in melanoma and prostate cancer
patients vaccinated with recombinant protein
tumor antigen NY-ESO1 (38, 39). TLR ligands
are especially effective when combined with
DC-based vaccines: imiquimod and poly I:C
were used to effectively boost a DC-based vac-
cine against glioblastoma-specific antigens (40).
Several studies have also utilized LPS to activate
tumor-antigen pulsed DCs prior to vaccination,
including in clinical trials for melanoma, breast
cancer, and pediatric malignancies (41–43).
CD40 Agonists
Ligation of the CD40 cell surface receptor on
DCs is a critically important signal for full ac-
tivation and effective de novo T cell priming
(Figure 1). The natural ligand CD40L is up-
regulated on CD4+T helper cells that have
been activated by antigen recognition, and this
expression results in further activation of the
APC. CD40 signaling can contribute to an-
titumor immune function through a number
of known mechanisms: promoting macrophage
function through induction of microbicidal
substances, such as reactive oxygen species and
nitric oxide; B cell activation through promo-
tion of isotype switching and differentiation
into antibody-secreting plasma cells; and li-
censing of full antigen-presentation function by
DCs with concurrent induction of costimula-
tory molecules (including CD70, CD80, and
CD86) necessary for CTL priming and activa-
tion (18). In addition, CD40 is expressed by a
variety of tumor cell types and thus may consti-
tute a direct immunotherapeutic target.
CD40-specific antibodies have shown very
potent antitumor activity in several mouse
tumor models, particularly when used in
combination with TLR ligands and tumor
antigen–specific vaccination. Considering the
encouraging results from animal studies that
were first published more than a decade ago, it
is surprising that experimental trials targeting
CD40 in cancer patients have been relatively
sparse. Most of the published clinical studies
have used either CD40-specific antibodies or
multimers of CD40L, and the results have
generally demonstrated good immunological
activity with few adverse side effects (44).
As monotherapies, CD40-targeting agents
have shown modest clinical activity, inducing
objective responses in 12% and 27% of
non-Hodgkin’s lymphoma and melanoma
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TIL:
tumor-infiltrating
lymphocyte
PBMC: peripheral
blood mononuclear
cell
patients, respectively (45, 46). Clinical trials
for colorectal cancer, multiple myeloma,
and melanoma have utilized CD40-specific
antibodies to activate DC-based vaccines
pulsed with tumor cell lysates or known tumor
antigens (47–49). Most patients generated
antigen-specific T cell responses, and objective
clinical responses were also documented in all
of these trials. One interesting recent approach
has utilized electroporation to introduce
mRNA encoding CD40 ligand, constitutively
active TLR4, CD70, and multiple melanoma
tumor antigens into autologous DCs (TriMix-
DC). A majority of vaccinated melanoma
patients developed antigen-specific T cell
infiltration into skin sites of delayed type IV
hypersensitivity, and tumor regressions were
observed in 6 of 17 evaluable patients who had
received interferon-α-2b in combination with
TriMix-DC (41). Tumor regressions were also
observed in a trial of patients with surgically
incurable pancreatic ductal adenocarcinoma
when treated with a combination of anti-CD40
antibody and the chemotherapy agent gemc-
itabine. Antitumor responses in this study were
attributed to CD40 activation of macrophages,
which infiltrated tumors and induced the
depletion of tumor stroma (50). It is clear that
CD40-targeting agents have demonstrated
encouraging antitumor activity in human
cancers, and more clinical trials assessing their
efficacy, either alone or in combination with
other treatments, are certainly warranted.
ADOPTIVE T CELL TRANSFER
Immunotherapy using T cells has emerged to
be a powerful treatment option for patients with
unresectable stage III and stage IV metastatic
melanoma. T cell immunotherapy includes
the adoptive transfer of autologous tumor-
infiltrating lymphocytes (TILs) together with
high-dose IL-2 (51, 52), T cells activated
against defined melanoma tumor antigens such
as HLA-binding MART-1 peptides (53–55), T
cells transduced with high-affinity TCRs that
specifically recognize tumor antigens (56, 57),
and T cells transduced with chimeric antigen
receptors (CARs) recognizing tumor-specific
cell surface proteins that are composed of hy-
brid immunoglobulin light chains with endo-
domains of T cell signaling molecules (58, 59).
Figure 2 illustrates the major forms of T cell
therapy currently being used to treat advanced
melanoma. Among these and other options
for T cell therapy, the combination of TILs
with high-dose IL-2 has had the longest clini-
cal history, with multiple clinical trials in cen-
ters across the world consistently demonstrat-
ing durable clinical response rates near 50% or
more in patients who have failed first-line and
second-line treatment modalities (52, 60–64).
Overall, T cell therapy has made tremen-
dous advances in the past decade. Although
TIL therapy is the most developed, transduc-
tion of activated peripheral blood mononuclear
cell (PBMC)–derived autologous T cells with
high-affinity TCRs for melanoma tumor
antigens, such as MART-1 and NY-ESO-1,
and MAGE-A3 are increasingly being used,
especially in cases where TIL therapy is not an
option. For example, PBMC transduction with
a TCR recognizing an HLA-A∗0201-restricted
NY-ESO-1 epitope has resulted in a high
rate of responses (65). Similarly, PBMC T
cells transduced with CARs recognizing the
highly specific melanoma antigen MCSP
(melanoma-associated chondroitin-sulphate
proteoglycan)-1 or abnormally overexpressed
gangliosides, such as GD3, represent promising
new approaches (59, 66). In addition, T cells
recognizing CD19 have proven particularly
potent against B cell lymphomas (67, 68). One
important advantage of T cell transduction
with CARs and TCRs is that these recombi-
nant molecules can be engineered to express
intracellular signaling domains of powerful T
cell costimulatory molecules such as CD28 and
members of the tumor necrosis factor receptor
(TNF-R) family, such as CD137, that drive
activation of strong antiapoptotic pathways in
T cells.
Notable Features of TIL Therapy
A recent summary report of clinical trials per-
formed over a decade by Steven Rosenberg
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ME64CH06-Hwu ARI 12 December 2012 17:37
a Tumor-inltrating lymphocytes (TILs)
b Peripheral blood mononuclear cells (PBMCs)
Rapid expansion
protocol
Resected
tumor Initial TIL
expansion
in IL-2
i. Stimulation with tumor antigens and IL-2
ii. Transduction with tumor
antigen-specic TCR
iii. Transduction with chimeric
antigen receptor
TIL expansion
with IL-2, anti-CD3,
and feeder cells
Re-infusion of
expanded TILs
Further
expansion
Infusion of
expanded or
engineered T cells
High-dose IL-2
or other cytokine
support
High-dose IL-2
or other cytokine
support
Prior
lymphodepletion
Figure 2
Adoptive T cell therapy for metastatic melanoma. There are currently two major sources of activated, antigen-specific T cells used in
adoptive cell therapy for melanoma and other cancers. (a) The first form of therapy uses tumor-infiltrating lymphocytes (TILs)
expanded ex vivo from surgically resected metastatic tumors cut into small fragments, or from single cell suspensions isolated from
tumor fragments. TILs are initially expanded over a few weeks with IL-2 in 24-well plates. Selected tumor-reactive TIL lines or pooled
bulk TILs are then further expanded in a “rapid expansion protocol” (REP) using anti-CD3 activation in the presence of irradiated
PBMC feeder cells and IL-2, usually for a period of two weeks. The final post-REP TIL product is infused into a waiting patient. The
most effective TIL therapy protocol currently involves a prior non-myeloablative chemotherapy regimen to transiently deplete
endogenous lymphocytes to “make room” for the adoptively transferred TIL product; this chemotherapy is given 7 days before the
expanded TIL infusion. (b) The second major approach for adoptive T cell therapy uses T cells expanded from autologous peripheral
blood (PBMC) that undergo one of three possible manipulations to enrich the cells for tumor antigen-specific T cells. (i)Thefirstof
these manipulations can be the activation of blood-derived CD8+or CD4+T cells with tumor antigen-pulsed antigen-presenting cells
(e.g., an HLA-binding peptide epitope). (ii ) The second manipulation involves the transduction of a high-affinity T-cell receptor
(TCR) gene recognizing a defined tumor antigen into the blood-derived T cells previously polyclonally activated with anti-CD3
antibody and a growth-promoting cytokine such as IL-2. (iii ) The third approach again involves the polyclonal activation of
blood-derived T cells, but this time the expanding cells are transduced with a chimeric antigen receptor (CAR) recognizing a cell
surface tumor antigen triggering tumor recognition and effector activity in vivo. In each case, the antigen-pulsed or genetically-modified
blood-derived T cells are further expanded over a period of a few weeks to generate numbers sufficient for adoptive transfer. Adoptive
cell therapy using these blood-derived T cells enriched for tumor specificity is not usually accompanied by a prior lymphodepleting
regimen, but this can be included in certain circumstances to improve the persistence of the transferred T cells in vivo.
and colleagues at the Surgery Branch of the
National Cancer Institute (NCI) has under-
scored the power of TIL adoptive cell therapy
for melanoma (52). Overall, TIL therapy was
found to induce complete, durable regressions
of metastatic melanoma at a higher rate than
any other treatment regardless of progression
of disease through prior treatment. Notably,
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ME64CH06-Hwu ARI 12 December 2012 17:37
among the 93 patients treated with TILs, 19
(20%) had complete remissions that have lasted
>3 years (52).
A distinct advantage of autologous TIL ther-
apy for metastatic melanoma is the broad nature
of the T cell recognition of both defined and
undefined tumor antigens against all possible
human leukocyte antigen (HLA) restrictions,
as opposed to the limited HLA coverage and/or
single-antigen reactivity of the newer TCR and
CAR transduction technologies (69). In addi-
tion, elegant studies that tracked the antigen
specificities of TILs associated with clinical ac-
tivity and isolated highly active T cell clones
have uncovered that the vast majority of CTLs
in TILs (the most critical population mediating
antitumor responses) do not recognize over-
expressed self/melanocyte differentiation anti-
gens, such as Melan-A/MART-1, gp100, and
tyrosinase, nor overexpressed tumor antigens
such as survivin, but instead recognize other
unknown antigens (70). This has raised the
question of whether the most potent trans-
ferred T cells in TIL therapy recognize mu-
tated, patient-specific antigens; these T cells
would not have been subjected to mechanisms
of central or peripheral tolerance and would
likely be of high affinity and avidity, presum-
ably leading to superior antitumor activity (71).
Another critical aspect of TIL therapy that
has made it such a powerful treatment option
is the development and application of a pa-
tient preparative regimen that transiently de-
pletes endogenous lymphocytes for a period of
a few weeks immediately before TIL infusion
(51). This involves pretreatment with a com-
bination of cyclophosphamide and fludaribine
starting one week prior to adoptive transfer
of expanded TILs. This protocol modification
was instrumental in catapulting objective re-
sponse rates to autologous TIL therapy from
20%–30% to >50% in the past decade (69, 70).
The rationale for prior lymphodepletion came
from work on animal tumor models showing
improved persistence and antitumor activity of
transferred T cells following lymphodepletion,
which is thought to eliminate the negative ef-
fects of other lymphocytes that may compete
for cytokines and T cell growth factors, in addi-
tion to depleting regulatory or inhibitory lym-
phocyte populations (72). Prior lymphodeple-
tion with cyclophosphamide and fludaribine is
now a routine regimen in centers across the
world performing TIL therapy for melanoma,
including our group at MD Anderson Cancer
Center, where we have reproduced the objec-
tive response rates originally observed at the
NCI (63, 64, 73).
The Future of T Cell–based
Immunotherapies
At present, TIL therapy has reached a tipping
point where we need to decide whether it
should be integrated into standard melanoma
care. Although it has shown great potential
to treat metastatic melanoma, a number of
issues need to be addressed before it enters
the mainstream of melanoma care. These limit
T cell therapy to specific types of patients,
depending on availability of a tumor specimen
for TIL derivation and the clinical status of
the patient. In addition, there is a need to
improve current manufacturing methods to
make them more practical and less costly, a
need to identify predictive biomarkers to better
select patients, and a need to perform definitive
clinical trials that finally prove efficacy for
licensing, especially for TILs.
Improvements in methods for expanding
TILs for therapy are needed, especially to min-
imize the time the T cells are in laboratory cul-
ture and to improve the memory and effector
characteristics of the T cells for longer persis-
tence and enhanced antitumor activity in vivo
(60, 73). TIL expansion has been a relatively
long and labor-intensive undertaking. Dissem-
ination of TIL therapy has also been ham-
pered by the need for large numbers of PBMC
“feeders” to perform the so-called “rapid ex-
pansion protocol” used to generate the final
infusion products, which consist of billions of
activated T cells (74). However, we now have
available new closed-system bioreactors and a
new artificial APC (aAPC) technology that can
overcome most of the current technical issues
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ME64CH06-Hwu ARI 12 December 2012 17:37
in large-scale TIL expansion. Based on the
immortalized K562 erythroleukemia cell line,
such aAPCs can also be genetically engineered
to express any desired T cell–activating or cos-
timulation molecule on the cell surface (75, 76).
Master cell banks of these first- and second-
generation aAPCs meeting regulatory guide-
lines are now available and promise to make
TIL therapy more practical and also grow T
cells with improved effector-memory qualities
that persist after adoptive transfer for longer pe-
riods of time. These aAPCs will also be critical
in expanding antigen-specific TCR-transduced
and CAR-transduced T cells for therapy by ex-
pressing the specific target on the aAPC sur-
face and the restricting HLA class I or class II
molecule (in the case of TCR transduction). It
is anticipated that, in the next decade, TIL and
other T cell production methods will be suf-
ficiently scaled-up with these new aAPC and
bioreactor technologies to make them widely
available to all melanoma patients through key
manufacturing and distribution sites across the
United States.
There is also a critical need to identify sur-
rogate and predictive biomarkers in order to
better select suitable patients for TIL therapy.
Recently, significant inroads have been made in
defining the phenotypes of T cells in TILs that
mediate tumor regressions. For example, CD8+
T cells are turning out to be critical, although
the exact subset of CD8+T cells exhibiting the
highest clinical activity in terms of memory and
effector markers still needs to be further defined
(52, 63, 64). In addition, analysis of the origi-
nal tumors used to grow TILs, together with
tracking of the yield and phenotypes of T cells
expanded for therapy, will be needed to deter-
mine what molecular signatures may be predic-
tive of good TIL expansion and which patients
will generate favorable responses. It is expected
that analysis of selected biomarkers in the blood
will be part of all future TIL therapy trials, and
eventually a validated set of biomarkers will ul-
timately be used to select patients for therapy.
One notable observation emerging from
TIL therapy trials at several centers is that pa-
tients treated with prior immunotherapy such
as IL-2, and more recently anti-CTLA-4 (ip-
ilimumab, discussed in the next section), had
higher clinical response rates and more durable
responses, suggesting a synergistic effect of
prior immunotherapy with TIL therapy (52).
These observations have prompted the plan-
ning of clinical trials that will combine adop-
tive TIL therapy with other immunotherapies,
such as cancer vaccines, ipilimumab, and anti-
PD-1. The rationale for this is twofold: (a)to
use these other treatments before TIL expan-
sion to increase T cell activation and enhance
infiltration into tumors, and (b) to use them con-
currently with TIL infusion to enhance tumor
cell killing, antigen release, and TIL function
in vivo.
IMMUNE CHECKPOINT
BLOCKADE
Development of a new class of effective cancer
immunotherapy agents has recently become
possible owing to advances in the understand-
ing of T cell activation and regulation. T cell
activation is initiated by interaction of the
TCR with antigen bound to MHC molecules.
However, effective T cell activation requires
costimulatory signals mediated by the binding
of CD28 on the T cell surface to B7 proteins
(such as CD80 or CD86) on APCs (Figures 1
and 3). These two signals allow T cells to begin
to proliferate, to acquire antitumor effector
functions, and eventually to migrate to disease
sites for tumor cell killing (77). T cell activation
is also tightly regulated by inhibitory signals
in order to avoid prolonged immune responses
that can potentially damage normal tissues.
These inhibitory mechanisms can be extrinsic
to T cells via cytokines such as IL-10 and
immunosuppressive cells such as regulatory
T cells and myeloid-derived suppressor cells.
Inhibitory signals can also be intrinsic to T
cells via immune checkpoint molecules, such as
cytotoxic T lymphocyte–associated protein 4
(CTLA-4) or programmed cell death 1 (PD-1)
(77, 78).
CTLA-4 is expressed by activated CD4
and CD8 T cells. It is a homologue of T cell
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Cytokine release
Cytokine release
Antibodies to block coinhibitory
signals: e.g. anti-CTLA-4, anti-PD-1
T cell
activation
Antigen-
presenting
cell
CD28 CD86
TCR MHC-Ag
T cell
ab
c
PD-1
CTLA-4
CTLA-4
PD-L1/2
T cell
inhibitory
Other coinhibitors
Antigen-
presenting
cell
Antigen-
presenting
cell
Figure 3
Immune checkpoint blockade therapies. (a) T cell activation starts with interaction of the T cell receptor
(TCR) on a T cell with major histocompatibility complex (MHC) bound to antigen (Ag) on an antigen-
presenting cell (APC). Optimal activation of the T cell requires additional signals that are provided by the
interaction between CD28 and CD86. (b) T cell activation is limited by cytotoxic T lymphocyte–associated
protein 4 (CTLA4), which is upregulated on activated T cells, where it outcompetes CD28 for binding to
CD86 on an APC. Additional regulation of T cell activity is also provided by later inhibitory signals through
other molecules such as PD1 (programmed cell death 1), which binds to PD1 ligand 1 and 2 (PD-L1/2).
Other coinhibitors of T cell activation include BTLA (B and T lymphocyte attenuator), LAG-3 (lymphocyte
activation gene 3), TIM3 (T cell immunoglobulin and mucin domain-containing protein 3), and VISTA
(V-domain immunoglobulin suppressor of T cell activation). (c) Strategies to maintain activated tumor-
specific T cells include the use of blocking monoclonal antibodies, such as antibodies targeting either
CTLA4 or PD1, to neutralize coinhibitory receptors. Therefore, these antibodies that block intrinsic
inhibitory immune checkpoints allow a sustained T cell response, including an increased production of
cytokines, such as tumor necrosis factor-α(TNF-α) and interferon-γ(IFN-γ).
costimulator CD28 but has a higher binding
affinity for its ligands. Upon T cell activation,
signaling pathways lead to the expression
of CTLA-4, which is then mobilized from
intracellular vesicles to the cell surface, where it
outcompetes costimulator CD28 for binding to
its ligands (e.g., CD86). Binding of CTLA-4 to
CD86 proteins interrupts CD28 costimulatory
signals and, as a result, limits T cell responses
(77, 78) (Figure 3). In addition to the intrinsic
restriction of effector T cell responses due to
expression of CTLA-4 on effector cells, there
can also be extrinsic restriction of effector T
cell responses due to the expression of CTLA-4
on regulatory T cells (79–81).
Because of the negative regulatory effects
of CTLA-4 on T cell responses, it was hypoth-
esized that blocking CTLA-4 signaling would
potentiate immune responses against tumor
cells. This idea of CTLA-4 signaling blockade
as anticancer therapy was first tested in animal
models by Jim Allison’s group in 1995. They
demonstrated that anti-CTLA-4 antibodies
were able to cause rejection of syngeneic
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ME64CH06-Hwu ARI 12 December 2012 17:37
transplanted tumors in mice (82). These pre-
clinical studies led to the eventual development
of an antibody to block human CTLA-4,
ipilimumab, which was shown in phase III clin-
ical trials to improve overall survival of patients
with advanced melanoma (83). Initial phase I
and II clinical trials in patients demonstrated
that ipilimumab treatment resulted in signifi-
cant antitumor activity (84, 85). Subsequently, a
phase III randomized controlled trial in patients
with metastatic melanoma showed that ipili-
mumab improved the median overall survival
by 3.7 months (10.1 versus 6.4 months; p =
0.003) (83). However, the most striking feature
of this study was the fact that ∼23% patients
with advanced melanoma survived >4 years.
This trial led to the approval of ipilimumab
by the FDA in March 2011 for the treatment
of patients with metastatic melanoma. Most
recently, a second randomized phase III clinical
trial showed that addition of ipilimumab to
standard dacarbazine chemotherapy signifi-
cantly improved overall survival by 2.1 months
in patients with metastatic melanoma (86),
which further confirmed the therapeutic
efficacy of ipilimumab against melanoma.
More importantly, anti-CTLA-4 therapy has
demonstrated the ability of immunotherapeu-
tic agents to elicit durable responses that can
last for years in a subset of patients.
Another important T cell checkpoint that
can be targeted clinically is the interaction of
PD-1 and its ligands. PD-1 is mainly expressed
by activated CD4 and CD8 T cells, as well as
APCs. It has two ligands, PD-L1 and PD-L2,
with distinct expression profiles (87). PD-L1 is
expressed not only on APCs but also on T cells,
B cells, and nonhematopoietic cells, including
tumor cells. Expression of PD-L2 is largely
restricted to APCs, including macrophages
and myeloid DCs, as well as mast cells. The
role of PD-1 as a negative regulator of T
and B cells was best demonstrated by the
finding that PD-1-deficient mice developed
significant autoimmunity with high titers
of autoantibodies (88, 89). Subsequently,
blocking antibodies against PD-1 were shown
to activate immune responses that resulted in
reduction of tumor metastasis and growth in a
number of experimental tumor models (90, 91).
Consistent with the immune inhibitory role
of PD-1/PD-L1/2 signaling, forced expression
of PD-L1 in murine tumor cell lines allowed
enhanced tumor growth in vivo, which was
otherwise kept in check by T cells. The inciting
effect of PD-L1 on tumor growth was reversed
by blocking anti-PD-L1 antibodies (92).
Consistent with these preclinical animal
studies, a phase I trial in 39 patients with re-
fractory metastatic melanoma, colorectal can-
cer, prostate cancer, non-small-cell lung can-
cer (NSCLC), or renal cell carcinoma (RCC)
demonstrated that anti-PD-1 antibody (MDX-
1106) treatment resulted in complete or par-
tial response in three patients and less signif-
icant tumor regression in two other patients
(93). A more recent phase I clinical trial with
an anti-PD-1 antibody (BMS-936558) showed
an 18%–28% objective response rate in patients
with advanced NSCLC, RCC, and melanoma
(94). In addition, another almost concurrent
phase I trial with anti-PD-L1 antibody demon-
strated an objective response rate of 6%–17%
in patients with advanced NSCLC, melanoma,
and RCC (95). Data from these early-phase
clinical studies show a very promising poten-
tial for employing blocking antibodies against
the inhibitory PD-1/PD-L1/2 signaling path-
way in anticancer immunotherapy.
In addition to CTLA-4 and PD-1, other
coinhibitory molecules on T cells include
BTLA (B and T lymphocyte attenuator),
LAG-3 (lymphocyte activation gene 3), TIM3
(T cell immunoglobulin and mucin domain-
containing protein 3), and VISTA (V-domain
immunoglobulin suppressor of T cell activa-
tion) (78). Blocking antibodies to these T cell
coinhibitors are currently being investigated,
but they are in the early stages of develop-
ment as potential anticancer agents. Moreover,
combination therapies using blocking antibod-
ies against these inhibitory immune-checkpoint
molecules along with other means of activating
T cells, as discussed below, may be required
for optimally effective cancer immunotherapy
(77).
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As with any novel cancer therapy, treatment
with immune checkpoint blockade agents is
sometimes associated with a distinct set of on-
target toxicities due to inflammatory conditions
termed immune-related adverse events (irAEs).
For example, among melanoma patients treated
with ipilimumab, up to 60% manifest irAEs
including dermatitis, colitis, hepatitis, and hy-
popituitarism (83). Therefore, early recogni-
tion, diagnosis, and treatment, including symp-
tom control and suppression of inflammatory
conditions with steroids, are critical for min-
imizing the adverse effects while maximizing
the therapeutic benefits of this promising anti-
cancer agent. The early phase I results targeting
the PD-1 pathway have shown less overall tox-
icity in cancer patients, although future studies
are required to confirm this. Investigations into
biomarkers/pathways that are associated with
or predict clinical benefit or toxicities will be
important as the field of cancer immunother-
apy moves forward. Recent studies in these ar-
eas have been promising (96, 97), and additional
studies are under way.
In summary, the recent successes with im-
mune checkpoint blockade agents have pro-
vided clear data to indicate that the immune
system can be harnessed to treat cancer and
that the exquisite abilities of immune responses
to adapt to mutations within tumor cells, as
well as generate memory cells to thwart recur-
rences, can lead to durable clinical benefit in pa-
tients. Furthermore, since ipilimumab and anti-
PD-1/PD-L1 target T cell–specific molecules,
as opposed to tumor-specific molecules, they
can potentially be effective against multiple tu-
mor types. Therefore, currently there are on-
going phase I/II trials with anti-CTLA-4 and
anti-PD-1 in multiple tumor types, including
NSCLC, prostate and pancreatic cancers, and
renal cell carcinoma. There are two ongoing
phase III clinical trials with anti-CTLA-4 in
patients with metastatic prostate cancer, and
their data should be available within the next
year. A phase III clinical trial of anti-PD-1 in
RCC is expected to begin patient accrual within
the next year. The exciting study results and
remarkable patient benefit with anti-CTLA-4
and anti-PD-1 have provided a strong founda-
tion on which to build for even greater success
as we determine how to best select patients for
treatment and how to combine immunother-
apy with other agents to increase the number
of patients who benefit.
CONCLUSIONS AND
FUTURE DIRECTIONS
Though outside the scope of this article, recent
generations of kinase-targeted agents such as
vemurafenib, which specifically inhibits the
mutated proto-oncogene BRAF expressed
by ∼50% of melanoma patients, have shown
striking clinical activity (98). Yet, although
these agents have induced objective responses
in the majority of treated patients, the dura-
bility of responses is only ∼7 months, and
nearly all patients eventually succumb to their
disease. In contrast, some patients treated
with immunotherapies, such as high-dose IL-2
or anti-CTLA-4 (ipilimumab), have demon-
strated long-term, durable responses; however,
as described above, the overall response rates
to these agents are low. Therefore, the ra-
tional combination of targeted therapies with
immunotherapies may allow higher rates of
more durable responses. In order to optimize
these combinations, three factors need to be
considered.
First, the effects of specific targeted agents
on the immune system must be evaluated. For
example, we have demonstrated that unlike
earlier generations of targeted agents, BRAF
inhibitors do not adversely affect immune re-
sponses in patients (99). In addition, it has been
demonstrated that BRAF inhibitors can induce
T cell infiltration into melanomas (100). In
contrast, other targeted agents such as imatinib
(Gleevec R
) have been demonstrated to inhibit
T cell function (101). The processes of T cell
activation and tumor growth share common
pathways, such as the MAPK/MEK pathway
and PI3K pathway, and therefore, it may
be anticipated that targeted agents blocking
these pathways have the potential to inhibit
immune function. Detailed studies of specific
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ME64CH06-Hwu ARI 12 December 2012 17:37
immune subsets affected are needed in order
to consider combination therapies with these
agents.
Second, elucidating the role of specific
oncogenic signaling pathways in the tumor
immune microenvironment is required. For ex-
ample, a number of immunosuppressive factors
have been described that are produced directly
by tumor cells or by stromal cells in response
to oncogene activation in tumors (102, 103).
Understanding the effects of oncogene activa-
tion on downstream immune modulation in the
tumor microenvironment will be critical for uti-
lizing targeted therapies to potentially reverse
immunosuppression, and may lead to synergy
between these strategies and immunotherapies.
Finally, preclinical studies are needed that
directly evaluate the combination of targeted
and immune therapies. This is challenging with
most current xenograft models because these
mice lack a functioning immune system. Trans-
plantable tumors in syngeneic mice that have
normal immune systems often lack specific
mutations that can be targeted. On the other
hand, many genetically engineered mouse mod-
els, while appearing more physiologic from a
cancer biology perspective, lack the antigenic
diversity seen in most human cancers; the over-
all number of mutations in tumors from these
models is most often low, in contrast to many
immunogenic human cancers such as cutaneous
melanoma. Because targeted agents may have
adverse effects on the immune system, studies of
dosing and scheduling may be important in the
development of ideal combination regimens.
Although many factors need to be consid-
ered, the combination of targeted therapies
with immunotherapies holds great promise.
Low-hanging fruit includes the combination of
BRAF inhibitors with anti-PD-1 or anti-PD-
L1 in melanoma patients; both of these agents
have significant clinical activity and are well tol-
erated. The future of cancer therapy clearly lies
in exploring new combination therapies, and we
look forward to seeing the results of many ex-
citing trials in the near future.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
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Annual Review of
Medicine
Volume 64, 2013
Contents
Abiraterone and Novel Antiandrogens: Overcoming Castration
Resistance in Prostate Cancer
R. Ferraldeschi, C. Pezaro, V. Karavasilis, and J. de Bono pppppppppppppppppppppppppppppppppp1
Antibody-Drug Conjugates in Cancer Therapy
Eric L. Sievers and Peter D. Senter ppppppppppppppppppppppppppppppppppppppppppppppppppppppppp15
Circulating Tumor Cells: From Bench to Bedside
Marija Balic, Anthony Williams, Henry Lin, Ram Datar, and Richard J. Cote ppppppppp31
Cytokines, Obesity, and Cancer: New Insights on Mechanisms Linking
Obesity to Cancer Risk and Progression
Candace A. Gilbert and Joyce M. Slingerland pppppppppppppppppppppppppppppppppppppppppppppp45
Glioblastoma: Molecular Analysis and Clinical Implications
Jason T. Huse, Eric Holland, and Lisa M. DeAngelis pppppppppppppppppppppppppppppppppppppp59
Harnessing the Power of the Immune System to Target Cancer
Gregory Liz´ee, Willem W. Overwijk, Laszlo Radvanyi, Jianjun Gao,
Padmanee Sharma, and Patrick Hwu pppppppppppppppppppppppppppppppppppppppppppppppppppp71
Human Papillomavirus Vaccines Six Years After Approval
Alan R. Shaw ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp91
Reduced-Intensity Hematopoietic Stem Cell Transplants for
Malignancies: Harnessing the Graft-Versus-Tumor Effect
Saar Gill and David L. Porter ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp101
The Need for Lymph Node Dissection in Nonmetastatic
Breast Cancer
Catherine Pesce and Monica Morrow pppppppppppppppppppppppppppppppppppppppppppppppppppppp119
The Role of Anti-Inflammatory Drugs in Colorectal Cancer
Dingzhi Wang and Raymond N. DuBois ppppppppppppppppppppppppppppppppppppppppppppppppp131
The Human Microbiome: From Symbiosis to Pathogenesis
Emiley A. Eloe-Fadrosh and David A. Rasko ppppppppppppppppppppppppppppppppppppppppppppp145
The Rotavirus Saga Revisited
Alan R. Shaw ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp165
v
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Staphylococcal Infections: Mechanisms of Biofilm Maturation and
Detachment as Critical Determinants of Pathogenicity
Michael Otto pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp175
Toward a Universal Influenza Virus Vaccine: Prospects and Challenges
Natalie Pica and Peter Palese pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp189
Host Genetics of HIV Acquisition and Viral Control
Patrick R. Shea, Kevin V. Shianna, Mary Carrington,
and David B. Goldstein pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp203
Systemic and Topical Drugs for the Prevention of HIV Infection:
Antiretroviral Pre-exposure Prophylaxis
Jared Baeten and Connie Celum ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp219
Hyperaldosteronism as a Common Cause of Resistant Hypertension
David A. Calhoun pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp233
Mechanisms of Premature Atherosclerosis in Rheumatoid
Arthritis and Lupus
J. Michelle Kahlenberg and Mariana J. Kaplan pppppppppppppppppppppppppppppppppppppppppp249
Molecular Mechanisms in Progressive Idiopathic Pulmonary Fibrosis
Mark P. Steele and David A. Schwartz ppppppppppppppppppppppppppppppppppppppppppppppppppp265
Reprogrammed Cells for Disease Modeling and Regenerative Medicine
Anne B.C. Cherry and George Q. Daley pppppppppppppppppppppppppppppppppppppppppppppppppp277
Application of Metabolomics to Diagnosis of Insulin Resistance
Michael V. Milburn and Kay A. Lawton pppppppppppppppppppppppppppppppppppppppppppppppppp291
Defective Complement Inhibitory Function Predisposes
to Renal Disease
Anuja Java, John Atkinson, and Jane Salmon ppppppppppppppppppppppppppppppppppppppppppp307
New Therapies for Gout
Daria B. Crittenden and Michael H. Pillinger ppppppppppppppppppppppppppppppppppppppppppp325
Pathogenesis of Immunoglobulin A Nephropathy: Recent Insight
from Genetic Studies
Krzysztof Kiryluk, Jan Novak, and Ali G. Gharavi ppppppppppppppppppppppppppppppppppppp339
Podocyte Biology and Pathogenesis of Kidney Disease
Jochen Reiser and Sanja Sever ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp357
Toward the Treatment and Prevention of Alzheimer’s Disease:
Rational Strategies and Recent Progress
Sam Gandy and Steven T. DeKosky ppppppppppppppppppppppppppppppppppppppppppppppppppppppp367
Psychiatry’s Integration with Medicine: The Role of DSM-5
David J. Kupfer, Emily A. Kuhl, Lawson Wulsin pppppppppppppppppppppppppppppppppppppppp385
vi Contents
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ME64-frontmatter ARI 18 December 2012 10:19
Update on Typical and Atypical Antipsychotic Drugs
Herbert Y. Meltzer ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp393
Ataluren as an Agent for Therapeutic Nonsense Suppression
Stuart W. Peltz, Manal Morsy, Ellen M. Welch, and Allan Jacobson pppppppppppppppppp407
Treating the Developing Brain: Implications from Human Imaging
and Mouse Genetics
B.J. Casey, Siobhan S. Pattwell, Charles E. Glatt, and Francis S. Lee pppppppppppppppppp427
Genetic Basis of Intellectual Disability
Jay W. Ellison, Jill A. Rosenfeld, and Lisa G. Shaffer ppppppppppppppppppppppppppppppppppp441
Sickle Cell Disease, Vasculopathy, and Therapeutics
Adetola A. Kassim and Michael R. DeBaun pppppppppppppppppppppppppppppppppppppppppppppp451
Duty-Hour Limits and Patient Care and Resident Outcomes: Can
High-Quality Studies Offer Insight into Complex Relationships?
Ingrid Philibert, Thomas Nasca, Timothy Brigham, and Jane Shapiro ppppppppppppppppp467
Quality Measurement in Healthcare
Eliot J. Lazar, Peter Fleischut, and Brian K. Regan ppppppppppppppppppppppppppppppppppppp485
Indexes
Cumulative Index of Contributing Authors, Volumes 60–64 ppppppppppppppppppppppppppp497
Article Titles, Volumes 60–64 ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp501
Errata
An online log of corrections to Annual Review of Medicine articles may be found at
http://med.annualreviews.org/errata.shtml
Contents vii
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