Engineered T-Cell Therapy: The Next Direction for
RCC Immuno-oncology?
JJ H. Zhang, MD,1 Neal A. Patel, MD,1 Alexandra Drakaki, MD, PhD,1,2 Allan J. Pantuck, MD1,*
1) Institute of Urologic Oncology, Department of Urology, University of California Los Angeles, Los Angeles CA
2) Department of Hematology and Oncology, University of California Los Angeles, Los Angeles CA
ABSTRACT
Synthetic biology in the form of engineered antigen specific T-cells for
cancer immunotherapy has demonstrated its potential to revolutionize
cancer treatment. However, whereas engineered T-cell therapy is already well
established in the treatment of hematologic malignancies, it remains only in
the pre-clinical and early clinical development stages in solid organ cancers
including RCC. In this review, we consider three T-cell target antigens that
have already reached the clinic for kidney cancer, and discuss future novel
directions including harnessing the immune system against patient specific
neoantigens.
INTRODUCTION
.
Synthetic biology in the form
of engineered antigen specific
T-cells for cancer immunotherapy
holds promising potential to
revolutionize the treatment of advanced
solid malignancies. Chimeric
Antigen Receptor T-cells, or CAR
T-cells, are engineered to express
chimeric antigen receptors to target
tumor-associated antigens independently
of the major histocompatibility
complex (MHC).1 Hence, they
mimic both antibody-based antigen
recognition with T-cell receptor
function to enable antitumor activity
by lysis of the target cells. The
genetically engineered CAR fusion
protein is transduced ex vivo by means
of retroviral or lentiviral vectors
into autologous T-cells collected by
leukapheresis. Subsequently, CAR
T-cells are re-infused into patients
following a lymphodepleting conditioning
regimen to enable further
T-cell expansion and personalized
targeted therapy.2
.
The primary advantage of CARs
is their ability to recognize tumors based
on binding with a single chain variable
fragment (scFv) derived from a tumorspecific
antibody, and therefore to target
antigens expressed on the cell surface
without MHC restriction. Autologous
CAR T-cell therapy eliminates the
potential risk of allogeneic reaction at
the expense of a longer manufacturing
time due to leukapheresis requirement
for every patient, leading to treatment
delays and higher manufacturing
costs.3 The concept of adoptive transfer
of allogeneic CAR T-cells using “off the
shelf” as opposed to “made to order,”
personalized T-cells aims to address
these limitations. The use of allogeneic
CAR T-cells from healthy donors has
been explored with distinct advantages
over autologous therapies, including
the potential for standardization
of CAR T-cell therapy, increased
availability of therapy, ease of redosing
or combination of CAR T-cells
against multiple targets, decreased
time and potentially decreased cost.3
However, one prominent drawback
of allogeneic T-cells is the risk of a
life-threatening graft vs host disease
(GVHD) necessitating further gene
editing techniques to avoid the native
TCRs of the donor cells recognizing
and attacking recipient host tissues
as foreign. The second drawback of
allogeneic T-cells includes risk of rapid
elimination by the host immune system,
leading to treatment failure.3
.
T cell receptor-engineered
T-cells (TCR-T) represent an alternative
way to utilize autologous T lymphocytes
to target tumor cells. Mechanistically
they differ from CAR-T as they rely
on antigen specificity derived from
recombinant transduced antigenspecific
T-cell receptors rather the
antibody binding and recognition,
which therefore requires MHC copresentation
of the tumor antigens to
initiate a further intracellular immune
signaling cascade.4 This is potentially
advantageous as targets are not
limited to cell surface proteins but can
be expanded to include intracellular
antigen fragments that are presented
by MHC proteins. In order to design an
effective TCR-T, unique polypeptides
that are presented by tumors cells must
be identified and then a TCR with a
higher affinity to that specific antigen
can be genetically engineered.5 If an
appropriate target is selected, TCR-T
can be a highly effective therapy because
only a small amount of tumor antigen is
needed to stimulate a robust response
as TCR-T rely on native T-cell signaling
transduction mechanisms.6 However,
similarly to CAR-T, polypeptides
that are also cross-expressed in
normal tissue must be screened out
to limit on target, off tumor toxicity
resulting from cytotoxicity of normal
cells sharing expression of the target
antigen. For example, TCR-T cells
targeting MART-1 and MAGE-A3 led
to lethal cardiotoxicity in patients with
metastatic melanoma in clinical studies,
as both target antigens are highly
expressed in cardiac tissue.7,8 Both
TCR-T and CAR-T have demonstrated
striking advancements in the treatment
of hematologic malignancies resulting
in new standard of care paradigms
and the potential for long-term durable
cures of refractory liquid tumors, but
currently with only limited efficacy in
the treatment of solid tumors.2,4
.
Background
.
CAR T-cells have evolved over three
generations of CAR constructs to
improve the antitumor cytotoxicity
and CAR-T cell persistence through the
addition of costimulatory domains.1,2,9
The first-generation CAR construct
includes a single-chain variable
fragment (scFv) antigen-recognition
domain, a transmembrane domain,
and an intracellular T-cell activation
domain derived from CD3 zeta chain.
The 2nd generation CAR that is utilized
by commercial CAR T-cell products
in hematologic malignancies included
the addition of a costimulatory domain
(either CD28 or 4-1BB). Finally, the
3rd generation CAR incorporates two
distinct costimulatory domains (e.g.,
both CD28 and 4-1BB).2,9 The choice of
costimulatory domain may affect T-cell
proliferation and persistence1,10
.
The earliest established clinical
use of CAR T-cells lies in Hematologic
malignancies including leukemias
and lymphomas.2 The Landmark
Phase II ELIANA trial of anti-CD19
CAR T-cell therapy Tisagenlecleucel-T
demonstrated 81% overall remission
within 3 months11 and led to the FDA
approval of tisagenlecleucel-T in August
2017 for Acute Lymphoblastic Leukemia
(ALL) in pediatrics and adults up to
age 25.11 The first CAR T-cell therapy
for lymphoma was FDA approved after
the ZUMA-1 trial of Axicabtagene
ciloleucel that demonstrated efficacy
of autologous anti-CD19 CAR T-cell
therapy in patients with relapsed,
refractory large B-cell lymphoma after
failure of conventional therapy.12 In
total, three CAR T-cell products have
been approved to treat relapsed or
refractory aggressive B-cell lymphomas:
Tisagenlcleucel, axicabtagene ciloleucel,
and lisocabtagene maraleucel.13 In
contrast, data on CAR T-cell therapy
in solid tumors thus far suggests
less robust responses and greater
challenges.2,14 To date, no CAR T-cell
products have been FDA approved for
treatment of solid organ malignancies,
but some progress has been achieved
in pre-clinical and clinical studies of
CAR-T and TCR-T in osteosarcoma and
gynecologic malignancies.15,16 Ovarian
cancer TCR-T candidate targets have
focused on melanoma-associated
antigen 4 (MAGE-A4) and New York
esophageal squamous cell carcinoma 1
(NY-ESO-1) both commonly expressed
by ovarian cancer cells. The ongoing
NCT03132922 clinical trial for MAGE-
4 TCR-T in multiple cancers including
ovarian, bladder, esophageal, head and
neck, bladder, melanoma, and synovial
sarcoma demonstrated interim partial
response in 7 of 28 patients and stable
disease in 11 of 28 patients at the
cost of significant adverse events.17
Clinical studies have been conducted
to evaluate human epidermal growth
factor receptor 2 (HER2)-specific
CAR T-cells in patients with HER2-
positive sarcoma, demonstrating
T-cell persistence for at least 6 weeks
without significant toxicity.16 A positive
clinical response was demonstrating by
administering a single agent ultra-low
dose of HER2-Car T-cells to 19 sarcoma
patients with recurrent or refractory
metastatic disease, with subsequent
dose escalation to bypass the need
for concurrent lymphodepleting
chemotherapy.16 However, none of the
19 patients demonstrated a complete
response although 4 of 17 measurable
patients had stable disease for 12 weeks
to 14 months by RECIST criteria.16
.
CAR T-cells for Renal Cell
Carcinoma
The utilization of CAR T-cells for
solid organ malignancies, including
renal cell carcinoma (RCC), is subject
to numerous challenges including
suppression of T-cell function,
inhibition of T-cell localization, toxicity
leading to adverse events, and lack of
therapeutic response. As of 2020, there
were 196 clinical trials of CAR T-cells
targeting 57 unique solid tumor entities
registered at clinicaltrials.gov, the
majority of which were performed in the
USA and China.9 Clear cell renal cell
carcinoma (ccRCC) is an immunogenic
tumor type with moderate tumor
mutational burden of 1.42 mutations
per megabase18 that has proven to
benefit from both cytokine-based and
checkpoint inhibitor immunotherapies
in advanced and metastatic disease.19,20
However, despite its theoretical promise
as an immune-sensitive malignancy,
no large clinical trials yet exist for
CAR T-cell therapy in RCC. Safety
and efficacy are two major limitations
that prevent CAR-T therapy from
proceeding to clinical trials in RCC.
To maximize both safety and efficacy
of CAR T-cell immunologic response,
antigen selection is vital to reduce offtarget
toxicity. In the current review,
we examine the furthest developed
candidates for CAR-T therapy in RCC.
.
CAIX
Carbonic anhydrase-IX (CAIX) is a
54/58 kDa transmembrane tumorassociated
antigen and marker of
hypoxia that belongs to the family
of carbonic anhydrases, a family of
zinc metalloenzymes that catalyzes
hydration of CO2 for pH balance in
living organisms.21 The CAIX gene is
directly activated at a transcriptional
level by hypoxia-inducible factor
(HIF)-1a leading to proton transport
to extracellular medium to lower pH.
Therefore CAIX expression serves
as a surrogate marker for hypoxia in
some tumors.21,22 Specifically for RCC,
CAIX is overexpressed in over 90%
of ccRCC and over 80% of metastases
but not on neighboring normal renal
parenchyma.21,23 Patients with Von
Hippel Lindau (VHL) mutation
characterized by predisposition to
ccRCC have also been demonstrated to
have higher CAIX expression than those
with wildtype VHL.24 CAIX serves as
an important prognostic biomarker in
patients with ccRCC, with high CAIX
score on immunohistochemical staining
associated with improved disease
free survival and overall survival.25
Conversely, low CAIX expression and
absence of VHL mutation is associated
with more advanced disease and
decreased survival.24 In addition to
RCC, CAIX is overexpressed in several
other solid tumor types including
carcinomas including ovarian, breast,
esophageal, bladder, colon, non-small
cell lung, dysplasia of cervix and
others.21 CAIX has also been proposed
historically to be a prognostic marker
for favorable response in IL-2 treated
patients with RCC,26 though this was
not demonstrated prospectively when
tested in the SELECT study.
.
Prior to preclinical studies,
in vitro and in vivo studies focused
on constructing CAR using anti-
CAIX scFv.21,27 Lo et al evaluated five
anti-CAIX single chain antibodies
as candidates for CAR construction
and constructed two generations of
anti-CAIX CARs using the selected
scFvG36 CAR-targeting moiety. They
reported in vitro comparisons of
both21 to confirm superior effector
functions of second generation G36-
CD28z CAR T-cells compared with first
generation constructs in all in vitro
assays including IFN-y, IL-2, and IL-
17 cytokine secretion, cytolytic activity,
proliferation, and clonal expansion.21
The same group then reported in vivo
superior antitumor activity of second
generation CAR T-cells against RCC21
after adoptive transfer of CAR T-cells
combined with high-dose interleukin
(IL)-2 into RCC-established mice,
demonstrating tumor cell apoptosis and
regression of CAIX+sk-rc-52 tumors in
vivo.21
.
The first clinical study of
T-cells genetically modified to express
a CAR against CAIX was published
in 2006 as a proof of principle that
autologous CAR T-cell transfer can
be accomplished in metastatic RCC to
provide tumor-specific immunity.28
A single chain antibody-type receptor
construct that recognizes CAIX was
transduced into primary human T-cells.
These autologous genetically retargeted
T-lymphocytes were administered
to three patients with CAIX-positive
metastatic clear cell carcinoma who had
already undergone radical nephrectomy
with metastasis refractory to treatment
with interferon alpha.28 The study
was not designed to assess clinical
efficacy but did confirm off-tumor
T-cell mediated cytotoxic effects: two
of three patients required cessation of
therapy due to hepatotoxicity per NCI
Common Toxicity Criteria grades 2-4.28
Liver biopsy confirmed cholangitis
with T-cell infiltration of bile ducts
and CAIX expression on bile duct
epithelial cells, suggesting antigenspecific
immunologic mechanism.28
A follow-up study by the same group
utilized CAIX CAR-T in 12 patients with
CAIX-expressing metastatic RCC and
demonstrated increased plasma levels
of interferon-gamma, IL-2, and tumor
necrosis factor (TNF)-alpha. Similar
to prior study, they confirmed grade
2-4 hepatotoxicity at the lowest CAR T
doses with CAIX expression and T-cell
infiltration on bile duct epithelium,
but with the notable novel finding that
pre-treatment with CAIX monoclonal
antibody G250 helped to circumvent
CAR-specific hepatotoxicity.29 This
provided additional proof of principle
that the on-target toxicity is antigendirected,
as blockage of CAR-specific
antigen expressed on normal tissue
improved the toxicity profile to allow
higher doses.29 There is a dose
escalation and expansion clinical trial
of CAIX-targeted CAR-T cells in the
treatment of advanced RCC that is
ongoing at The Affiliated Hospital of
Xuzhou Medical Center (ClinicalTrials.
gov Identifier NCT04969354).30 New
progress has been made in creating
CAIX-targeted CAR T-cells with
different cellular composition in the
ccRCC mouse model, more specifically
with a CD4/CD8 ratio of 2:1 (CAR 4/8)
to balance cytolytic CD8 T-cell killing
capacity with cytokine-induced effect
of CD4 T-cells.31 Indeed, early results
demonstrated superior antitumor
efficacy in the ccRCC orthotopic mouse
model, increased memory phenotype,
and decreased exhaustion genes
compared to CAR8 T-cell groups.31
More recent attempts to target CAIX
with CAR-T cells while avoiding the
observed on-target off-tumor toxicities
noted above have led to the development
of dual-targeted CAR-T constructs that
require targeting and binding of two
unique antigens to mediate cellular
cytotoxicity. Early pre-clinical data on
such a dual construct that targets both
CAIX and CD70 (see section below) has
been reported.32
.
CD70
CD70, a ligand for CD27, is a
costimulatory receptor involved in
T-cell proliferation and survival.33,34
CD70 was initially identified as a
diagnostic marker for ccRCC by gene
expression profiling, real time RT-PCR
and IHC.35 A postulated mechanism
of CD70 overexpression is due to
dysregulated pVHL/HIF pathway in
RCC.36 RCC and other solid tumors
can constitutively overexpress CD70,
making it an effective target of CAR-T
cells in vitro and in vivo.37,38 Clinical
studies of CD70-expressing RCC and
other targeted treatment modalities
have demonstrated its potential as a
target: an antibody-drug conjugate
targeting CD70 (SGN-CD70A) has
been tested in a phase I clinical trial
for patients with CD70-positive
metastatic RCC demonstrating modest
clinical results including 13 of 18 with
stable disease but only 1 with partial
response per RECIST 1.1.39 Aside from
RCC, other CD70-expressing tumors
include glioblastoma, and hematologic
malignancies.
.
Published preclinical data
supports the feasibility and safety of
using anti-human CD70 CAR to treat
cancer patients whose tumors express
CD70.40 Seven candidate anti-human
CD70 CARs consisting of extracellular
binding portion of CD27 fused with
41BB and/or CD3-zeta were constructed
for in vitro studies and in vivo adoptive
transfer into a CD27-CD3-zeta CAR
murine model. In vitro results
demonstrated that the CAR consisting
of extracellular binding portion of
CD27 fused with 41BB and CD3-zeta
conferred the highest IFNy production
against CD70-expressing tumors.40
In vivo data for renal cell carcinoma
demonstrates that mouse xenografts
treated with CD70 CAR-T cells showed
significantly decreased RCC burden,
longer survival times than mice
treated with controls (PBS, T-cells, or
mock CAR-T cells). In addition, higher
cytokine levels of IL-2, TNF-alpha, and
IFNy were secreted in peripheral blood
of mice treated with CD70 CAR-T cells
compared to controls, suggesting that
CD70 CAR-T cells may be effective
in treating CD70+ RCCs in vivo.38
.
Clinical trials with CD70 CAR-T cells
have recently entered the clinic, with
the TRAVERSE trial using allogeneic,
TALEN gene edited ALLO-316 anti-
CD70 T-cells being given Fast Track
Designation for the US FDA based on its
potential to address an unmet medical
need for patients with advanced RCC
who have progressed on approved
therapies.41–43
.
HERV-E
VHL-deficient ccRCC commonly
express transcripts derived from novel
human endogenous retrovirus HERV-E.
In current literature there are no in-vitro
or in-vivo studies of CAR-T targeting
HERV-E in RCC, but advancements
have been achieved in the development
of TCR-T targeting HERV-E.44–47
HERV-E was first identified as a target
antigen of RCC-specific CD8+ T-cells
due to expression in RCC cell lines and
fresh RCC tissue but not in normal
kidney or other tissues.47 To provide
a clinical proof of principle, T-cells
targeting to HERV-E family antigens
mediated regression of metastatic RCC
in a stem cell transplant recipient.47
Subsequently, HERV-E expression was
demonstrated to restrict to ccRCC by
mechanism of inactivation of the VHL
tumor suppressor and stabilization of
HIFs.46 HERV-E expression in ccRCC
demonstrated linear correlation to
HIF-2alpha levels, while transfection
of normal VHL successfully silenced
HERV-E expression.46 Cherkasova
et al confirmed that T-cells could
recognize HLA-A+0201-positive
HERV-E-expressing kidney tumor
cells suggesting HERV-E envelope
peptides as tumor-restricted targets.45
In a separate paper, RNA-seq analysis
was performed on RCC tumor samples
to determine whether response to
Nivolumab was associated with HERV
expression, with finding of no association
between T-cell reactivity to HERVs and
nivolumab response,48 though other
published data have supported such an
association.49 Taken collectively, these
studies suggest prominent potential for
future TCR-T or CAR-T against HERV-E
in ccRCC. Studies of other tumors have
demonstrated the feasibility of CAR
T-cell specific for other HERV subtypes:
In vivo studies of CAR T-cell generated
for breast cancer demonstrated
downregulation of HERV-K expression
in tumors of mice treated w/ CAR
T-cell for HERV-K, upregulation of 53,
downregulation of MDM2 and p-ERK.50
Additionally, HERV-K env-specific CAR
T-cells demonstrated lysis of HERV-K
env(+) tumor targets in melanoma.51
A clinical trial at National Institutes
of Health (NCT03354390) is currently
ongoing to evaluate the effectiveness
and safety of HERV-E TCR transduced
autologous T-cells when infused in
patients with metastatic ccRCC.52
.
Neoantigens and other Tumor
Antigen Targets
Personalized neoantigen-based
immunotherapy, based on a patient’s
tumor-specific somatic mutational
profile, represents the most
individualized form of immunotherapy
when incorporated into neoantigen
long peptide vaccines, dendritic cell
vaccines, and neoantigen-reactive
T-cells (NRTs).53 Neoantigens are
epitope peptides that originate from
somatic variants in tumor cells and
bind with a patient’s MHC to elicit
T-cell mediated antitumor response.
Neoantigen candidates may be
identified for a specific patient through
genomic and transcriptomic profiling
of the tumor and administered via
personalized neoantigen vaccination.
Neoantigens are advantageous as
immunologic targets due to specific
expression in tumor cells and not
normal cells, thereby minimizing the
risk of autoimmunity.53 Neoantigenbased
cancer immunotherapy has
demonstrated therapeutic efficacy in
multiple solid tumors including small
cell lung cancer54 and glioblastoma.55
Robust data has been published in the
pancreatic cancer literature utilizing
TCR-T cells targeting neoantigen
mutant KRAS G12D expressed in a
patient’s tumors, leading to overall
partial response of 72% by RECIST
criteria at 6 months.56 There is
currently limited data on neoantigenbased
immunotherapy in renal cell
carcinoma, but at least one case report
has demonstrated the feasibility
of neoantigen-reactive T-cells in a
patient with metastatic collecting
duct carcinoma refractory to tyrosine
kinase inhibitor. Post-therapy biopsy
demonstrated reduction in mutant
allele frequency corresponding to
12/13 of the neoantigens compared
to pre-therapy biopsy, indicating
therapeutic efficacy against tumor cells
carrying these neoantigens. The patient
demonstrated stable tumor burden
and significant reduction in bone pain
within 3 months.53
.
Renal cell carcinoma has a
relatively low tumor mutational burden
(TMB) but discrepantly high response
to PD-1 inhibition, which counters
the association between high TMB
and response to immune checkpoint
blockade.57 This discordance may lie in
small insertions and deletions (indels),
as whole-exome sequencing data
demonstrates the highest proportion
of indels in RCC when compared to
a pan-cancer cohort including 5777
solid tumors.58 Therefore, neoantigenbased
therapy may be particularly
beneficial for renal cell carcinoma
due to high immunogenicity of RCC
despite relatively low mutation load:
neoantigens derived from indel
mutations were found to be 9x enriched
for mutant specific binding compared
to single nucleotide variant derived
neoantigens, suggesting that Indels
may be the key to activating increased
neoantigens and increased mutantbinding
specificity in RCC.58
.
Other specific tumor-associated
antigens highly aberrantly expressed
and mutated in RCC have been identified
as potential RCC-specific neoantigen
targets for mRNA vaccine development
including DNA topoisomerase II alpha
(TOP2A), neutrophil cytosol factor 4
(NCF4), formin-like protein 1 (FMNL1)
and docking protein 3 (DOK3).59 Other
potential tumor antigen candidates
for engineered T-cell therapy in RCC
include vascular endothelial growth
factor receptor 1 (VEGFR1) associated
with RCC angiogenesis that has
demonstrated good peptide-specific
cytotoxic lymphocyte response when
administered in a phase I vaccine trial.57
Hypoxia-inducible protein 2 (HIG2)
is a growth factor expressed in 86% of
RCC that demonstrated HIG2-specific
CTL response in 8 of 9 patients after
vaccination of a specific HIG2 peptide.57
.
CONCLUSIONS
Engineered T-cell therapy is
well established in hematologic
malignancies but remains in preclinical
and early clinical development
for clinical applicability in solid organs
including RCC. Current literature
suggests that CAIX, CD70 are the
primary candidate target antigens for
CAR T-cell design for RCC, and HERV-E
has demonstrated great promise as a
target in ccRCC TCR-T therapy. Future
strategies should direct towards finding
an optimal target antigen for RCC and
minimizing off-target toxicity prior to
large-scale clinical trials. The current
clinical studies of CAR T-cell therapy
in other solid organs include patients
with refractory or recurrent metastatic
disease after failure of conventional
chemotherapy. In this landscape and in
part due to the risk of adverse events,
we anticipate that the optimal CAR
T-cell therapy candidate in the RCC
space should also demonstrate failure of
conventional approved therapies. CAR
T-cells for RCC should be intended to
target advanced and refractory disease,
or those with strict contraindication
to more established immunotherapy.
Furthermore, future directions of CAR
T-cell therapy include its potential use in
combination with established immune
checkpoint blockade for synergistic
effect. With potential life-threatening
adverse events representing a major
barrier to CAR T-cell therapy in RCC,
we emphasize a need to confirm safety
and efficacy before progressing to large
clinical trials.
DISCLOSURES
A.J.P. is a consultant for T Cure, a
company that has licensed and is
developing HERV-E CAR-T for renal cell
carcinoma. No additional disclosures
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Correspondence to: Allan J. Pantuck, MD, MS, FACS
UCLA Institute of Urologic Oncology, Department of Urology; David Geffen School of Medicine at UCLA.
Email: apantuck@mednet.ucla.edu
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