T cells genetically engineered to express chimeric antigen receptors (CAR) have proven an impressive therapeutic activity in patients with certain subtypes of B cell leukaemia or lymphoma, with promising efficacy also demonstrated in patients with multiple myeloma. However, in patients with solid tumors, objective responses to CAR-T cell therapy remain sporadic and transient. Key challenges relating to CAR T cells include the lack of tumor exclusive target, restricted CAR-T cell trafficking to tumor sites, antigen escape and heterogeneity as well as a highly immunosuppressive microenvironment. In this report, we review the current state of the CAR-T technologies as a clinical treatment in solid tumor and we highlight the preclinical innovative designs of novel CAR T cell products that are being developed to increase and expand the clinical benefits of these treatments in patients with solid malignancies.
2. 2
ABSTRACT:
T cells genetically engineered to express chimeric antigen receptors (CAR) have proven an
impressive therapeutic activity in patients with certain subtypes of B cell leukaemia or lymphoma,
with promising efficacy also demonstrated in patients with multiple myeloma. However, in patients
with solid tumors, objective responses to CAR-T cell therapy remain sporadic and transient. Key
challenges relating to CAR T cells include the lack of tumor exclusive target, restricted CAR-T cell
trafficking to tumor sites, antigen escape and heterogeneity as well as a highly
immunosuppressive microenvironment. In this report, we review the current state of the CAR-T
technologies as a clinical treatment in solid tumor and we highlight the preclinical innovative
designs of novel CAR T cell products that are being developed to increase and expand the clinical
benefits of these treatments in patients with solid malignancies.
3. 3
PLAN:
INTRODUCTION
1 Specificity of solid tumors and associated challenges for CAR-T therapies
1.1. Trafficking and infiltration into tumor tissue
1.2. Immunosuppressive tumor microenvironment
1.3 Tumor heterogeneity
1.4 Paucity of tumor-specific targets
2 Clinical investigations of CAR-T cells in solid tumors
3 Strategies to overcome CAR-T Cell therapy roadblocks for solid tumors
3.1 Trafficking into the tumors
3.2 Tumor heterogeneity and antigen dilemma
3.3.1 Ensuring tumor specificity
3.3.2 Avoiding antigen loss
3.3 Overcoming the solid tumor microenvironment
3.4 Mitigating Clinical toxicities
CONCLUSION
REFERENCES
4. 4
INTRODUCTION:
Chimeric antigen receptor (CAR) are genetically engineered, artificial fusion proteins that
incorporate an extracellular antigen-recognition domain, a transmembrane and hinge domain that
anchors the receptor on the cell surface and an intracellular T-cell signaling domain that is
activated upon antigen engagement. The CAR construct is transfected into autologous or
allogeneic peripheral blood T cells using plasmid transfection, mRNA or viral vector transduction.
The T cells are then infused into the patient to target surface exposed tumor antigen. Upon CAR
engagement of its associated antigen, primary T-cell are activated thus leading to cytokine
release, cytolytic degranulation and T cell proliferation.
Genetic engineering of T cells to express CAR directed against specific antigens has opened the
door to a new era of cancer therapy. The greatest advances for CAR T cells have been
established in the treatment of hematological malignancies with the United States Food and Drug
Administration (FDA) having approved five CAR-T cell therapies. Kymriah (tisagenlecleucel,
Novartis) and Yescarta (axicabtagene ciloleucel, Gilead-Kite), were approved for clinical
application in 2017, Tecartus (brexucabtagene autoleucel, Gilead-Kite) in 2020 and Breyanzi
(lisocabtagene maraleucel, BMS-Juno). These CAR-T products targeting the CD19 antigen
expressed in B cells allow patients with relapse or refractory B cell malignancies achieved
complete remission rates up to 90% (1). Abecma (idecabtagene vicleucel, BMS-Juno) a BCMA-
CAR-T was also recently approved in multiple myeloma.
Kymriah was first approved for the treatment of patients up to 25 years of age with B-cell precursor
acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. This approval
followed several key studies that demonstrated complete remission (CR) rates between 60 and
90% in patients with heavily pretreated, relapsed/refractory B cell ALL (2). Subsequently,
Yescarta, was approved for large B-cell lymphoma patients who have failed at least 2 prior
therapies. This therapy results in CR in approximately half of patients with refractory B cell
lymphoma, with some remissions having been sustained for over three years (3). Kymriah was
also approved for adult patients with relapsed or refractory large B-cell lymphoma after two or
more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL), high grade B-
cell lymphoma, and DLBCL arising from follicular lymphoma. Tetcartus was approved for the
treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL). The results
of a study in which 87 percent of patients responded to a single infusion of Tecartus, including 62
percent of patients achieving a complete response (CR) (4). Breyanzi was approved for relapsed
or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma, high-grade B-cell
lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3. Its
approval was based on safety and efficacy data from a multicenter clinical trial of 268 patients
with refractory or relapsed large B-cell lymphoma, 73 percent of patients achieved a response,
including 54 percent who achieved complete remission (5).
In contrast to these promising results in hematologic malignancies, CAR-T cell therapy has been
much less effective against solid tumors. Solid tumors present unique set of challenges, including
a lack of robustly expressed tumor exclusive antigen targets, an immunosuppressive tumor
microenvironment (TME) and a poor infiltration rate by CAR-T. The goal of this report is to review
obstacles to therapeutic success of CAR-T in solid tumors, key learnings from clinical trials and
current strategies developed to tackle the specificity of solid malignancies.
5. 5
1. Specificity of solid tumors and associated challenges for CAR-T therapies
1.1. Trafficking and infiltration into tumor tissue
Tumor cells present in the blood and are usually easily captured by CAR-T cells; in
contrast, solid tumors exist deep in the body, and it is difficult for T cells to access them.
In contrast to liquid tumors, solid tumors present a physical barrier that limit adoptively
transferred T cells abilities to infiltrate, target and kill tumor cells. Barriers to infiltration
include tumor vasculature with downregulated expression of adhesion molecules
necessary for T cell extravasation from the endothelium into tumors, as well as a dense
fibrotic network of extracellular matrix (ECM) protein that hinders T cell mobility (6). In
addition, the microenvironmental conditions resulting from abnormal metabolism of
tumors, which are usually characterized by elevated interstitial fluid pressure, a low pH,
hypoxia, and a reduced bioenergetic status, also have important roles in restricting T cell
activity (7).
1.2. Immunosuppressive tumor microenvironment
Solid tumors are blended with suppressive cell populations such as myeloid-derived
suppressor cells (MDSCs), regulatory T cells (Tregs), tumor-associated macrophages
(TAMs) and cancer-associated fibroblasts (CAFs) (Figure 1). In addition to tumor cells
these cells facilitate tumor growth and proliferation by producing growth factors, local
cytokines, and chemokines including VEGF and IL-4, IL-10 and (TGF)-β. Cells from the
TME also express a broad range of immune checkpoints such as PD-L1 and ligands for
LAG-3, CTLA-4, TIM-3 and TIGIT. All together this TME restrict the influence of CAR-T
cell treatment.
Figure 1: Scheme of the solid tumor microenvironment that consists of 1) tumor vasculature; 2) stromal cell
including CAFs 3) immunosuppressive cells, including myeloid cells, macrophages, and regulatory T cells
(Tregs); 4) suppressive metabolites; 5) inhibitory ligands, including PD-1; and 6) immunosuppressive
cytokines (8)
6. 6
1.3 Tumor heterogeneity
Solid tumors are highly heterogeneous in antigen expression thus presenting a major
challenge for targeted treatment such as CAR-T cell therapy.
Clinical trials of CD19 CAR T cells in ALL have reported cases of outgrowth of CD19-
negative leukemia, resulting in resistance to CD19 CAR-T therapy. The possibility of
antigen loss is even more pressing in solid tumors which tend to display high antigen
heterogeneity.
1.4 Paucity of tumor-specific targets
An ideal CAR target should be highly and homogeneously expressed throughout the
tumor, across multiple patients, and have no (or minimal) expression in vital healthy
tissues. Unfortunately, the vast majority of tumor antigens targets to date, for both
hematological and solid malignancies, have shared antigen expression in subsets of
healthy cells. Consequently, targeting of tumor-associated antigens (TAAs) with CAR-T
carries the risk of on target, off tumor toxicity. In hematological malignancies, anti CD19
CAR-T can for example lead to sustained B cell aplasia but this side effect is not life-
threatening and can be managed with regular substitution of immunoglobulins. In
comparison, in solid tumors the target antigens can be expressed at low levels on
epithelial cells like hearth and lung and lead to serious adverse events (9).
.
2. Clinical investigations of CAR-T cells in solid tumors
A report published in September 2020 (10) and analyzing the outcome of 42 clinical trials using
CAR-T cells against solid tumors registered on clinicaltrials.gov reported that out of 375 treated
patients listed in publications reporting on clinical outcome,13 had a complete response, 35 had
a partial response, 4 had a mixed response, 121 had a stable disease, 109 had a progressive
disease, 8 had no evidence of disease, 5 were not evaluable, and of 80 patients the clinical
outcome was not disclosed. These clinical trials were often conducted in cancer with poor overall
survival such as glioblastoma and pancreatic ductal adenocarcinoma but as depicted in Table 1,
CAR-T cells therapies were assessed in a wide range of different solid tumors and with various
CAR targets. While most treatment were shown to have manageable side effects, the overall
response rate were rather disappointing in comparison to the impressive clinical benefit obtained
with CAR-T in hematological malignancies. However, a few case reports shown encouraging
results notably in pancreatic cancer with Claudin-18.2 CAR-T (11) and in glioblastoma with
IL13Rα2, HER2, CMV, and EGFRvIII CAR-T. One patient treated with IL13Rα2 CAR-T mediated
a transient (7,5 months) complete response in a patient with recurrent multifocal glioblastoma,
with dramatic improvements in quality of life and a return to normal life activities (12). Although
the patient subsequently progressed at new locations distinct from his previous tumors, such case
reports the potential of CAR-T cell therapy in solid tumors and give a glimpse to a potential bright
future.
8. 8
breast
breast
CD44v6, CD70, CD133, CEA, c-MET, EpCAM, HER2, mesothelin,
Muc1 (cleaved from), Nectin4, GD2
TNBC c-MET, mesothelin, MUC1, TnMuc1, NKG2D-Ligands, ROR1
colon colorectal CD133, CEA, EGFR, HER2, MUC1, NKG2D-Ligands
colon EpCAM, HER2, NKG2D-Ligands
kidney renal CD70, EGFR, VEGFR2, ROR2, AXL
neuroblastoma B7-H3, CD171, EGFR, GD2, PSMA
wilms tumor B7-H3, EGFR, GPC3
stomach
gastric
CD44v6, CEA, claudin 18.2, EGFR, EpCAM, HER2, MUC1,
NKG2D-Ligands, PSCA, ROR2
prostate prostate CD44v6, EpCAM, NKG2D-Ligands, PSCA, PSMA
head/neck esophageal EpCAM, HER2, MUC1
nasopharyngeal EpCAM, LMP1, NKG2D-Ligands
SCCHN ErbB dimers, HER2
salivary gland HER2
thyroid cancer ICAM1
skin
melanoma
B7-H3, CD20, CD70, c-MET, GD2, gp100/HLA-A2, IL13R
2, VEGFR2
bladder bladder HER2, Nectin4, NKG2D-Ligands, ROR2, PSMA, FBP
soft tissue synovial sarcoma B7-H3, EGFR
clear cell sarcoma B7-H3, EGFR
soft tissue sarcoma B7-H3, EGFR, GPC3, ROR2
bone osteosarcoma B7-H3, EGFR, GD2
ewing sarcoma B7-H3, EGFR
abdomen peritoneal CEA, EpCAM, mesothelin
eye retinoblastoma B7-H3, EGFR
uveal melanoma GD2
ovary/testis germ cell tumor B7-H3, EGFR, GPC3
peripheral
nerves
malignant peripheral nerve
sheath tumor B7-H3, EGFR
Table 1: Targeted antigens targeted on different solid tumors by CAR-T cells in trials registered on clinicaltrials.gov
3. Strategies to overcome CAR-T Cell therapy roadblocks for solid tumors
3.1 Trafficking into the tumors
Several strategies are being evaluated to improve homing of CAR-T cell to the tumor site.
Direct injection of CAR-T in the tumor are being studied in several trials notably using
intraventricular delivery in glioblastoma, hepatic artery infusions in liver metastases,
intrapleural delivery in malignant pleural mesothelioma and peritoneal administration in
ovarian cancers (13). The use of implantable biopolymer devices to deliver CAR-T directly to
the surface of solid tumors is also being assessed and researchers showed that regional
delivery and expansion of CAR T cells in biopolymer scaffolds implanted at the tumor site in
contrast to systemic administration led to superior antitumor responses in mouse models of
pancreatic cancer and melanoma (14). Bioengineering approaches to increase CAR-T
9. 9
homing are focusing on taking the advantage of chemokines that are secreted by tumors cells
for which T cell do not express the corresponding chemokine receptor (e.g., CXCL8 by
melanoma or CCL2 by neuroblastoma). The engineering of CAR-T cells to express these
chemokine receptors has been shown to increase CAR-T cell transmigration thus resulting in
increased anti-tumor activity (8). CAR-T cell has also being engineered to express the enzyme
heparinase, which degrades sulfate proteoglycans in the extracellular matrix and can promote
tumor T cell infiltration (13).
3.2 Tumor heterogeneity and antigen dilemma
3.2.1 Ensuring tumor specificity
Ensuring tumor specificity and avoiding side effect due to on-target off-tumor toxic effect is
one of the major hurdles to apply CAR-T therapies in solid tumor. Mesothelin is one of the key
golden targets which has emerged as a promising tumor associated antigen for solid tumors
given its wide overexpression in various cancer and limited expression in healthy tissue.
Several clinical trials have demonstrated a favorable safety profile of mesothelin targeted
CAR-T (15). However, most target in solid tumor are not as “clean” as mesothelin and one
strategy to ensure tumor specificity of CAR-T is to engineer CAR that target tumor-associated
aberrant glycosylation. As an example, MUC1 is over-expressed and aberrantly glycosylated
in more than 90% of breast cancer cases. CAR can be engineered to specifically detect under
glycosylated cancer associated MUC1 and not heavily glycosylated MUC1 present on normal
tissues (16). Several other strategies based on genetic engineering of CAR-T also allow to
increase targeting specificity. As an example, the SynNotch CAR-T cells have a have a unique
property, called gating, that allows them to target specific cancers very precisely. The gating
function works similarly to logic gates, a tool often used by computer programmers: if condition
A is met, then do action B. A SynNotch protein on the surface of the T cell can be designed
to recognize a first antigen. When it does, the synNotch protein instructs the T cell to activate
its CAR T properties, enabling its ability to recognize a second antigen. Because the T cell
has to follow these specific instructions, it can only kill cells with both antigens (6). A similar
AND-gate strategy to create tumor specific CAR-T is to leverage the specificity of the tumor
environment such as the hypoxic characteristic. By fusing an oxygen sensitive subdomain of
HIF1α to a CAR scaffold, researchers were able to develop CAR T-cells that are responsive
to a hypoxic environment, a hallmark of certain solid tumors (18).
3.2.2 Avoiding antigen loss
The solid tumor heterogeneity leading to potential antigen loss and emergence of resistance
to CAR-T therapy can be addressed with CAR-T cells programmed to target multiple tumor
antigens. This can be achieved either by engineering a single-chain bispecific CAR that
encodes tow ligand-binding domains in a single receptor, or by co-expressing multiple
receptor chains in a single T cell. This strategy was notably tested using a trivalent CAR-T
targeting HER2, EphA2 and IL13Rα2 in glioblastoma thus allowing to overcome antigenic
heterogeneity and leading to improved treatment outcomes (17). Antigen loss can also be
overcome combining CAR-T with bispecific antibodies: EGFRvIII-specific CAR-T cells were
unable to eliminate heterogenous GBM and led to the proliferation of EGFRvIII-
/EGFR+
GBM
cells. To tackle this problem, researchers developed a CART.BiTE (an EGFRvIII specific
10. 10
CAR-T secreting EGFR-specific BiTE) and confirming its ability to eradicate heterogeneous
tumors in GBM mouse models (19).
3.3 Overcoming the solid tumor microenvironment
Solid tumor microenvironment encompasses limited key cytokines expression beneficial to T
cell function and upregulated soluble immune inhibitory factors. Several trials are currently
evaluating combination strategy with immune checkpoints inhibitors. Beyond co-
administration with checkpoints inhibitors, CAR-T function in the microenvironment can also
be enhanced by genetic engineering of the T cells. Several strategies using gene editing tools
such as TALEN® have been used to disrupt inhibitory receptors such as PD-1, TGF-β or
CTLA-4. CAR-T can also be engineered to overexpress a truncated receptor for such
inhibitory receptor. Thus, when the immunosuppressive ligands (PD-1, TGF-β or other ligand
of choice) bind the dominant negative receptors on the CAR-T cells in the tumor
microenvironment, no immunosuppressive signal is transduced (13). All these approaches
resulted in improved effector function of CAR-T cells in preclinical models. As an alternative
to counteracting immunosuppressive molecules in the TME, “armored” CAR-T cells are
engineered to secrete pro-inflammatory cytokines such IL-12 in order to create a more
favorable environment for CAR-T cell (IL-12 enhances IFN-γ secretion which can inhibit Treg
cell mediated suppression) and leading to higher anti-tumor activity (6). All these strategies
can be combined to generate “SMART” CAR-T that are able to sense and react to their
environment in a tailored, highly regulated, and antigen-specific manner. As an example,
researchers repurposed TCR, CD25 and PD1, three major players of the T cell activation
pathway by inserting a CAR into the TCRα gene, and IL-12P70 into either IL2Rα or PDCD1
genes. This process results in transient, antigen concentration-dependent IL-12P70 secretion,
increases CAR T cell cytotoxicity and extends survival of tumor-bearing mice (20).
Other strategies are focusing on targeting non malignant cells of the tumor stroma like CAFs,
MDSCs, TAMs and tumor-associated endothelials cells. These non malignant cells are
promoting tumor growth and secreting ECM and cytokines which hinder immune cells from
penetrating the tumor. Targeting these cells could disturb the “cold tumor” environment and
turn the tumor into a “hot tumor“ infiltrated by T cells thus making the tumor susceptible to
checkpoints blockers. CAFs express high level of fibroblast activation protein-α (FAP) and are
expressed in a wide range of tumor. Preclinical studies have demonstrated that anti-FAP CAR
T-cells are an effective way of targeting CAFs and unlock CD8+ infiltration (21). Moreover, a
phase I clinical trial (NCT01722149) on 3 patients showed that intra-pleural administration of
anti-FAP CAR T-cells was well tolerated without any evidence of treatment related toxicity. All
together, these initial results suggest that FAP-CAR could be a promising therapeutic agent
to be used in combination with checkpoint blockers.
Another potential interesting combination strategy to tackle solid tumor microenvironment is
the association of CAR-T with oncolytic virus (OV). The presence of OV provide a danger
signal that can revert tumor immunosuppression, which could facilitate CAR-T cell trafficking,
proliferation, and persistence in the tumor microenvironment. Moreover, the direct lytic effect
of OV on cancer cells results in tumor lysis and release of tumor-associated antigens (TAA),
which can induce an anti-tumor adaptive response that could potentially mitigate tumor
escape by antigen loss. OV can also be armed with therapeutic transgenes that could further
11. 11
enhance the effector functions of T cells (22). Interestingly, OV can be engineered to express
truncated CD19 thus enabling subsequently after virus infection the tumor to be targeted by
CD19-CAR T cells. This strategy would overcome both the challenge of the tumor
microenvironment and the antigen heterogeneity in solid tumors.
3.4 Mitigating Clinical toxicities
In addition to the risk of on-target, off tumor toxic effect, patient receiving CAR-T are also at risk
of sometimes lethal sides effects in the form of cytokine release syndrome (CRS) and
neurotoxicity. These risks are currently being addressed trough 1/ inducible safety control 2/
engineering effort to enhance tumor targeting-specificity.
Suicide genes can be implemented into CAR-T cells that lead to cell death upon small molecules
induction of the suicide gene. CAR-T cell co-expression of CD20 or truncated EGFR can be for
example depleted with the administration of anti CD20 (rituximab) and anti EGFR (cetuximab).
Other suicide switch based on small molecules induction include iCasp9 and HSV-TK (24). These
traditional suicide genes can quickly mitigate toxicity, but they also irreversibly eliminate
therapeutic CAR-T cells. Novel strategies that enable temporal control of CAR signaling are very
promising to prevent toxicity and cell exhaustion. For example, a switch off (SWIFF) CAR was
engineered by fusing a protease target site and a degron to the C-terminal end of a CAR. In the
absence of small molecule protease inhibition, the protease site is cleaved, protecting the CAR
from degron-mediated degradation; the presence of Asunaprevir (a protease inhibitor) inhibits the
cleavage of the degron from the CAR, leading to the degradation of the CAR by the T-cell
proteolytic pathways (25). The STOP-CAR is another strategy based on the incorporation of
chemically disreputable heterodimer (CDH) domains, that enables drug mediated “pausing” of
CAR-T cell (6). All together these strategies will allow the development of CAR-T with superior
safety and efficacy.
12. 12
CONCLUSION:
Homing / Penetration:
• Direct injection in the tumor
• Implantable biopolymer
• CAR-T expressing chemokine
receptors
• CAR-T expressing ECM degrading
enzymes
Tumor Heterogeneity and antigen
dilemma:
• “Golden target” like Mesothelin
• CAR targeting tumor antigen
glycoform
• SMART CAR-T (SynNotch and co)
• Multi-CAR / Single-chain bispecific
CAR
• Combination with BiTE
Tumor microenvironment:
• Combination with checkpoint
inhibitors
• KO of inhibitory receptors in CAR-T
/CAR-T with dominant negative
inhibitory receptor
• Armored CAR-T secreting cytokines
• Targeting tumor associated cells like
CAF
• Combination with oncolytic virus
Clinical toxicities:
• Suicide swith (EGFRt, CD20, iCasp9,
HSV-TK)
• SWIFF CAR
• STOP CAR/ GO CAR
Table 2: Summary of strategies to overcome challenges for CAR-T cell therapies in the context of solid tumors
Exciting approaches are currently under development to increase the efficacy and scope of CAR-
T cell therapies in solid tumors (Table 2). The recent advances in gene editing technologies like
TALEN® and CRISPR-CAS 9 have enabled robust and specific genomic modifications in primary
T cells thus allowing an increasing list of rapid modification of CAR-T cells such as adding on-off
switches or creating highly intelligent T-cells with complex functionality. Of note, the allogeneic
CAR-T approach allowed by the knock-out of the endogenous TCR receptor is a huge step to not
only streamline the cumbersome and expensive CAR-T manufacturing process but also to
address patient with heavily pre-treated solid tumors that often suffer from intrinsic T cells deficits
/ poor autologous immune cell fitness. The path toward the clinical application of such innovative
treatment is on track and an allogeneic CAR-T has recently reach the clinic in renal cell carcinoma
(NCT04696731): This anti CD70 CAR-T is gene edited to lack TCRα and CD52 to respectively
minimize the risk of graft versus host disease and enable a window of persistence in the patient.
In addition, a rituximab and CD34 recognition domains have been incorporated in between the
scFv and the linker domain as a suicide switch.
13. 13
The conquest of solid tumors with such complexly engineered products will require iterative
learning because all possible CAR-T configuration cannot be evaluated simultaneously, therefore
rapid testing on small cohort and versioning of these therapeutic candidates are key to generate
human data that inform to design of the next iteration of product and should lead to successful
deployment of CAR-T in solid tumors. Multiple combination approaches also need to be evaluated
in the clinic to find the perfect therapy that could have a powerful synergistic effect with CAR-T.
Finally, it is also important to note that only 1% of the total cellular proteins are expressed on cell
surface meaning that many potential tumor targets are not available to CAR. TCR could address
this issue and should be highly investigated as well.
As rapidly as the CAR-T field is moving, the one prediction we can make for certain is that 5 to 10
years from now, the field will look entirely different. We are just at the beginning and the hope to
see CAR-T becoming a clinical alternative to patient with solid tumors is real.
14. 14
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