Cancer Immunology: CAR T-cell Therapy on Renal Cell Carcinoma

Qingyang Huang

1,*

and Song Ying

2,*

School of Human Nutrition, McGill University, Montreal H9X 3V9, Canada

Department of Health, Kinesiology & Applied Physiology, Concordia University, Montreal H4B 1R6, Canada

Keywords:

CAR, Renal Cell Carcinoma, RCC.

Abstract: Chimeric antigen receptor T (CAR-T) cell therapy is a revolutionary tool for cancer treatment. Studies have

shown its potential in treating hematological malignancies. Renal cell carcinoma (RCC) as the most common

kidney cancer, would develop malignant tumor in the lining of kidney tubules. It has the highest mortality

rate among all genitourinary cancers. The main issue for RCC is its recurrence rate after surgery treatment.

As CAR T-cell therapy has shown its benefits in treating the leukemia and lymphomas, its use in RCC is

taking in consideration to reduce the chance of recurrence. Currently, there are some clinical trials are ongoing

to measure its feasibility. It is also important to pay attention to the CAR T-cell associated toxicities, on-target

off-tumor effect and tumor infiltration that would affect CAR T-cell therapy during the clinical trials. This

review focused on presenting ongoing clinical trials of CAR T cell on RCC and its limitations. Some future

perspectives are introduced to provide goals in later research.

1 INTRODUCTION

Renal cell carcinoma (RCC) is an aggressive kidney

disease originates in the lining of tubules. (Motzer,

1996) The ratio for both affected men and women is

about 2:1. Other than age and sex, cigarette smoking

and obesity are also risking factors. According to

studies, for cigarette smokers, the increase in risk for

RCC doubles. Obesity in both women and men

increases in mortality rate of RCC. (Yu, 1986)

Moreover, about 2% of the RCC has hereditary

syndrome. (Cohen, 2005) When a first-degree family

member has RCC, the risk for the second-degree

family member would be fourfold. (Motzer, 1996)

Generally, clear cell renal cell carcinoma (ccRCC) is

one of the typical RCC which represents around 3/4

of the cases. However, some patients would develop

the advanced RCC including locally invasive or

metastatic RCC (mRCC) as the cancer cells would

spread with a fast speed in the body. (Cohen, 2005)

Normally, surgery resection is the only effective

treatment for renal cell carcinoma because of its

chemoresistance. The patient would need to remove

the cancer cell affected kidney or having a kidney

transplant. Partial and radical nephrectomy are used

to treat localized RCC. For metastatic RCC, it

requires systemic therapies which are associated with

high mortality. (Hsieh, 2017) The approval of

cytokine-based immunotherapies (IFN-a and IL-2)

and tyrosine kinase inhibitors (TKIs) show effect on

reducing the mortality of metastatic RCC. (Schepisi,

2020) Other treatment including radiation therapy

and arterial embolization as the palliative therapy are

for patients who cannot have surgery. Patient’s health

condition and the stage of RCC are the general factors

that affect the chance of recovery and treatment

methods.

The recurrence rate of renal cell carcinoma

after nephrectomy is about 30%. (Chin, 2006)

In recent years, CAR T-cell therapy has become

one of the effective cancer treatments. It was

originally designed to treat hematologic neoplasms,

and have been used to treat solid tumors, including

RCC. (Schepisi, 2020) CAR-T cells are T cells that

have been genetically modified to create an artificial

T cell receptor for use in immunotherapy, which are

recombinant cell surface antigen receptors that have

changed the specificity and activity of T lymphocytes

and other immune cells in the blood. (Curran, 2012)

CARs have an extracellular antigen-identifying

domain made up of monoclonal antibody fragments

that recognize a particular protein on the cell

membrane of malignant cells and an intracellular

stimulating region that triggers CAR T-cell activation

and activity by signaling through the T-cell receptor

(TCR). (Minutolo, 2019) T cells must grow before

they can be used for CAR transduction and

Huang, Q. and Ying, S.

Cancer Immunology: CAR T-Cell Therapy on Renal Cell Carcinoma.

DOI: 10.5220/0012015600003633

In Proceedings of the 4th International Conference on Biotechnology and Biomedicine (ICBB 2022), pages 171-177

ISBN: 978-989-758-637-8

 2023 by SCITEPRESS – Science and Technology Publications, Lda. Under CC license (CC BY-NC-ND 4.0)

171

amplification. In this process, transduction can take

many forms, but in clonal growing and durable T

cells. Based on this principle, CAR can target

antigens expressed on the cell surface, as well as

various T cell subpopulations, T cell progenitors, and

other immune cells.

CAR T-cell therapy is also known as a "living

drug," since its effects might last for years. Because

the cells may live in the body for a long period, they

may be able to detect and target cancer cells if and

when they reoccur. (Sadelain, 2013) Importantly,

CARs with high potential and signaling quality can

control T cell proliferation and persistence, as well as

the degree of engineered T cell activation in the

cancer microenvironment, both of which are traits

that have a significant impact on cancer-targeted T

cell effectiveness and safety. (Watanabe, 2018)

Nowadays, techniques have been implemented to

improve cancer treatment for solid tumors, primarily

by overcoming challenges posed by T cell features

and the tumor environment. Companion diagnostics,

such as IHC and CTC detection tests, can be used to

improve CAR T-cell therapy of solid tumors. (Ma,

2019)

Therefore, to overcome this hurdle, CAR T-cell

treatment show its prospect in treating RCC. This

review summarizes the current CAR T-cell treatment

clinical trials on renal cell carcinoma and its

limitations. Moreover, the future perspectives for the

use of CAR T-cell therapy on RCC are explored.

2 CURRENT TRIALS OF CAR T-

CELL THERAPY ON RENAL

CELL CARCINOMA

For decades, surgery has been the only effective

treatment because of its chemoresistance. To

overcome this hurdle, CAR T-cell therapy shows its

advantages in treating tumors compared to the

previous modalities of adoptive cell therapy such as

TCR and TIL. Unlike TCR and TIL, CAR T-cell

therapy is a non-MHC-restricted approach, therefore

it can target the tumor cells without recognition of

MHC, as most of cancer cells would trigger the loss

of MHC expression to escape the T-cell immune

response. (Rohaan, 2018) Currently, FDA has

approved CD19 CAR T-cell therapy for Acute

Lymphoblastic Leukemia (ALL), Diffused large B-

cell lymphoma (DLBCL) and many other NHL.

Although there is no CAR-T cell therapy for RCC

approved by FDA right now, some clinic trials are

still ongoing.

2.1 CAR T-cells CCT 301-38 or CCT

301-59 in Relapsed /Refractory

Stage IV RCC

The recent clinical trial evaluates the safety and

efficacy of the two autologous CAR T-cell CCT301-

38 and CCT301-59 with escalation and expansion on

does. CCT301-59 targets the neurotrophic tyrosine

kinase, receptor-related 2 (ROR2), as the CCT301-38

directed against AXL gene expression. In patients

with kidney cancer, ROR2 expression is associated

with genes responsible for mitosis and metastasis.

AXL gene is involved in cell proliferation,

angiogenesis, immunity, stem cell maintenance and

other therapeutic processes. A total of 66 patients

participated in the clinical trial. Patients who tested

positive for ROR2 were treated with CCT301-59,

while patients who tested positive for AXL but

negative for ROR2 were treated with CCT301-38.

Peripheral blood mononuclear cells (PBMCs) are

needed to produce CCT301-38 and CCT301-59.

During the production of CCT201-38 and CCT301-

59, the trial requires patients to undergo a conditional

chemotherapy of regiment of cyclophosphamide and

fludarabine for lymphodepletion. After the injection

of CCT301-38 or CCT301-59 to After depleting

lymphocytes, patients would intravenously inject one

dose of CCT301-38 or CCT301-59. The estimate

primary completion date for these phases I and II

trials are in June 2022. (ClinicalTrials.gov, 2018)

2.2 CAR T-cell Therapy with PARPi

This research shows the application of CAR T-cell

therapy on targeting CD70 is through introducing a

single chain antibody against CD70 and generation of

CD70 CAR-T cells that have an effective anti-tumor

function both in vitro and vivo. (Ji, 2021) Moreover,

the PARP inhibitor (PARPis) is used to enhance the

effectiveness of this CAR T-cell therapy by

increasing the recruitment of CD8+ T cells to the

TME in this trial. The second-generation humanized

CAR was first used to augment its anti-tumor

efficacy. (Pantelidou, 2019) The introduction of

PARPi olaparib (OLA) to CD70 CAR T-cell therapy

in RCC show its effects on promoting the apoptosis

of RCC cells but protecting CAR-T cells from

apoptosis. It also shows a more effective repression

of RCC cells with a better survival rate. The OLA-

mediated CAR T-cell therapy starts with the

cGAS/STING signaling pathway, which is a key

activator for PARPi treatment to promote infiltration

of CD8+ CAR T-cell. It then up-regulates the IFN-B

expression and the expression of both CCL5 and

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CXCL10. Both would improve the amount of CD8+

CAR T-cells and enhance the tumor lysis due to the

secretion of granzyme B. These demonstrated that

cGAS-STING pathway determines the Penetration

and permanence of OLA-mediated CAR T-cell

therapy in TME. This approach shows its potential in

treating the solid tumors. (Ji, 2021)

2.3 Metastatic Renal Cell Carcinoma

with CAIX CAR-engineered T cells

Metastatic renal cell carcinoma (mRRC) is well

known for its treatment-resistance. The patients with

mRRC often with poor survival of less than one year

after diagnosis. (Gupta, 2008) Therefore, the CAR T-

cell therapy is applied to treat mRRC. However, CAR

T-cell therapy may develop a toxicity in the body due

to its “on-target” effect. Carbonic anhydrase-IX

(CAIX) is a transmembrane protein that is over-

pressed in RCC. It is generally used as a diagnosis

marker or drug target. In the trial, 12 mRCC patients

with CAIX-pressing were injected by CAR-T cell that

is engineered against CAIX. The patients would pre-

treat with a CAIX monoclonal antibody (mAb) G250.

The results indicate that there are no toxicities in the

liver. Moreover, this trial surprisingly enhances the T-

cell persistence in the therapy. Therefore, by pre-

treating patients with CAIX mAb, it helps to prevent

on-target toxicity from CAR T-cell therapy on RCC

and improve the peripheral persistence. This strategy

can be applied on the use of CAR T-cell therapy in

other cancer. More research is needed. (Lamers,

2013)

3 LIMITATION

CAR-T cells binding to target antigens expressed on

the cell surface is independent of MHC receptors. It

caused T cell activation and a powerful antitumor

response, which is revolutionary for leading a

remarkably effective and long-lasting clinical

response. When targeting solid tumors, CAR-T cells

have shown mild clinical efficacy in malignancies.

(Neelapu, 2017) The development of T cell in vitro

growth technology and genetic engineering enables

the rapid generation of tumor antigen effector cells,

which promotes the applicability of cancer

immunotherapy. However, the serious toxicity of

CAR T-cell therapy, targeting of non-tumor cells, cell

metastasis and tumor invasion remain unresolved.

3.1 CAR-T cell-associated Toxicities

CAR-T cells recognize hLA-independent and reduce

the risk of cross-reaction by binding to larger

epitopes. (Casucci, 2014) Genetic engineering may

improve the toxicity characteristics of traditional

chemotherapeutic drugs by improving the accuracy of

T cell recognition of targets. Nonetheless, cell

therapies are unique in that up to 10 years of

extraordinary long-term persistence can be achieved

using adoptive cellular therapy in human trials. The

timeline for this persistence will potential toxicity to

extend far beyond traditional small-molecule drugs

timeline. (Scholler, 2021)

Side effects after CAR T-

cell therapy may be rapid, slow, moderate, severe,

and even persist throughout the T cell cycle, thus

preventing the development of CAR T-cell therapy.

Data showed that nearly all patients with acute

lymphoblastic leukemia and lymphoma treated with

CAR-T cells had at least some mild toxicity, while

23-46% showed production of parapsychological

cytokines and severe in vivo T cell proliferation.

(Frey, 2016)

Cytokine release syndrome (CRS) is a systemic

inflammatory response that leads to immune

activation caused by exogenous cytokines produced

by CAR-T cells, leading to dysfunction in most

organs. (Lee, 2014) Specifically, patients with

leukemia (77-93%) and with lymphoma (67-91%)

treated with CAR-T cells experienced more CRS of

any grade, compared with patients treated with

axicabtagene ciloleucel and tisagenlecleucel for

relapsed or refractory B-All. (Halford, 2020)

CRS-

associated cytokines may be produced directly by

injected CAR-T cells or macrophages, which may

produce cytokines in response to injected CAR-T

cells. (Brudno, 2016)[24] And elevated serum levels

of several cytokines, including interleukin-2 (IL-2),

IL-2, IL-2-receptor -α, IL-8, IL-10, tumor necrosis

factor and so on, are associated with fever,

tachycardia, hypotension, and other toxicity after

CAR-T cell infusion. The severity of CRS and the

increase of serum cytokines are associated with the

disease burden, and the higher the disease burden, the

greater the toxicity. Clinically, the characteristics of

CRS ranging from mild to severe include fever,

creatine, aversion to eating, rapid heartbeat,

decreased blood pressure, increased capillary osmotic

pressure, loss of cardiac function, abnormal renal

function, weakened liver function, and disseminated

coagulation in the blood vessels. (Bonifant, 2016)

Patients in clinical trials of CAR-T cells often

develop neutropenia and lymphocytopenia after

chemotherapy and CAR-T cells. After CAR-T cell

Cancer Immunology: CAR T-Cell Therapy on Renal Cell Carcinoma

173

infusion, bacteremia, salmonella, urinary tract

infections, and viral infections such as influenza,

respiratory syncytial virus, and shingles virus have

been observed. (Brentjens, 2010) Besides, elevated

cerebrospinal fluid cytokine levels can induce ICANS

presenting with delirium, encephalopathy, aphasia,

drowsiness, inattention, agitation, tremors, seizures,

and rare cerebral edema.

3.2 On-Target off-Tumor Effects

Solid tumor antigens are usually expressed at

different levels in normal tissues, so antigen selection

is critical for CART engineering, not only to protect

the therapeutic effect, but also to inhibit the

extratomatous cross-reaction of overactive toxic

engineered T cells. Exposure of high doses of CAR-

T cells to heart, lung, or liver tissue at the time of

initial cell injection leads to rapid death. Even if the

tumor is successfully targeted, a rapid increase in

overall T-cell activity driven by CAR signals during

treatment may result in tumor-lysis syndrome, which

rapidly removes large numbers of tumor cells in a

short period of time, endangering cell life. The

differences between patients in T cell response and

risk of toxicity make it challenging to predict the

optimal number of T cells to be transfused. (Morgan,

2010) Therefore, allowed to control the regulation of

the dose and time T cell function of system

engineering is an important priority. (Sadelain, 2013)

3.3 CAR-T cell Trafficking and Tumor

Infiltration

Compared with hematological malignancies, CAR T-

cell therapy in solid tumors is limited by the ability of

CAR T cells to transport and infiltrate solid tumors

because of physical tumor barriers such as

immunosuppressive tumor microenvironment and

tumor stroma that limit CAR T-cell penetration and

mobility in Figure 1. (Murad, 2018) After infusion,

CAR-T cells need to enter the malignant site, navigate

the complex tumor environment, form effective

interactions with cancer cells, exert their cytotoxic

activity, and ultimately persist. Many

immunosuppressive cells can infiltrate solid tumors

in the tumor microenvironment, including medullary

suppressor cells (MDSCs), tumor-associated

macrophages (TAMs), and regulatory T cells (Tregs),

which promote the production of cytokines,

chemokines, and growth factors. In addition, immune

checkpoint pathways such as PD-1 or CTLA-4 can be

used to modulate antitumor immunity, causing T cell

dilation and short-term T cell persistence, resulting in

less effective CAR T-cell therapy. (Quail, 2013)

Furthermore, increased tumor hardness, an increased

deposition of tumor ECM proteins and the significant

presence of cancer-associated fibroblasts have been

shown to promote immunosuppression through

various mechanisms. More simply, the thick network

of collagenous fibers surrounding some tumor islets

may constitute a physical barrier to t-cell lymphocyte

invasion of tumor cell regions. (Yamauchi, 2018)

Figure 1: Tumor metastasis and invasion and immunosuppressive tumor microenvironment. (Sterner, 2021) CAR-T cell

trafficking to tumors may be hampered by aberrant tumor blood vasculature with pericyte detachment, deregulation of

chemokine-chemokine receptor interaction, extracellular matrix (ECM) protein deposition by cancer-associated fibroblasts

(CAF), MDSCs, Tregs, and encounters with TAMs.

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4 FUTURE DEVELOPMENT

4.1 Reduction of CAR-T cell-associated

Toxicities

Cytotoxicity can be reduced by altering the affinity of

CAR-T cell antigen binding domains. In this way,

tumor cells can increase their response to higher

concentrations of antigen and achieve higher levels of

activation. (Sterner, 2021) As a result, decreased

antigen affinity is predicted to avoid targeting healthy

tissues with low levels of antigen. Compared with

antigen binding regions with low affinity, antigen

binding regions with micromolar affinity were more

selective for tumors with higher antigen expression

levels. (Liu, 2015) The 4-1BB domain receptor was

associated with reduced toxicity and increased T cell

tolerance, while the CD28 costimulatory domain was

associated with CAR-T cell activity. The 4-1BB

costimulation domain can be specifically targeted at

tumors with high burden and antigen density. In

contrast, in the low affinity antigen binding domain

CAR, the CD28 costimulatory domain may be

required to reach the desired T cell activation

threshold. (Salter, 2018)

Changes in hinge and transmembrane regions that

activate CAR-T cells can also affect cytokine

production. For example, CD8-derived hinge and

transmembrane amino acid sequence changes can

reduce cytokine levels and reduce THE proliferation

of CAR-T cells targeting CD19 CAR93.These

improved hinged and transmembrane region CARs

resulted in complete remission in 50% of B-cell

lymphoma patients in a Phase 1 clinical study, so

optimizing these domains may be an effective way to

reduce toxicity. (Ying, 2019)

4.2 ON-Switch Control Mechanisms

Adoptive transfer of T-cells expressing the CAR has

yielded extraordinary in the treatment of B-cell

malignancies. Other cancers are less responsive to

this technique. In the case of solid tumors, CAR T-

cell metabolic fitness must be ideal in order for them

to reach the tumor and carry out their cytolytic

activity in an often-hostile environment. (Pellegrino,

2020)

However, there is a risk that shutting off all CAR-

T cells in a patient may allow residual tumor cells to

proliferate unregulated and fast. A mechanism was

discovered to switch off CAR-T cells selectively,

using a small molecule-controlled caspase that

promotes T cell death. (Ciceri, 2009) Another way to

supplement is to keep the cells dormant until the small

molecule drug signalling is introduced (Fig. 2). This

ON switch provides for titratable T cell activity

regulation (dial-up or down). When certain "no-kill"

ligands are found, another strategy is to develop

negatively regulated co-receptors that can overcome

the death response. (Fedorov, 2013)

Figure 2: ON-switch control mechanisms. (Wu, 2015) (A). The small molecule medication signal is used to trigger CAR-T

cell active. (B). CAR-T cells are switched off selectively using a tiny chemical that causes T cell death.

Cancer Immunology: CAR T-Cell Therapy on Renal Cell Carcinoma

175

4.3 Improvement of CAR-T cells

Trafficking

Tumor and T cell metabolism, via modulating tumor

microenvironment and T cell destiny and activity,

have now been discovered to function in determining

immune response. CAR-T cell treatment can be

enhanced by focusing on this element. The expression

of chemokine receptors on CAR-T cells is a recently

established technique that looks to dramatically

increase CAR-T cell trafficking. (Whilding, 2019) In

animal models, CAR-T cells targeting the fibroblast

activating protein (FAP) exhibited improved

cytotoxic efficacy by decreasing tumor fibroblasts.

(Wang, 2013)

5 CONCLUSION

CAR T-cell therapy on RCC has showed its effect in

treating the solid tumor or reducing the “on-target”

effect. However, its limitation still needs sustainable

investigation to improve the efficacy. Currently,

some studies have given ideas to reduce its toxicity

and improvement of trafficking. Therefore, these

methods may take in consideration for their

application on CAR T-cell therapy on RCC. The

approval of designated CAR T-cell therapy for

specific cancer has confirmed its importance in

certain tumors as the first-line treatment. It is

encouraging to have more CAR T-cell therapy related

to cancer treatment to broaden the horizons.

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