Review Article | Open Access
Targeting CTLA-4 in Cancer: Biological Insights with a Focus on Renal Cell Carcinoma
Juan Wu1, Ya-fei Ren2, Jun Xie1, Dong-sheng Li1
1Department of Rheumatology and Immunology, Jiangxi Province Ganzhou City People's Hospital, Ganzhou City, Jiangxi Province, China.
2Department of Rheumatology and Immunology, Guilin Medical University Affiliated Hospital, Guilin City, Guangxi Zhuang Autonomous Region, China.
Correspondence: Dong-sheng Li (Department of Rheumatology and Immunology, Jiangxi Province Ganzhou City People's Hospital, 17 Hongqi Avenue, Ganzhou 341000, Jiangxi Province, China; Email: email@example.com ).
Annals of Urologic Oncology 2022; 5(2): 68-74. https://doi.org/10.32948/auo.2022.12.15
Key words immune checkpoint inhibitors, renal cell carcinoma, anti-CTLA-4, biological insights
The ability to evade immune surveillance and programmed cell death is a major mechanism for evasion of cancer . Various tumors may express biomarkers that prevent the host from generating an immune response . In fact, this is essential for that host's regulation of cell proliferation to prevent damage to the nuclear content. It is well known that cell division halts after sustained cell damage to allow repair. When repair is not possible, cell death is induced to prevent the development of defective cell. The rare cases of spontaneous response of RCC provide information that the immune system may be able to suppress RCC through antitumor immunity . Immunotherapy is an increasingly popular and researched treatment that uses the body's own immune system to fight metastatic cancer . Immune checkpoint inhibitors (ICI) upregulate the immune response by blocking programmed cell death protein 1 (PD-1) receptors, ligands of PD-1, or cytotoxic T lymphocyte-associated protein 4 T cells, leading to a new era of immunotherapy . CTLA-4 and PD-1 are inhibitory receptors with molecular significance. A large number of these agents have been developed, studied, and are currently marketed as effective therapies for the treatment of mRCC and many other malignancies. This review describes CTLA-4 in detail.
T cell activation is a complex process involving multiple stimulatory and inhibitory receptors. The initial step requires antigen-specific T cells to recognize MHC peptides, but also requires costimulatory signals from the interaction between membrane proteins on antigen presenting cells, including B7 family members CD 80 (also known as B7-1) and CD 86 (also known as B7-2), and CD28 on T cells [14-16]. A variety of signals influence the activation status of T cells, but cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death 1 ligand 1 (PD-L1) are the only immune checkpoints that currently have routine clinical application in patients with RCC [17, 18]. In addition, the biological and clinical significance of several other B7 family members is only now being elucidated .
The fact that CTLA-4 acts on the cell surface suggests a strategy to enhance T cell immunity by using CTLA-4 inhibitory antibodies. Allison et al. has demonstrated the negative effects of CTLA-4 and established the antagonistic effects of CTLA-4 and CD28 on T cell stimulation. The study showed in detail that binding of CTLA-4 to B7 ligand abolished IL-2 secretion by T cells and T cell proliferation following TCR activation. Blocking CTLA-4 with anti-CTLA-4 antibodies leads to rejection of pre-established tumors, and mice lacking the Ctla4 gene (Ctla4-/-mice) develop severe lymphoproliferative and lethal autoimmune phenotypes [27-29]. Further studies have shown that CTLA-4 is involved in activating an intrinsic signaling cascade in T cells. It has been reported [30-34] that CTLA-4 activation inhibits IL-2 production and T cell proliferation and induces cell cycle arrest through interaction with pathways regulating cell survival and proliferation, including PI3K, NF-κB, and MAPK pathways. In addition, the interaction of anti-CTLA-4 monoclonal antibodies with CTLA-4 may activate antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-mediated lysis. We found that complement activation was lower in patients receiving ipilimumab (IgG1 antibody) than in patients receiving tremelimumab (IgG2 antibody) [35, 36]. Ipilimumab isotype IgG1 has a high affinity for FcγRIIIa, the Fc receptor mediating ADCC. More interestingly, patients with polymorphisms in this receptor were more responsive to ipilimumab .
Multiple signals, both stimulatory and inhibitory, modulate the activation of T cells by tumour cells or antigen-presenting cells. Tumour peptides are presented by major histocompatibility complex (MHC) glycoproteins and recognized by antigen-specific T cells. CTLA-4 acts as a negative regulator of T cell activation by binding to B7 ligands CD80 and CD86 expressed on antigen-presenting cells, thereby preventing the co-stimulatory interaction between CD28 and the B7 ligands. Ipilimumab binds to CTLA-4 and blocks the inhibitory signaling of the CTLA-4: B7interaction. PD-1 acts as a negative regulator of T cell activity predominantly by binding to PD-L1 on either tumor cells or antigen-presenting cells, leading to downstream signaling that inhibits anti-tumor T cell responses.
CTLA-4 expression in RCC
RCC is essentially a metabolic disease characterized by reprogramming of energy metabolism, and many of the genes mutated in RCC encode proteins that play a role in regulating cellular processes of oxygen and glucose consumption . In particular, the metabolic flux is distributed through glycolysis [39-42], Mitochondrial bioenergetics and oxidative phosphorylation are impaired during lipid metabolism [40, 43, 44]. In addition, RCC is one of the most immunoinvasive tumors [45, 46]. Emerging evidence suggests that activation of specific metabolic pathways has a role in regulating angiogenic and inflammatory characteristics [47, 48]. VHL mutations in mRCC increase the transcriptional activity of its target genes (e.g VEGF, glucose transporter 1, and erythropoietin), independent of oxygen levels, promoting angiogenesis and immunosuppression . The complexity of cell interactions and the depletion of available nutrients may create a nutrient-competitive environment for T cells and accumulate waste products that may damage T cells . Rcc-bm exhibits metabolic changes resulting in altered pathways related to energy metabolism and oxidative stress, as well as accumulation of immunosuppressive metabolites such as tryptophan (TRP) [38, 49]. The enhanced activity of a series of interconnected oncogenic signaling networks centered on the PI3K-AKT pathway represents a generalizable feature in different BM histologies . CTLA4 inhibits CD28 signaling and PI3K/Akt/mTORC1 signaling, resulting in decreased glycolysis and mitochondrial oxidative capacity . Blocking the negative regulators of PD-1 and CTLA4, which impair CD28 signaling to inhibit T cell release, favors antitumor activity .
By survival analysis, it was found that high TII score had better prognosis than low TII score. GSEA analysis showed that the genes in high TII score group were rich in immunosuppressive pathways, such as ERBB signaling pathway, MAKP signaling pathway, mTOR signaling pathway and TGFβ signaling pathway . A large number of clinical studies have confirmed that Anti-PD-1 and Anti-CTLA-4 antibodies can effectively inhibit the immune escape of cancer cells. Different from radiotherapy and chemotherapy drugs, the mechanism of immunotherapy is not to kill cancer cells directly, but to attack cancer cells indirectly by enhancing the specific anti-tumor cells of DC-CIK cells. Experimental study confirmed that the combination therapy can provide the synergistic anti-tumor effect of DC-CIK cells by suppressing proliferation, differentiation and early activation of RCC cells and regulating the immune stimulation and inhibiting the secretion of cytokines . In RCC, about 1% of TIMCs express CTLA-4  and the expression increased with the increase of tumor stage. In papillary RCC, up to 2.7% of TIMCs expressed CTLA-4 . Polymorphisms in the CTLA-4 gene are associated with a higher risk of advanced ccRCC . Allison and co-workers first demonstrated that administration of a CTLA-4 blocking antibody in mice prevented tumor establishment and induced rejection of established tumors .
Ipilimumab is a human IgG1 mAb that can inhibit the function of CTLA-4 and was first approved and recommended for the treatment of melanoma in 2011 . It selectively blocks the interaction between the negative regulation of CTLA-4 on activated T cells and its ligands CD80/CD86 expressed on immune cells. In a phase 2 trial (NCT 00057889), the efficacy of ipilimumab monotherapy was evaluated in patients with metastatic RCC disease treated with ipilimumab high-dose (HD) (3 mg/kg every 3 weeks) versus low-dose (LD) (3 mg/kg once followed by 1 mg/kg every 3 weeks) . Of the 40 patients treated with HD ipilimumab, 5 achieved PR (12.5%), including patients who had previously progressed on IL-2 therapy . Of the 21 patients with LD, only 1 had PR.no CRs in either arm. Grade 3 or higher TRAEs (Treatment-related Adverse Events), particularly autoimmune-related enteritis and endocrine defects, were present in 33% of patients. The most common autoimmune events were enterocolitis (18%), hypophysitis (7%), and dermatitis (4%). No further studies have been conducted with ipilimumab monotherapy in RCC.
Tremelimumab is another anti-CTLA-4 monoclonal antibody. In phase 1 trial (NCT00372853) tremelimumab was administered intravenously to patients with mRCC at doses of 6, 10, or 15 mg/kg every 12 weeks in combination with sunitinib at 50 mg daily for 4 weeks, followed by 2 weeks or 37.5 mg daily . Two of the five patients receiving tremelimumab 6 mg experienced unexpected rapid onset renal failure with sunitinib 50 mg, and one of the seven patients receiving tremelimumab 10 mg/kg plus sunitinib 37.5 mg died suddenly. The expansion cohort was treated with tremelimumab 10 mg/kg plus sunitinib 37.5 mg. However, dose-limiting toxicities were observed in three or seven patients. Of the nine patients evaluable, 43% achieved a partial response, but the regimen did not progress further due to toxicity.
Ipilimumab (anti-CTLA-4 antibody) and Nivolumab (anti-PD-1 antibody)
In a Phase 3 Checkmate 214 study in advanced RCC (NCT 02210117), 1096 patients were randomized to receive the combination of ipilimumab and nivolumab (n=550) and sunitinib (n=546). The co-primary endpoints of this study according to IMDC criteria were OS, PFS, and ORR (Objective Response Rate) in intermediate and low risk patients. ORR, PFS, and OS in the favorable risk group, and incidence of adverse events (AEs) in patients were secondary endpoints. In intermediate/low risk patients, combination therapy was associated with improved survival (HR: 0.63; 99.8% confidence interval: 0.44-0.89) and ORR (42 vs 27%), but no PFS reached the prespecified threshold (HR: 0.82; 99.1% confidence interval: 0.64-1.05). Of note, the combination of ipilimumab and nivolumab also improved the complete response rate (9 vs 1%). In patients at favorable risk, the combination did not result in a benefit in OS and ORR compared with sunitinib, however, complete response rates significantly favored the nivolumab and ipilimumab arms (11 vs 6%). There were 8 treatment-related deaths in the combination arm and 4 in the sunitinib arm. Increase in lipase, fatigue, diarrhea, rash, nausea, and decrease in appetite, and asthenia were the most common high-level AEs in the combination arm, while hypertension, palmar-plantar redness, fatigue, diarrhea, lipase increased, asthenia, vomiting, and anemia were the most common high-level AEs in the sunitinib arm. Despite this, the quality of life assessment showed that the combination arm was significantly better than the sunitinib arm [59, 60]. There was a statistically significant improvement in overall response rate (ORR) compared with sunitinib standard of care in first-line treatment of intermediate and low-risk patients . However, nivolumab in combination with ipilimumab is approved as a representative first-line treatment for patients with mRCC at intermediate or low risk of IMDC . Studies described in the above paragraph are summarized in Table 1.
The first-line treatment modality for ccRCC has changed, particularly in intermediate/low risk patients, with the addition of nivolumab and ipilimumab in combination. However, more studies and better designed further studies are needed to explore the possibility and effectiveness of different drug combinations, while still focusing on their side effects, leading to better tumour outcomes. Future studies will likely identify biomarkers of subsequent immune response to better select candidates for neoadjuvant immunotherapy.
We thank Dr. Peng Zhang for his guidance and help. Thanks to our friends who helped us.
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.Approval from institutioalethical committee was taken.
Availability of data and materials
All data generated or analysed during this study are included in this publication.
Juan Wu conceptualised, designed the study and was responsible for the writing of the original draft. Ya-fei Ren, Jun Xie and Dong-sheng Li reviewed and revised the manuscript. All authors approved the version of the manuscript to be submitted.
The authors declare no conflict of interest.
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