NY-ESO-1 Gains Momentum as a Therapeutic Target

As the immunotherapy research field grows, NY-ESO-1 is emerging as a high-priority target for cancer vaccine development and adoptive T-cell therapies. Promising results have been obtained from early studies, prompting the rapid expansion of the field. Consequently, NY-ESO-1 was the target of 37% of all active clinical trials utilizing T-cell receptor (TCR)-based adoptive T-cell therapy, according to an analysis of studies updated as of June 2018.¹

Figure. Immunotherapy Opportunities for Targeting NY-ESO-1²

NY-ESO-1, fully identified as New York esophageal squamous cell carcinoma-1, is encoded by the CTGAG1B gene. It is a member of the cancer-testis antigen family of proteins, whose expression in healthy individuals is restricted to placental trophoblasts during development and to testicular germ cells in adults. Expression of NY-ESO-1 is reactivated in several tumor types, however: myxoid/round cell liposarcoma (89%-100%), neuroblastoma (82%), synovial sarcoma (80%), melanoma (46%), ovarian cancer (43%), and several other tumors to a lesser extent (20%- 40%).² The restricted expression profile of NY-ESO-1 in healthy adult tissues makes this protein an ideal anticancer target because there is a low risk of off-target toxicities caused by treatment. The protein also has been shown to spontaneously elicit both humoral and cellular immune responses in patients with cancer, making NY-ESO-1 a prime target for immunotherapy-based treatments. Several studies have found that NY-ESO-1 is able to stimulate IgG responses in many cancer types.^2,3 The findings from an analysis of 1969 tumors of various cancer types confirmed stimulation of an anti—NY-ESO-1 humoral response in the serum of patients with esophageal, lung, hepatocellular, prostate, gastric, colorectal, or breast cancers.³

Research conducted in patients with melanoma has also identified cellular immune responses to NY-ESO-1 by CD4- and CD8-positive T cells.² Several epitopes throughout the protein are recognized by these T cells, suggesting a broad range of potential targets that may be used in the development of vaccine-based therapies. Another avenue of exploration involves combinations of therapies aimed at NY-ESO-1 with immune checkpoint inhibitors (Figure).²

NY-ESO-1 Expression As a Prognostic Biomarker

The expression of NY-ESO-1 is heterogeneous between tumors, even within a given type of cancer. This observation has led many investigators to explore the utility of NY-ESO-1 expression as a prognostic biomarker for disease state and outcome. The value of this tool remains controversial, however, as results have been variable across studies and cancer types.

For many cancers, expression of NY-ESO-1 is associated with poor prognosis or advanced disease stage. In cutaneous melanoma, for example, tumor expression of the NY-ESO-1 antigen was found to correlate with significantly reduced median relapse-free survival, from 70 months for patients with negative expression to 45 months for those with positive expression (risk ratio, 0.664; P = .032).⁴

Similarly, hypomethylation of NY-ESO-1 in non—small cell lung cancer (NSCLC), which correlated with increased gene and protein expression, was found to be associated with a significant reduction in overall survival (OS).⁵ In patients with synovial sarcoma and patients with myxoid liposarcoma, NY-ESO-1 protein expression was found to be associated with the presence of necrosis, as well as advanced tumor stage.^6,7

Analysis of NY-ESO-1 expression patterns in patients with head and neck cancer suggested that prognosis may be affected by not only expression, but also localization of the protein, with simultaneous cytoplasmic and nuclear expression significantly reducing OS and increasing the risk of death compared with other localization patterns.⁸

In contrast, NY-ESO-1 expression may be associated with improved prognosis in patients with breast cancer. In patients with triple-negative breast cancer, NY-ESO-1 expression was found to be associated with higher levels of tumor-infiltrating lymphocytes, which correlated with increased disease-free survival and favorable prognosis.⁹

Table. Select Clinical Trials Targeting NY-ESO-1

Expression of NY-ESO-1 in hepatocellular carcinoma was similarly found to be significantly correlated with infiltration of immune cells into tumors. Additionally, an index reflecting the number of co-expressed tumor-associated antigens (TAAs), including NY-ESO-1, was associated with median survival time, which increased from ≤28 months for those with a low TAA index to >60 months for those with a high TAA index (P <.01).¹⁰ Conflicting results between tumor types have hindered the widespread clinical use of NY-ESO-1 expression as a prognostic biomarker. In contrast, detection of an immune response against NY-ESO-1 may hold more promise as a tool for monitoring disease status and prognosis. A number of studies have found that the degree of the NY-ESO-1- specific humoral immune response increases with disease progression according to the type of cancer.²

However, a cellular immune response conveys an improved prognosis for patients across multiple cancer types, with the presence of circulating antigen-reactive T cells responding to NY-ESO-1 associated with improved OS in patients with melanoma as well as with recurrence-free survival in patients with NSCLC.^11,12 These results highlight not only the potential for the use of a detectable NY-ESO-1— targeted immune response as a tool for disease prognosis but also the promise of immunotherapy as a treatment method for diverse NY-ESO-1–positive cancers.

Advances in Adoptive T-Cell Therapy

As the field of adoptive T-cell—based immunotherapy has grown, NY-ESO-1 has emerged as a prime target for treatment of a variety of cancers. These therapies include the use of chimeric antigen receptors (CARs) and TCRs artificially expressed on the surface of T cells. Artificial receptors on these T cells are engineered to recognize antigens on the surface of cancer cells, such as NY-ESO-1, and stimulate a cellular immune response against the malignancy. Early studies using adoptive T-cell therapies in the targeting of NY-ESO-1 have shown promise, prompting the rapid proliferation of clinical trials utilizing this line of treatment.² Many of these studies are still in the early stages (Table).

Recent efforts in advancing the field of adoptive T-cell therapies have focused on improving the efficacy of these technologies. The development of TBI-1301 by Takara Bio represents one such advancement. TBI-1301 is a TCR T-cell therapy engineered from autologous T lymphocytes, which also encode a small interfering RNA to knock down expression of the endogenous TCR for preferential expression of the NY-ESO-1—specific TCR. TBI-1301 is currently in phase I/II clinical trials for treatment of synovial sarcoma (NCT03250325) and solid tumors (including ovarian cancer, synovial sarcoma, esophageal cancer, and melanoma [NCT02869217, NCT02366546]).

More work is needed before these therapeutics can become clinically available, but early results from a phase I study (NCT02869217) presented at this year’s American Society of Clinical Oncology Annual Meeting (ASCO 2019) suggest that TBI-1301 in combination with cyclophosphamide exhibits a favorable safety profile with demonstrated antitumor activity.¹³

GlaxoSmithKline is evaluating GSK3377794, which employs TCR T-cell technology with specific peptide enhanced affinity receptor T cells, which utilize an enhanced-affinity TCR (NY-ESO-1c259).^14,15 This technology was shown to have an acceptable safety profile and efficacy in a phase I/IIa clinical trial, with progression-free survival observed in 52% of patients after 1 year and a median survival of 35 months.¹⁵

GSK3377794 is currently being evaluated in phase II trials in combination with the PD-1 inhibitor pembrolizumab (Keytruda) in patients with multiple myeloma (NCT03168438) and NSCLC (NCT03709706). A phase II study of GSK3377794 in combination with fludarabine and cyclophosphamide is also planned, initially with synovial sarcoma and then expanding to other solid tumors (NCT03967223). The estimated enrollment is 65 patients.

Investigators at Roswell Park Comprehensive Cancer Center in Buffalo, New York, also are seeking to advance the field by not only using autologous T-cell transplants to engineer adoptive T-cell therapies, but also by modifying patients’ own hematopoietic stem cells to serve as a “living drug.” The goal of this work is to create a long-term supply of antitumor T cells targeting the NY-ESO-1 antigen that can provide sustained immunotherapy for patients.¹⁶ A small phase I study testing these TCR T cells is currently recruiting, with an estimated enrollment of 15 patients with recurrent or refractory ovarian, fallopian tube, or primary peritoneal cancer (NCT03691376).

A number of other clinical trials, sponsored by both the public and private sector, are currently recruiting that utilize targeting of NY-ESO-1 by adoptive T-cell therapies. For example, Immunocore is exploring the use of NY-ESO-1—targeted TCR T cells in patients with advanced NSCLC, melanoma, urothelial carcinoma, or synovial sarcoma (NCT03515551).

Baylor College of Medicine is currently recruiting patients to test this technology in the treatment of pancreatic cancer (NCT03192462) and breast cancer (NCT03093350). And the National Cancer Institute is seeking participants for a clinical trial targeting multiple cancer types (melanoma, meningioma, breast cancer, NSCLC, and hepatocellular cancer; NCT01967823) and is collaborating with investigators at Roswell Park Comprehensive Cancer Center to investigate the use of anti-NY-ESO-1 adoptive T-cell therapy targeting adult solid neoplasms (NCT02650986).

NY-ESO-1 Cancer Vaccines

Vaccination with an NY-ESO-1 antigen has also been explored as a means to stimulate an immune response against cancer cells. In contrast to adoptive T-cell therapies, which introduce anti—NY-ESO-1 T cells into a patient, cancer vaccines rely on activation of the body’s natural anti–NY-ESO-1 humoral and cellular immune responses.

These technologies deliver NY-ESO-1 antigen to stimulate an immune response, which can subsequently recognize NY-ESO-1 on cancer cells. A number of peptides are capable of stimulating an immune response at varying levels of efficacy. For stimulation of CD4-positive T cells, NY-ESO-180-109 has been found to be most effective, while NY-ESO-1157- 165 stimulates the most robust CD8-positive T-cell response.²

As with adoptive T-cell therapies, recent research efforts have focused on improving the extent of immune stimulation with these cancer vaccines. One means of achieving this is to promote the simultaneous stimulation of dendritic cells (DCs), which are potent activators of T cells. This can be achieved using LV305, a lentiviral vector that delivered the NY-ESO-1 antigen to DCs and resulted in robust stimulation of an antitumor immune response in a mouse model.¹⁷

Use of LV305 in clinical trials is in the early stages, but shows promise. The results of a recent phase I study in patients with sarcoma, ovarian cancer, melanoma, and lung cancer demonstrated a favorable safety profile for treatment, as well as a disease control rate of 56.4% in the entire cohort and an NY-ESO-1—specific CD4-positive/ CD8-positive T-cell induction rate of 57% in patients with sarcoma.¹⁸

Other studies have bypassed targeting DCs in the host, instead opting to deliver DCs directly to patients as an adjuvant. With this method the DCs are either combined with peptide vaccination or have been transduced with the NY-ESO-1 peptide, such that the cells act as both adjuvant and delivery system for vaccination.

A phase I clinical trial is currently recruiting patients with melanoma to explore the safety, feasibility, and immunological efficacy of the latter strategy compared with a T-cell infusion alone (NCT01946373). A phase II, open-label, randomized study also treating patients with melanoma is currently under way to evaluate the safety and immunogenicity of DCs used as an adjuvant for NY-ESO-1 peptide vaccination compared with the adjuvant Montanide (NCT02334735). Early results presented at ASCO 2019 revealed that the use of DCs as an adjuvant was able to induce seroreactivity to the NY-ESO-1 peptide, albeit to a lesser degree than the standard adjuvant.¹⁹

Activation of DCs may be improved by combining them with other anticancer therapeutics. In a recently concluded open-label phase II study (NCT02609984), CMB305, an immunotherapeutic that combines LV305 with the toll-like receptor 4 agonist GLA-SE, was evaluated for the ability to boost DC activation. CMB305 was tested in combination with atezolizumab (Tecentriq), a checkpoint inhibitor monoclonal antibody that blocks PD-L1. According to results presented at ASCO 2019, patients with sarcoma or myxoid round cell liposarcoma treated with CMB305 plus atezolizumab achieved a stronger anti—NY-ESO-1 immune response than patients treated with atezolizumab alone.²⁰ However, the future of CMB305 is unclear. Immune Design, the company developing the therapy, halted a phase III trial in metastatic synovial sarcoma in October 2018 and has since been acquired by Merck & Co.²¹

Combination therapeutics for NY-ESO-1— based cancer vaccines utilizing other checkpoint inhibitors, as well as demethylating agents, are currently under way for various cancers, including myelodysplastic syndrome and acute myeloid leukemia (NCT02750995, NCT03358719); ovarian, fallopian tube, or primary peritoneal cancer (NCT02166905); and melanoma (NCT01176474).

The use of checkpoint inhibitors in combination with NY-ESO-1—based cancer vaccines may help stimulate more robust activation of the patient’s own immune system. Additionally, demethylating agents such as decitabine (5-aza-2’-deoxycytidine) are used to combat problems that may arise as a result of heterogeneity in NY-ESO-1 expression. Treatment with this class of drugs has been shown to increase expression of NY-ESO-1 broadly in lung cancer cell lines,5 which may allow for better detection by the vaccination-primed immune system.

Investigators are also combining cancer vaccine strategies with adoptive T-cell therapy, supplementing the body’s natural immune response for more complete targeting of NY-ESO-1—positive cancer cells. Clinical trials are currently under way to explore this combined approach, targeting multiple types of neoplasms and sarcomas (NCT02775292, NCT03450122, NCT01697527).

References

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