NY-ESO-1 targeting in non-small cell lung cancer: promise and challenges of letetresgene autoleucel

Introduction

Immunotherapy has transformed the therapeutic landscape of non-small cell lung cancer (NSCLC), significantly improving survival outcomes. Nonetheless, a considerable fraction of patients, around 40%, do not derive meaningful benefit from immune checkpoint inhibitors (ICIs) (1). Primary resistance, immune escape under therapeutic pressure, and tumour heterogeneity collectively represent key biological mechanisms underlying the failure to achieve durable responses (2).

Adoptive cell therapy represents a compelling next step by leveraging ex vivo modified T lymphocytes that can be reinfused as potent, living therapeutics. While chimeric antigen receptor (CAR) T cells have revolutionized the treatment of haematological malignancies (3), their application to solid tumours like NSCLC has been limited due to challenges such as target antigen heterogeneity, suboptimal trafficking of T cells into tumors, immunosuppressive microenvironments and off-tumor toxicities. T-cell receptor-engineered (TCR-T) therapies provide an alternative strategy by redirecting T cells to recognize intracellular tumor antigens presented via human leukocyte antigen (HLA) molecules (4).

Among tumor-associated antigens, the cancer-testis antigens the New York esophageal squamous cell carcinoma 1 (NY-ESO-1)/LAGE-1a have emerged as attractive targets due to their immunogenicity, restricted expression in normal tissues and prevalence in solid tumours (5,6). Early-phase trials targeting NY-ESO-1 with TCR-T cells in synovial sarcoma and melanoma demonstrated promising objective response rates (50–61%), laying the groundwork for further investigations (7). Building on these findings, letetresgene autoleucel (lete-cel), a genetically modified autologous CD4⁺/CD8⁺ T-cell product targeting NY-ESO-1 via an HLA-A*02-restricted receptor, has been evaluated in NSCLC. Recently, Altan et al. (8) reported the largest pilot studies to date evaluating a lete-cel in advanced NSCLC.

Altan et al. (8) conducted two multicenter pilot studies evaluating lete-cel in patients with advanced NSCLC. The first was a single-arm phase I study (NCT02588612) testing lete-cel monotherapy. The second, a multi-arm phase I/II study (NCT03709706), explored lete-cel alone or in combination with pembrolizumab across distinct cohorts. All patients had to be HLA-A*02:01/02:05/02:06 positive and have NY-ESO-1 and/or LAGE-1a antigen-expressing tumors. After leukapheresis, patients received lymphodepleting chemotherapy (cyclophosphamide and fludarabine), followed by lete-cel infusion. The multi-arm study included three cohorts: arm A (lete-cel monotherapy in patients without actionable driver mutations), arm B (lete-cel plus pembrolizumab in driver-negative patients), and arm C [lete-cel plus pembrolizumab in patients with epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), or other targetable mutations]. The primary endpoints of both trials were safety and preliminary efficacy. As expected for early-phase designs both planned to enroll a limited patient numbers (approximately 10 patients in the single-arm and 45 across the three arms of the multi-arm study).

Results

Over 2,500 patients were pre-screened for HLA and antigen expression in both trials, yet <1% ultimately received the TCR-T therapy. In the multi-arm trial, 45% of screened patients were HLA-A*02 positive, while only 12% and 4% demonstrated NY-ESO-1 or LAGE-1a positivity, respectively. The requirement for dual biomarker positivity drastically reduced patient eligibility. Moreover, the choice of screening assay warrants closer scrutiny. In this trial, the immunohistochemistry (IHC) cutoff was very permissive with only 10% of tumor cells needed to stain positive, yet adoptive T-cell therapies generally require a much higher density of target-expressing cells for effective cytotoxicity. Likewise, relying on polymerase chain reaction (PCR) only confirms transcript presence in tumour tissue and provides no quantitative insight into the proportion of individual cells expressing the antigen, which is critical for predicting in vivo efficacy. In the single-arm study, 41 patients met both HLA and antigen expression criteria. Across both trials, 43 patients underwent leukapheresis, but only 18 ultimately received the lete-cel infusion. This substantial drop-off highlights additional attrition during the manufacturing and bridging phases, resulting from clinical deterioration, patient withdrawal, or production failures prior to infusion.

The strict inclusion criteria also raise concerns about equity and generalizability. HLA-A02 is unevenly distributed across ethnic groups, meaning an HLA-restricted therapy inherently favours certain populations. For instance, the HLA-A02:01 allele is present in roughly 27% of individuals of European descent but only 12% of those of African descent (9). Thus, entire patient subsets may be ineligible simply due to genetic background. This underscores a broader challenge, namely that novel TCR-T therapies targeting a single HLA-restricted epitope will exclude a large fraction of patients in populations where the requisite HLA allele is less common.

Despite the limited number of treated patients (n=18), the safety profile of lete-cel revealed expected toxicities related to both the lymphodepleting chemotherapy and T-cell infusion. No treatment-related deaths occurred, and the most common treatment-emergent adverse event, particularly grade ≥3, was cytopenia, consistent with the known myelosuppressive effects of lymphodepleting chemotherapy. Patient selection for these treatments should therefore carefully consider prior therapies and baseline organ function, particularly cumulative bone marrow suppression in heavily pretreated patients and renal clearance, which affects fludarabine metabolism.

Cytokine release syndrome (CRS) occurred in 40% of patients in the single-arm trial (2 of 5), with one ≥ grade 3 event. In the multi-arm cohort, CRS occurred in 9 of 13 patients (69.2%), with two events classified as grade 2. The median time to CRS onset was approximately 5 days post-infusion (range, 1–8 days), with more severe cases emerging around days 7–8. This timing is consistent with the kinetics of TCR-transduced T cell expansion and cytokine-mediated inflammation. Neurotoxicity consistent with immune effector cell-associated neurotoxicity syndrome (ICANS) was observed infrequently (n=2, both grade 1). The addition of pembrolizumab in some patients did not appear to increase toxicity compared to lete-cel alone.

These pilot studies revealed only minimal signs of anti-tumor activity. Among 18 patients treated, a single partial response (PR) was reported, yielding an overall response rate (ORR) of 5.6%. This response occurred in the single-arm study, giving that cohort an ORR of 20% (1 of 5 patients). No responses were seen in the multi-arm study (0 of 13).

Median progression-free survival (PFS) was 1.8 months in the single-arm study and similarly short (1.5 months) in the pembrolizumab combination arm C. The exception was arm A (monotherapy, without actionable driver mutations), with a PFS of 5.3 months, likely driven by prolonged stable disease achieved by most of the patients (5 out of 6). Median overall survival across cohorts ranged from 9 to 10 months, with the caveat of small numbers and the potential influence of post-trial therapies.

Given the low ORR in the whole study, it is important to ascertain whether the rare responses observed were truly due to the adoptively transferred T cells. All patients received high-dose cyclophosphamide/fludarabine before T-cell infusion; these cytotoxic agents could theoretically have some direct anti-tumour effect or immune modulatory benefit. In this trial, the only patient who showed a response rate, had a minor tumour regression during pre-infusion bridging therapy with pemetrexed, potential representing a confounding factor. However, the duration of the response (18 months) far exceeds cytotoxic effects of chemotherapy in refractory NSCLC. Interestingly, pharmacokinetic analyses demonstrated lete-cel expansion and persistence in all infused patients, including non-responders, confirming that lack of efficacy was not due to poor engraftment.

Discussion

The pilot trials of lete-cel in advanced NSCLC highlight several fundamental challenges in the successful integration of TCR-T cell therapy within the lung cancer treatment paradigm. First, the identification and enrolment of eligible patients remains a major obstacle. The requirement for both a specific HLA type and tumour antigen expression significantly limits the eligible population and, among those identified, many are unable to proceed through the complex and time-intensive treatment process. This considerable attrition not only hampers feasibility but also contributes to elevated costs and operational complexity, potentially impeding broader clinical adoption (10).

Second, toxicity remains a critical issue. Lymphodepletion is necessary to facilitate T-cell engraftment, but it introduces chemotherapy-associated toxicities such as cytopenia, in addition to immune-mediated adverse events like CRS. Although toxicities observed in the lete-cel studies were generally manageable with appropriate supportive care, late-onset CRS and other unexpected events stress the importance of administering these therapies in specialized centres equipped for intensive monitoring and intervention. Third, and most importantly, clinical efficacy was minimal. Unlike the breakthroughs seen in hematologic cancers, TCR-engineered cells against a single peptide/HLA target yielded only low tumor responses in NSCLC patients. Solid tumours pose several barriers to effective TCR-T activity, including antigen heterogeneity, an immunosuppressive microenvironment and multiple inhibitory signalling pathways (11). These factors likely reduced the antitumor efficacy of lete-cel, despite adequate T-cell persistence observed in the blood post-infusion. Furthermore, NY-ESO-1 and LAGE-1a expression in lung tumours may be heterogeneous or at lower levels compared to sarcoma tumours, thereby reducing effective target engagement (12). The lack of observed benefit in the pembrolizumab combination arms, where none of the patients responded and PFS was shorter than in the monotherapy cohort, raises further concerns about synergistic potential. These disappointing outcomes may stem from small sample sizes but are also consistent with the inherently refractory nature of heavily pretreated, oncogene-driven tumours that often exhibit primary resistance to immunotherapy (13).

Comparative insights from other adoptive cell therapies under investigation for NSCLC are reported in Table 1. CAR-T cells, which recognize cell-surface antigens independent of HLA, have shown remarkable success in leukaemia, but translating this to lung cancer has been difficult (3). Early-phase CAR-T trials in NSCLC targeting antigens like mucin 1 (MUC1), mesothelin, carcinoembryonic antigen (CEA), EGFR, and others are currently under investigation and have thus far reported disease control as the best response (16). Toxicity from CAR-T in lung cancer can include CRS and on-target off-tumour effects, but novel designs are being tested to improve safety and efficacy (17). Tumour-infiltrating lymphocyte (TIL) therapy, which involves the expansion of a polyclonal population of a patient’s own tumour-infiltrating T cells, offers another personalized immunotherapeutic approach, which does not require a predefined antigen or HLA restriction (16). Its toxicity profile overlaps with other cell therapies due to the prerequisite lymphodepletion and is further complicated by the frequent administration of high-dose IL-2 post-infusion to support TIL expansion, which can induce significant systemic toxicities (14). Nonetheless, early clinical signals suggest that a polyclonal, patient-specific T cell repertoire may be more capable of recognizing a wide array of tumour antigens, potentially overcoming immune evasion mechanisms that limit the efficacy of monospecific engineered products like lete-cel (18). Furthermore, a phase I dose-escalation study demonstrated that escalating doses of TILs can be safely administered with enhanced in vivo persistence in advanced NSCLC, underscoring the feasibility of this approach in heavily pretreated patients (19).

Future research is focused on expanding the antigenic targets of TCR-T therapy to include mutations like Kirsten rat sarcoma viral oncogene homolog (KRAS), particularly relevant in smoker-associated NSCLC, or other cancer-testis antigens with broader expression patterns (20,21). Nevertheless, each new target will still be constrained by HLA specificity (11). Advances in T-cell engineering, such as incorporation of costimulatory domains, resistance to immunosuppressive signals, or expression of cytokines, may ultimately enhance persistence and function in hostile tumour niches.

In conclusion, while lete-cel represents a novel and technically advanced cellular therapy, these early clinical experiences illustrate the considerable hurdles that remain for effective implementation in NSCLC. Continued efforts to refine target selection, optimize cell product functionality, and design rational combination strategies will be essential to fully harness the potential of TCR-T therapy in this challenging disease context.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-625/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-625/coif). R.C. reports grants paid to Institution by Roche, AstraZeneca, Pfizer, Clovis, Lilly Oncology, MSD, BMS, Abbvie, Takeda, Janssen, and Novartis; and consulting fees from AstraZeneca, Boeringher Ingelheim, Lilly Oncology, Roche, Pfizer, MSD, BMS, Takeda, Janssen, Bayer, and Novartis. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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