T cell receptor (TCR)-based therapy in advanced non-small cell lung cancer: a new hope?

Improvements have been made with regards to lung cancer treatment with immune checkpoint inhibitors (ICIs) targeting the programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) axis that are now used in a vast array of settings, alone or in association with chemotherapy (CT). Although advances are undeniable, outcome of metastatic lung cancer remains poor. The 5-year updates of the pivotal trials testing ICIs have shown that survival rates remain low. The Keynote 189 study (1), evaluating pembrolizumab plus CT vs. CT alone in patients with advanced non-squamous non-small cell lung cancer (NSCLC) showed a 5-year overall survival (OS) rate in the pembrolizumab group of only 19.4%. Similarly, the Keynote-024 study (2) evaluating pembrolizumab vs. CT in patients with PD-L1 tumour proportion score ≥50% on cancer cells showed a 5-year OS rate in the pembrolizumab group of 31.9% [95% confidence interval (CI): 24.5–39.5%]. Finally, the Keynote 407 study (3) showed similar results in the squamous setting.

Despite these positive results, there remains substantial room for improvement in treatment efficacy. Adoptive cell therapies (ACTs), are personalized immunotherapies that are based on the generation of artificial tumour-reactive T cells, such as engineered T cells expressing transgenic T cell receptors (TCRs) or chimeric antigen receptors (CARs). Another approach is the infusion of ex vivo expanded endogenous T cells such as tumour-infiltrating lymphocytes (TILs).

Specifically, TCR-based therapy can generate a T-cell immune response by using genetically engineered lymphocytes to target antigens derived from tumour-specific proteins presented by human leukocyte antigen (HLA) molecules on the tumour cell surface. TCR-based therapies rely on the following steps: patient screening for HLA typing and target tumour-specific protein, leukapheresis, generation of TCR-transduced T cells, lymphodepletion, and infusion of the TCR-transduced T cells.

New York oesophageal squamous cell carcinoma 1 (NY-ESO-1) and L antigen family member 1 isoform A (LAGE-1A) are cancer testis antigens (CTAs) that have known immunogenicity potential, are upregulated on certain tumours and have limited expression on normal tissue. Furthermore, NY-ESO-1 and LAGE-1A have been shown to share 84% of protein sequence and therapies targeting NY-ESO-1 have shown previous efficacy in haematological malignancies as well as in some solid tumours (4-9).

Letetresgene autoleucel (GSK3377794) is an affinity enhanced T-cell therapy that consists of autologous CD4⁺ and CD8⁺ T cells genetically modified to express a TCR that recognizes the NY-ESO-1/LAGE-1A shared epitope, SLLMWITQC, upon presentation on HLA-A*02:01, HLA-A*02:05, or HLA-A*02:06. In NSCLC, NY-ESO-1 and LAGE-1A are upregulated in both driver oncogene-positive and negative tumours, making them potential targets for letetresgene autoleucel.

Altan et al. (10) evaluated the safety and tolerability of letetresgene autoleucel alone (study 208749, NCT 02588612) or in association with pembrolizumab (study 208471, NCT 03709706) in patients with advanced NSCLC. The studies were respectively, a single-arm, open-label, pilot study and a multi-arm open-label phase Ib/IIa study. The second study was comprised of three arms: letetresgene autoleucel alone (arm A) and two arms (arm B, never opened: without oncogenic addiction; arm C: presence of an oncogenic addiction such as EGFR mutations or ALK translocation) of letetresgene autoleucel in combination with pembrolizumab.

Both studies included patients with advanced NSCLC (stage IIIB or IV), who were HLA-A*02-positive (HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06), and had tumours expressing NY-ESO-1 or LAGE-1A evaluated on tumour tissue from a formalin-fixed, paraffin-embedded archival sample or fresh biopsy. NY-ESO-1 was evaluated by immunohistochemistry (IHC) and LAGE-1A using reverse transcription-polymerase chain reaction (RT-PCR). HLA type was evaluated using DNA extracted from a blood sample.

The primary endpoints were: safety and tolerability of letetresgene autoleucel (single-arm study) and the safety, tolerability, and efficacy [investigator assessed objective response rate (ORR)] (multi-arm study) of letetresgene autoleucel in patients who received treatment alone or in combination with pembrolizumab. Both studies had the following secondary endpoints: time to response, duration of response (DOR), disease control rate and progression-free survival (PFS). OS was an exploratory endpoint.

The single-arm and multi-arm studies included 5 and 13 patients, respectively. All patients presented with stage III/IV adenocarcinoma that was pre-treated. Although some patients were heavily pre-treated some received letetresgene autoleucel as early as the second-line setting (median of 3 and 2, range, 1–5 and 1–4).

In the single-arm study, patients were mostly HLA*02:01 positive and all were NY-ESO-1 positive.

In the multi-arm study, patients were mostly HLA*02:01 positive and 11 (85%) patients had NY-ESO-1-positive tumours, and 2 (15%) patients had LAGE-1A-positive tumours. Only one patient in the single arm study presented with EGFR mutation and several patients in the multi-arm study (arm C) presented with actionable oncogene drivers (4 EGFR mutations and 2 ALK translocation). A majority of patients had received prior immunotherapy, except those whose tumours harboured actionable driver mutations.

The authors report that more than 1,000 patients were pre-screened in the single-arm study and that 41 of the patients identified as positive for HLA-A*02 and antigen expression consented to single-arm study to pursue screening. In the multi-arm study, 1,638 patients were tested and 45% were HLA-A*02 positive. Of the 525 and 348 patients tested for NY-ESO-1 and LAGE-1A only 12% and 4% were positive. These high attrition rates are problematic as a high number of patients need to be screened in order for only very few to be treated. Not only are these high rates due to the intrinsic tumour characteristics, but patients are also selected on the capacity to undergo leukapheresis and lymphodepletion. This step-wise approach is time-consuming and contributes to the high attrition rates. A number of patients withdrew from the studies after leukapheresis due to stable disease (SD) at the time of T-cell expiry, withdrawal at investigator’s decision, and low cell yield at apheresis (9 underwent leukapheresis and 5 were effectively treated in the single-arm study) and failed eligibility, lack of fitness, death due to underlying disease, withdrawal at patient/investigator discretion, and study closure (34 patients underwent leukapheresis, of whom 13 underwent lymphodepletion and letetresgene autoleucel infusion in the multi-arm study).

Letetresgene autoleucel alone or in association with pembrolizumab was confirmed as safe as there was no fatal treatment emergent adverse event (TEAE) and the most frequent grade 3 or more treatment related adverse event was cytopenia. Cytokine release syndrome (CRS) was frequent in the multi-arm study, mostly occurring several days following infusion. Specific adverse events such as Guillain-Barré syndrome (GBS), graft-vs.-host disease (GvHD) and immune effector cell-associated neurotoxicity syndrome were closely monitored and there were no reports of GBS or GvHD. All of these adverse events were reported as manageable and treated with tocilizumab if needed.

Overall, the efficacy of letetresgene autoleucel was low. ORR was 20% (95% CI: 0.5–71.6%) in the single-arm study, as only one patient had partial response (PR), one had SD and three had progressive disease (PD) as best response. The median PFS was 1.81 months (95% CI: 0.46–18.23) and median OS was 8.71 months [95% CI: 0.72–not applicable (NA)].

In the multi-arm study, none of the patients presented with tumour response. In arm A, the median PFS was 5.32 months (95% CI: 1.45–5.52) and the median OS was 9.33 months (95% CI: 3.15–9.33). In arm C, the median PFS was 1.48 months (95% CI: 0.62–2.83) and the median OS was not reached (95% CI: 0.62–NA).

The two studies reported within this paper are of great interest as they report the safety, tolerability and efficacy of TCR therapy in NSCLC and are the largest studies published in this setting. With regards to safety, letetresgene autoleucel was well tolerated and no new safety concern signals were raised. It is also relevant to note that the adjunction of ICIs, such as pembrolizumab, did not increase the toxicity of either letetresgene autoleucel nor pembrolizumab.

Another strength of the trials was their ability to perform large-scale HLA-typing and target expression testing. However, it is important to underline the extremely high attrition rate: in order to treat 18 patients, more than 2,500 were screened; less than 1% of screened patients were ultimately treated. This raises several questions and challenges that will need to be addressed in order to improve access to HLA-restricted therapies. Several options are available, as discussed by the authors: including HLA-typing into standard next generation sequencing (NGS) platforms could be an option.

With regards to efficacy, the presented trials are disappointing as only one patient across the single- and multi-arm studies presented with response (PR). It is relevant to note that this patient was heavily pre-treated (3 prior lines including CT and immunotherapy) and had no actionable driver mutations making his 18-month response impressive. Furthermore, he had high levels of NY-ESO expression. These particular characteristics could be a starting point for future patient selection.

Nonetheless, the PFS was extremely short in the two studies. These poor results are also discussed by the authors, suggesting that T cell trafficking and infiltration of the tumour could explain the low efficacy rates. Other factors at play could be the existence of inhibitory ligands in the tumour microenvironment and endogenous TCRs that can exhaust CAR T cells, defects in antigen presentation and HLA loss with prior exposure to PD-1 blockade. A way to better select patients would be to screen for HLA loss of heterozygosity beforehand. It is however underwhelming that despite stringent patient selection, with a personalised therapy, response rates and survival times would be so low. Further screening for HLA loss of heterozygosity could be a solution but even fewer patients would eventually be treated. As we aspire to provide precision medicine through patient and tumour specific profiling, the use of TCR-based approaches seems appropriate. However, the right target needs to be found and this might not be NY-ESO-1/LAGE-1A epitope-HLA complex in lung cancer.

Another reason for low efficacy could be the heterogeneous expression of NY-ESO-1. The NY-ESO-1 IHC CTA test and LAGE-1A RT-PCR CTA tests used in the trials were experimental and the authors suggest that the cut-offs used could be suboptimal leading to patients with low and/or heterogeneous expression being included. The T-cell expansion and persistence was similar as to what has been observed in previous trials and did not seem to explain the low efficacy observed in these two trials.

There is still hope for TCR-based therapies although major challenges remain such as early screening of HLA-types, identifying an optimal TCR target and anticipating resistance mechanisms such as defects of antigen presentation. Future studies will need to take all these findings into account in order to perform trials that could include upfront HLA screening and several targets using basket trial models in order to limit high attrition rates.

There are currently several ongoing trials with TCR-based therapies using original and novel strategies such as personalised and bioinformatics-driven approaches (NCT0377881, NCT05194735). Other trials are investigating the use of new generations CAR-T cells (NCT04503278, NCT0434864) and autologous TILs (NCT05681780, NCT05676749). We are at the dawn of adoptive cell therapies use in solid tumours and NSCLC. Although many challenges remain, these exciting new treatment strategies could be the backbone of future highly personalised cancer-treatment.

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-2025-882/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-882/coif). E.G.L. reports consulting fees from Astra Zeneca, Boehringer-Ingelheim, Bristol-Myers-Squib, Janssen, Lilly, MSD, Pfizer, Roche, Sanofi, and Takeda. The other author has 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/.

References

1. Garassino MC, Gadgeel S, Speranza G, et al. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol 2023;41:1992-8. [Crossref] [PubMed]
2. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50. J Clin Oncol 2021;39:2339-49. [Crossref] [PubMed]
3. Novello S, Kowalski DM, Luft A, et al. Pembrolizumab Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer: 5-Year Update of the Phase III KEYNOTE-407 Study. J Clin Oncol 2023;41:1999-2006. [Crossref] [PubMed]
4. Robbins PF, Morgan RA, Feldman SA, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 2011;29:917-24. [Crossref] [PubMed]
5. Ramachandran I, Lowther DE, Dryer-Minnerly R, et al. Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma. J Immunother Cancer 2019;7:276. [Crossref] [PubMed]
6. D'Angelo SP, Melchiori L, Merchant MS, et al. Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1 c259T Cells in Synovial Sarcoma. Cancer Discov 2018;8:944-57. [Crossref] [PubMed]
7. Gyurdieva A, Zajic S, Chang YF, et al. Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma. Nat Commun 2022;13:5296. [Crossref] [PubMed]
8. Nishihori T, Hoffman JE, Huff A, et al. Safety and efficacy of letetresgene autoleucel alone or with pembrolizumab for relapsed/refractory multiple myeloma. Blood Adv 2023;7:1168-77. [Crossref] [PubMed]
9. Stadtmauer EA, Faitg TH, Lowther DE, et al. Long-term safety and activity of NY-ESO-1 SPEAR T cells after autologous stem cell transplant for myeloma. Blood Adv 2019;3:2022-34. [Crossref] [PubMed]
10. Altan M, Lopes G, Hiltermann TJN, et al. Safety and Tolerability of Letetresgene Autoleucel (GSK3377794): Pilot Studies in Patients with Advanced Non-Small Cell Lung Cancer. Clin Cancer Res 2025;31:529-42. [Crossref] [PubMed]