Letetresgene autoleucel in advanced non-small cell lung cancer: a step towards truly personalized immunotherapy?

Treatment for non-small cell lung cancer (NSCLC) has undergone a remarkable transformation over the past decade due to the development of immunotherapy and targeted therapies. Immune checkpoint inhibitors (ICIs) targeting programmed death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) have improved survival outcomes, especially in patients with high PD-L1 expression. Five-year follow-up results from Keynote-024 have been reported, showing a median overall survival (OS) of 26.3 months and 31.9% of patients alive at 5 years (1). For patients harboring oncogenic driver mutations, such as EGFR, ALK, ROS1, or RET, tyrosine kinase inhibitors (TKIs) have dramatically improved survival outcomes and quality of life (2,3). However, primary and acquired resistance remains major clinical challenges, prompting a shift towards more individualized strategies. Personalized new approaches are necessary in the field of NSCLC.

Tumor-infiltrating lymphocyte (TIL) therapy and genetically engineered T-cell receptor T cell (TCR-T) represent two promising strategies to redirect autologous T cells against tumor-specific antigens. These therapies have demonstrated remarkable success in treating hematological malignancies (4). However, solid tumors present a unique set of challenges for cellular therapies, including an immunosuppressive stroma, heterogeneous antigen expression, and poor tumor infiltration of T cells into tumor sites, all of which can hinder therapeutic efficacy (5).

Most of the current evidence for TCR therapy comes from studies of melanoma and synovial sarcoma. The pivotal trial of lifileucel, a TIL therapy, showed a meaningful clinical benefit in patients with metastatic melanoma with limited treatment options. The objective response rate (ORR) was 36% and disease control rate (DCR) was 80% with a median duration of response (DoR) not reached after a median follow-up of 18.7 months (6).

Another key piece of clinical evidence for TCR therapies comes from a pilot trial in which genetically engineered TCR-T cells were used to express the New York esophageal squamous cell carcinoma 1 (NY-ESO-1) specific T-cell receptor. The trial, conducted in patients with advanced melanoma and synovial sarcoma, demonstrated objective clinical responses in 61% of synovial sarcoma and 55% of melanoma patients (7). More recently, D’Angelo et al. reported positive results in terms of ORR for letetresgene autoleucel (lete-cel) patients with advanced/metastatic myxoid/round cell liposarcoma, which supported the FDA breakthrough therapy designation for lete-cel in this indicacion (8). These results provide a proof-of-concept that could extend to other solid tumors.

Related to lung cancer, a key piece of clinical evidence for TCR therapies comes from a phase I trial evaluating ADP-A2M10 SPEAR T cells, genetically engineered to express a high-affinity TCR targeting melanoma-associated antigen A10 (MAGE-A10) in HLA-A*02-positive patients with advanced NSCLC. The study included 11 patients, one of whom achieved a partial response (PR) after a second infusion, while four patients experienced stable disease (SD). The therapy demonstrated an acceptable safety profile, with manageable hematologic toxicities and limited cytokine release syndrome (CRS), and no off-target or alloreactivity-related adverse events were observed. These results support the feasibility of targeting MAGE-A10 with TCR-T cells in NSCLC and provide a rationale for further investigation of TCR-based therapies in this malignancy (9).

NY-ESO-1 and L Antigen Family Member 1a (LAGE-1a), closely related cancer-testis antigens, are promising targets for TCR-based therapies. These intracellular proteins are expressed in various malignancies including melanoma, sarcomas, and several NSCLC, while are absent in most normal adult tissues. However, their expression in NSCLC is relatively rare, with NY-ESO-1 detected in approximately 10–15% of tumors and LAGE-1a in an even smaller proportion. They share a common epitope presented by HLA-A*02:01, allowing engineered T cells to recognize both through the same TCR. This molecular similarity enables cross-recognition and supports their co-targeting in antigen-specific cellular immunotherapy approaches (10).

Two pilot studies were conducted to evaluate the safety, tolerability, and antitumor activity of lete-cel (GSK3377794), a genetically modified autologous TCR-T therapy targeting a shared NY-ESO-1/LAGE-1a epitope (11). These included the single-arm study 208749 (NCT02588612) and the multi-arm trial 208471 (NCT03709706), both including HLA-A*02:01 positive patients, who had tumors expressing at least one of the target antigens.

After lymphodepleting chemotherapy, patients received lete-cel as monotherapy or in combination with pembrolizumab. Over 2,500 patients with advanced NSCLC were evaluated for HLA-A*02:01 status (from blood sample) and tumor expression of NYESO-1 or LAGE-1a (from tumor issue). Despite this broad initial pool, only 71 patients (2.8%) met the stringent molecular and immunological eligibility criteria and proceeded to leukapheresis. Further attrition occurred due to manufacturing constraints, disease progression, or the failure to meet additional criteria. Finally, only 18 patients received the lete-cel infusion across both studies.

The primary objective of both studies includes safety and tolerability of lete-cel. For the multi-arm study, the primary objective also included efficacy (ORR) of lete-cel in patients who received treatment alone or in combination with pembrolizumab. In terms of safety, no fatal-related events occurred, regardless of the addition of pembrolizumab. Overall, lete-cel was well tolerated. The most common grade ≥3 treatment-related adverse events were cytopenia (related to the lymphodepleting chemotherapy) and mild CRS. Regarding efficacy, in the single-arm study one patient achieved a confirmed PR, one had SD and three patients experienced progression after treatment. Among the 11 patients treated in the multi-arm study, eight patients had SD and no patient achieved PR or complete response. Median progression-free survival (PFS) was 1.5 months in the pembrolizumab combination arm and 5.3 months in the lete-cel monotherapy arm while OS was 8.7 and 9.3 months, respectively.

These two studies provide two notable findings. First, they explore the combination of TCR-based cellular therapy and ICIs. This is an excellent strategy to overcome the immunosuppressive tumor microenvironment (TME) characteristic of solid tumors. The biological rationale is that activation of the immune system after T-cell infusion may help overcome immune suppression and sustain antitumor activity. Expanding on this point, the TME represents a major barrier to effective antitumor therapies. The composition of the TME (regulatory T cells, myeloid-derived suppressor cells and tumor-associated macrophages) affects responsiveness to ICIs and limit T-cell activation, promoting resistance. Reprogramming the TME toward a pro-immunogenic state is critical for improving therapeutic outcomes. Such modulation through checkpoint blockade may restore immune activity and potentiate the function of transferred T cells. Another rationale for combination therapy is the possibility is overcoming limitations in antigen presentation and tumor infiltration (12,13). In these studies, this combination was feasible and well tolerated, with no significant increase in toxicities. However, there is still no evidence of synergistic effect in terms of efficacy (PR was not achieved in the pembrolizumab arm). While the concept is promising from a mechanistic perspective, further investigation is needed. Second, these studies emphasize the importance of shifting research focus to more specific and personalized tumor targets. The use of NYESO-1 and LAGE-1a as a therapeutic target reflects the principles of precision oncology, since they are restrictedly expressed in normal tissues, making them attractive from a safety perspective. The authors of these studies suggested that the observed limited efficacy may be partly due to low and/or heterogeneous antigen expression levels. This raises the possibility that high levels of antigens or more defined inclusion levels could change the results of future clinical trials. Nonetheless, the low prevalence of these antigens in NSCLC limits the number of eligible patients. In consequence, these findings highlight a significant obstacle to widespread clinical application, suggesting that future research should prioritize identifying novel tumor antigens commonly expressed in NSCLC.

It should be noted that these studies reveal significant limitations. Most notably, the dramatic narrowing of the eligible patient population reflects the logistical and biological barriers inherent to TCR-T therapies. Among more than 2,500 patients screened, only 18 were treated. This was the result of strict inclusion criteria, requiring not only HLA-A*02-01 positivity, but also tumor expression of selected antigens, and suitability for leukapheresis, lymphodepletion, and delayed infusion. We take note of the fact that a complex process is needed, which highlights a disconnection between trial design and real-world clinical applicability. Another important consideration is timing. A rapid disease progression is common in patients with advanced NSCLC, especially in heavily pretreated patients. Therefore, the prolonged time between patient selection and treatment delivery may limit the feasibility of this approach in real-world clinical setting. Finally, the small sample size and heterogeneity in antigen expression across study arms preclude meaningful conclusions regarding ORR or overall clinical benefit.

With this in mind, we believe that lete-cel (GSK3377794) represents a proof of concept for TCR-T therapy in NSCLC. While clinical activity was limited, these studies demonstrate the potential of highly personalized immunotherapy in solid tumors. The comprehensive screening and selection process provide valuable information about human leukocyte antigen (HLA) and tumor antigen expression in the NSCLC population. Future efforts should focus on improving antigen selection, enhancing T cell persistence, and integrating antigen-HLA profiling early in the diagnostic process.

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-2025-866/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-2025-866/coif). S.M.R. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Pfizer, AZ, Pierre-Fabre, Sanofi, BMS, Takeda, Novartis, Lilly, and Regeneron; and support for attending meetings and/or travel: Roche, Lilly, Merck, Pfizer, BMS, Novartis, MSD, Lilly, Pierre-Fabre, and Janssen. A.B. reports Astrazeneca advisory board and invited speaker, BMS expert testimony and invited speaker, Jansenn congress funding, MSD invited speaker, Novartis invited speaker, Pfizer invited speaker and congress funding, Piere Fabre invited speaker and congress funding, Regeneron invited speaker, Roche invited speaker and advisory board, Sanofy advisory board and invited speaker; BMS Principal Investigator, Clinical Trial CA224-1044; Dizal Prinpial Investigator DZ2022E0005 & DZ2019E0001; and Pfizer Principal Investigator, Clinical Trial C4221016. M.M. reports advisory board, consulting fees or invited speaker: Amgen, AstraZeneca, Boehringer Ingelheim, BeOne, Bristol-Myers Squibb, Helsinn Therapeutics, Johnson & Johnson, MSD, Novartis, Pfizer, Pharmamar, F. Hoffmann-La Roche Ltd., Takeda, Sanofi, Johnson & Johnson, Regeneron, Cassen Recordatti, and Immedica; research funding (institution): Bristol-Myers Squibb, AstraZeneca, and F. Hoffmann-La Roche Ltd.; and travel and accommodation support: AstraZeneca, F. Hoffmann-La Roche Ltd., Pfizer, and MSD. The other authors have no conflicts of interest to declare.

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