bims-tuinly 2025-07-27 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–07–27
fifteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Adoptive cell therapy in colorectal cancer: Advances in chimeric antigen receptor T cells.
Evaluating functional anti-tumor T cell responses in autologous 2D co-cultures using flow cytometry.
Tumor-infiltrating lymphocytes in melanoma: diagnostic and prognostic implications from biopsy to circulation.
Improving lung cancer tumor-infiltrating lymphocyte (TIL) manufacturing.
The size of CD8+ infiltrating T cells is a prognostic marker for esophageal squamous cell carcinoma.
Investigating tumor-infiltrating lymphocytes as predictors of lymph node metastasis in deep submucosal invasive esophageal squamous cell carcinoma: a retrospective cross-sectional study.
To Assess the Predictive and Prognostic Role of PD-L1 and CD8 Following Neoadjuvant Chemotherapy in Breast Cancer.
Regulatory T Cells in Colon Cancer: Implications for Pathogenesis, Prognosis and Emerging Therapeutic Strategies.
A hexamerization-enhanced, Fc-silenced agonistic CD27 antibody amplifies T-cell effector functions as single agent and in combination with PD-1 blockade.
Impact of the PD-1/PD-L1 inhibitor SCL-1 on MDA-MB231 tumor growth in a humanized MHC-double knockout NOG mouse model.
Lifileucel tumor-infiltrating lymphocyte cell therapy in patients with unresectable or metastatic mucosal melanoma after disease progression on immune checkpoint inhibitors.
Tumour-infiltrating lymphocytes in refractory melanoma - not as hard as we thought?
Protocol for assessing pharmacokinetics and pharmacodynamics of human CAR-NKT cells in humanized mouse models using bioluminescence imaging.
Phase 2, Open-Label, Multicenter Study of Nelitolimod in Combination with Pembrolizumab in Anti-PD-1 Treatment-Naive Advanced Melanoma.
LARP4-mediated hypertranslation drives T cell dysfunction in tumors.

World J Gastrointest Oncol. 2025 Jul 15. 17(7): 106723

Adoptive cell therapy in colorectal cancer: Advances in chimeric antigen receptor T cells.

Meng-Yan Chen, Chen Wang, Yu-Gang Wang, Min Shi.

  Colorectal cancer (CRC) is the third most common cancer worldwide and remains a major treatment challenge, particularly in advanced and metastatic stages. Current standard treatments have limited efficacy, underscoring the urgent need for innovative strategies. Adoptive cell therapy (ACT), which involves in vitro expansion or genetic engineering of immune cells, is a promising approach to bolster anti-tumor immune responses. Key ACT modalities include chimeric antigen receptor (CAR) T cells, tumor-infiltrating lymphocytes (TILs), and T cell receptor (TCR)-engineered T cells. CAR-T cell therapy has shown success in hematological malignancies but faces significant challenges in solid tumors like CRC. These challenges include antigen heterogeneity, an immunosuppressive tumor microenvironment, on-target off-tumor toxicity, among other factors. To address these limitations, combinatorial approaches, such as immune checkpoint inhibitors, cytokines, and advanced gene-editing tools like CRISPR/Cas9, are being actively explored. These strategies aim to enhance CAR-T cell specificity, improve resistance to immunosuppressive signals, and optimize in vivo functionality. This review summarizes ACT approaches for CRC, with a focus on CAR-T therapy. It briefly introduces TILs and TCR-T cells, while emphasizing the major challenges faced by CAR-T therapy in solid tumors and discusses potential strategies to improve therapeutic outcomes.

Keywords:  Adoptive cell therapy; Chimeric antigen receptor T cells; Colorectal cancer; Immunotherapy; T-cell receptor-engineered T cells; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.4251/wjgo.v17.i7.106723
Methods Cell Biol. 2025 ;pii: S0091-679X(25)00002-0. [Epub ahead of print]196 161-169

Evaluating functional anti-tumor T cell responses in autologous 2D co-cultures using flow cytometry.

Lucas Baldran-Groves, Jeroen Melief, Andreas Lundqvist.

  Immune surveillance by T cells is a key determinant of cancer progression, and T cell-based immunotherapies have shown great promise as a treatment modality for cancer patients. As such, physiologically relevant methods to evaluate interactions between T cells and tumor cells are of particular interest. In vitro systems that enable the culture patient-derived tumor cells in the presence of autologous tumor-infiltrating lymphocytes (TIL) serve as an invaluable tool to understand the basic biological role of T cells in cancer and how their functioning might be modulated to gain therapeutic benefit. Hence, this chapter describes a flow cytometry-based approach to assess TIL activation by exposure to autologous tumor cells in culture. In particular, the chapter will focus on ways to assess the capacity of cytotoxic lymphocytes (CTL) to degranulate and secrete pro-inflammatory cytokines in such culture systems.

Keywords:  Cancer; Cytotoxic lymphocytes; Flow cytometry; Immunotherapy; Tumor-infiltrating lymphocytes (TIL)

DOI:  https://doi.org/10.1016/bs.mcb.2025.01.002
J Liq Biopsy. 2025 Sep;9 100308

Tumor-infiltrating lymphocytes in melanoma: diagnostic and prognostic implications from biopsy to circulation.

Hussain Noorwali.

  Melanoma is a highly aggressive skin cancer that arises from melanocytes and presents considerable clinical challenges due to its strong metastatic capacity and ability to evade the immune system. Tumor-infiltrating lymphocytes (TILs) reflect the host's immune activity within the tumor microenvironment and have gained recognition as important biomarkers for both diagnosis and prognosis in melanoma. A higher density of TILs-particularly CD8+ cytotoxic T cells-is associated with better overall survival and reduced risk of recurrence. Histopathological assessment of TILs, including classification systems like the Clark model, plays a key role in risk stratification, particularly in early-stage melanoma. Meanwhile, peripheral blood T-cell profiling offers a non-invasive approach to assess systemic immune status. Circulating T-cell subsets and their expression of activation or exhaustion markers (e.g., PD-1, CTLA-4) reflect tumor immune dynamics and may serve as potential indicators of disease progression or prognosis. Despite promising data, heterogeneity in TIL composition and peripheral immune profiles challenges consistent interpretation and clinical implementation. Future efforts should focus on standardizing TIL assessment, integrating tissue and blood immune markers, and leveraging computational tools to develop robust predictive models. This integrated immunological approach holds potential to refine melanoma prognosis and improve risk stratification. This review aims to provide an updated and comprehensive overview of the diagnostic and prognostic significance of TILs and peripheral T-cell markers in melanoma. By synthesizing current evidence and addressing key limitations, it underscores the importance of immune profiling in advancing melanoma evaluation and guiding future research directions.

Keywords:  Immune profiling; Melanoma; Peripheral T cells; Prognostic biomarkers; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.jlb.2025.100308
Cytotherapy. 2025 Jul 06. pii: S1465-3249(25)00764-9. [Epub ahead of print]

Improving lung cancer tumor-infiltrating lymphocyte (TIL) manufacturing.

Pamela K Noldner, Ying Zhou, Liliana Lyniv, Jose R Conejo-Garcia, Scott Antonia, Beth H Shaz.

   BACKGROUND: The successful treatment of melanoma using autologous in vitro expanded tumor infiltrating lymphocytes (TILs) has sparked clinical trials for the assessment of TIL efficacy against other cancers, including non-small cell lung cancer (NSCLC). This rise in clinical applications of TILs has increased the need for improved, more streamlined and cost-effective manufacturing protocols. The aim of this study was to simplify and reduce the cost of traditional TIL manufacturing protocols while maintaining GMP manufacturing compliance, yields, and quality of the TIL product.
METHODS: Resected lung tumors were cultured to expand TILs. In side-by-side experiments, we evaluated media formulations, supplementing reagents, reagent concentrations, TIL activation methods and cryopreservation protocols. The optimizations aim to reduce labor, reagent cost, culture times, and open step manipulations. The resulting TIL products were compared against TILs produced using the Moffitt Cancer Center published protocol. We compared cell yields, viabilities, phenotypes, and TIL cytotoxic activity against matched tumor organoids.
RESULTS: TILs were successfully expanded from 35 fragmented tumor samples using T-cell specific media in place of RPMI, human AB serum in place of human platelet lysate and α-CD3/CD28 nanobeads in place of feeder cells for cell activation. Culture duration was reduced from 6 to 7 weeks to 4 weeks and the final product contained an average of 200e9 TILs that were predominantly of the memory phenotype and effectively killed matched tumor cells. While TIL yields and phenotypes were comparable to those produced by the Moffitt Cancer Center protocol, cytotoxicity against matched tumor cells was superior.
CONCLUSION: Traditional TIL manufacturing protocols could be optimized and streamlined into a more cost-effective process for a TIL product that is cytotoxic to tumor cells and yields quantities suitable for clinical studies.

Keywords:  GMP manufacturing; cell therapy; non-small cell lung cancer; tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.1016/j.jcyt.2025.07.001
Sci Rep. 2025 Jul 22. 15(1): 26638

The size of CD8+ infiltrating T cells is a prognostic marker for esophageal squamous cell carcinoma.

Kengo Shigehara, Noriko Kawai, Tomohide Shirosaki, Yuma Ebihara, Aiko Murai, Akari Takaya, Serina Tokita, Kenta Sasaki, Naoki Shijubou, Terufumi Kubo, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Yutaka Hatanaka, Tomoko Mitsuhashi, Toshiaki Shichinohe, Yoshihiko Hirohashi, Satoshi Hirano, Toshihiko Torigoe.

  In many malignancies, an increased number of tumor-infiltrating lymphocytes (TILs) is recognized as a favorable prognostic factor, with exceptions such as renal cell carcinoma. However, the clinical significance of TIL size remains unclear. T-cell activation by mitogens increases cell size, partly via c-myc expression, suggesting that larger T cells may be more activated. We hypothesized that TIL size might be prognostically relevant in cancer patients. Here, we examined the relationship between the size and number of tumor-infiltrating CD8 + T cells and patient prognosis in 96 cases of esophageal squamous cell carcinoma (ESCC). We employed artificial intelligence (AI) analysis to quantify the mean size of intratumoral CD8+ T cells in each sample. Patients were then divided into "Large" and "Small" CD8+ T cell groups according to the median T-cell size. Similarly, we classified cases into "High" and "Low" groups based on CD8 + T-cell numbers. We found that patients in the Large CD8+ T cell group had significantly better overall survival than those in the Small CD8+ T cell group by a univariate analysis (p = 0.039), but the difference did not reach statistical significance in a multivariate analysis (p = 0.054). Patients in the High CD8 + T cell group had better outcomes than those in the Low CD8+ T cell group. There was no significant correlation between CD8+ T cell size and count, and their combination (Large/High) identified a subgroup of patients with the most favorable prognosis. Our findings suggest that CD8+ T cell size could serve as an independent prognostic marker in ESCC.

Keywords:  CD8; Esophageal squamous cell carcinoma; Lymphocyte size; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1038/s41598-025-10885-3
J Gastroenterol. 2025 Jul 25.

Investigating tumor-infiltrating lymphocytes as predictors of lymph node metastasis in deep submucosal invasive esophageal squamous cell carcinoma: a retrospective cross-sectional study.

Hirona Konishi, Yuji Urabe, Yoshiki Hatsushika, Satoshi Masuda, Takeo Nakamura, Kazuki Ishibashi, Junichi Mizuno, Takeshi Takasago, Hidenori Tanaka, Akiyoshi Tsuboi, Ken Yamashita, Yuichi Hiyama, Yoshihiro Kishida, Hidehiko Takigawa, Akira Ishikawa, Toshio Kuwai, Yoichi Hamai, Yuji Murakami, Shiro Oka.

   BACKGROUND: Various subtypes of tumor-infiltrating lymphocytes (TILs) are associated with prognosis in various cancer types. In esophageal squamous cell carcinoma (ESCC), TILs have been associated with prognosis in advanced stages of the disease. However, their significance in superficial esophageal squamous cell carcinoma (SESCC) remains unknown. In this study, we investigated the role of TILs in SESCC.
METHODS: First, we included 212 SESCC lesions with a diameter of 10-20 mm (65 pT1a-EP, 74 pT1a-LPM,40 pT1a-MM, and 33 pT1b-SM lesions) that were resected at our hospital from November 2007 to December 2019. We then examined changes in TILs related to tumor invasion. We evaluated the phenotype and number of TILs using triple immunofluorescence staining for CD4, CD8, and FoxP3. In addition, we selected 97 consecutive pT1b-SM lesions treated during the same period. These specimens were used to examine the association between TILs and lymph node metastasis (LNM) in pT1b-SM cases.
RESULTS: The number of CD4 + , CD8 + , and FoxP3 + TILs infiltrating the tumor increased significantly with increasing invasion depth. In pT1b-SM lesions, CD4 + , CD8 + , and FoxP3 + TIL counts were significantly higher in the invasive front (IF) than in the tumor center (CT). Moreover, in patients undergoing surgical resection or endoscopic submucosal dissection (regardless of additional chemoradiotherapy), the number and ratio of FoxP3 + TILs in IF were significantly higher in patients with LNM than in those without, suggesting their potential utility as predictive biomarkers.
CONCLUSIONS: The number and ratio of FoxP3 + TILs in the IF may be an indicator of LNM risk in SESCC.

Keywords:  Esophageal cancer; Lymph node metastasis; Tumor microenvironment; Tumor-infiltrating T-cells

DOI:  https://doi.org/10.1007/s00535-025-02286-0
Indian J Surg Oncol. 2025 Jun;16(3): 774-783

To Assess the Predictive and Prognostic Role of PD-L1 and CD8 Following Neoadjuvant Chemotherapy in Breast Cancer.

Pinki Pandey, Kapil Trivedi, Roopak Aggarwal, Alok Dixit, Alka Yadav, Savita Agarwal, Shailendra Pal Singh, Kailash Kumar Mittal.

  Neoadjuvant chemotherapy (NACT), introduced in 1970 for inoperable tumors, has become the standard treatment approach in locally advanced breast cancer (LABC). Pathological complete response (pCR) following NACT is an important indicator for disease-free survival. An increased number of CD8-positive tumor-infiltrating lymphocytes (TILs) in the tumor center is thought to indicate an effective antitumor-immune response. Aberrant expression of programmed death ligand-1 (PD-L1) allows tumor cells to escape the host immune system. Change in PD-L1 expression may serve as an indirect indicator to assess the response to NACT. The residual cancer burden (RCB) category defined by routine histopathological evaluation represents the extent of residual disease and may predict disease-free survival. In this study, we assessed the expression of PD-L1 and CD8 in pre- and post-NACT specimens and their role in predicting pathological response to NACT. This study was conducted for a period of 3 years at Uttar Pradesh University of Medical Sciences, Saifai. PD-L1 and CD8 expression was compared on pre- and post-NACT tissue specimens. Pathological response to NACT was assessed by the RCB system. A total of 62 cases were evaluated. The mean age of patients was 47.58 ± 11.16 years. Six (9.7%) patients achieved pCR (RCB-0). PD-L1 and CD8 expression was found to be positively associated with pathological response (P < 0.001 for both). Tumors with negative PD-L1 (OR = 0.02) and pre-NACT intermediate/low expression of CD8 in TILs (OR = 0.11) are less likely to show a response to NACT. Prognostic role of PD-L1 and CD8 was also assessed by the Nottingham prognostic index (NPI). The expression of PD-L1 and CD8-positive TILs correlate with response to chemotherapy. High PD-L1 and CD8-positive TILs may predict better response to neoadjuvant chemotherapy.

Keywords:  Breast cancer; CD8; Neoadjuvant chemotherapy; PD-L1; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1007/s13193-024-02139-x
Immunol Invest. 2025 Jul 21. 1-52

Regulatory T Cells in Colon Cancer: Implications for Pathogenesis, Prognosis and Emerging Therapeutic Strategies.

Faris Anad Muhammad, Abdulkareem Shareef, S Renuka Jyothi, Sachin Kumar, Ashish Singh Chauhan, Apurav Gautam, Maksuda Ashurova, Hayder Naji Sameer, Ahmed Yaseen, Zainab H Athab, Mohaned Adil, Ayda Abrari, Mahyar Mohammadifard.

   INTRODUCTION: Colon cancer is a highly heterogeneous malignancy with significant global incidence and mortality. The tumor microenvironment (TME) plays a pivotal role in disease progression and treatment response. Among key components of the TME are tumor-infiltrating lymphocytes (TILs), particularly regulatory T cells (Tregs) and effector T cells, whose balance influences cancer outcomes.
METHODS: This review analyzes recent findings regarding the role of Treg cells in colon cancer progression by evaluating preclinical and clinical studies that explore immune cell composition, function, and modulation within the TME.
RESULTS: Treg cells demonstrate a dual role in colon cancer. While they suppress effective anti-tumor immune responses, facilitating immune evasion, they may also mitigate chronic inflammation, which contributes to carcinogenesis. High intratumoral Treg levels are correlated with poor prognosis, reduced immunotherapy efficacy, and lower overall survival. Strategies to deplete or reprogram Tregs, such as immune checkpoint inhibition, modulation of T cell plasticity, and selective targeting, have shown promise in enhancing anti-tumor immunity.
DISCUSSION: Complete depletion of Tregs risks inducing autoimmune toxicity. Therefore, a precise understanding of Treg cell subsets and functions is essential. This review highlights the importance of developing targeted immunotherapeutic strategies that modulate Treg activity while preserving immune homeostasis in colon cancer treatment.

Keywords:  FOXP3; Regulatory T cell; Treg; colon cancer; immunotherapy; prognosis; targeted therapy

DOI:  https://doi.org/10.1080/08820139.2025.2529970
Sci Rep. 2025 Jul 24. 15(1): 26933

A hexamerization-enhanced, Fc-silenced agonistic CD27 antibody amplifies T-cell effector functions as single agent and in combination with PD-1 blockade.

Işıl Altıntaş, Kristina B Nürmberger, Andrea Imle, Anna-Lena Krause, Marike M van Beuge, Aras Toker, Andreea Ioan-Facsinay, Jordan Blum, Alexander Muik, Frank J Beurskens, Rob N de Jong, David P E Satijn, Friederike Gieseke, Bart-Jan de Kreuk, Maarten van der Kroef, Sina Fellermeier-Kopf, Tahamtan Ahmadi, Özlem Türeci, Esther C W Breij, Uğur Şahin.

  HexaBody-CD27 (GEN1053/BNT313) is an investigational novel agonistic CD27 antibody engineered to enhance T-cell costimulation and promote antitumor immunity. Through the introduction of a hexamerization-enhancing mutation in the IgG Fc domain, HexaBody-CD27 was designed to drive clustering and activation of CD27 via intermolecular Fc:Fc interactions between membrane-bound antibodies, independent of crosslinking by FcγR-bearing cells. HexaBody-CD27 carries an Fc-silencing mutation to prevent T-cell depletion through Fc-mediated effector functions. In vitro, HexaBody-CD27 induced CD27 receptor signaling independent of FcγR-mediated crosslinking in a reporter assay. It also enhanced T-cell proliferation, cytotoxic activity and proinflammatory cytokine secretion in primary human lymphocytes. In contrast to benchmark IgG1 CD27 antibodies, HexaBody-CD27 did not induce phagocytosis of T cells in vitro. HexaBody-CD27 promoted ex vivo tumor infiltrating lymphocyte (TIL) expansion in non-small cell lung cancer (NSCLC) specimens, in particular of CD8+ TILs. The combination of HexaBody-CD27 with an anti-PD-1 antibody enhanced T-cell proliferation, cytokine secretion, and cytotoxic activity in vitro compared to either compound alone. In conclusion, HexaBody-CD27 enhanced T-cell activation and effector functions in an FcγR-crosslinking-independent manner, without inducing T-cell depletion. The immune agonist activity of HexaBody-CD27 was potentiated in combination with PD-1 blockade.

Keywords:  Combination therapy; Costimulatory molecules; Immunotherapy; Monoclonal antibody; T cell

DOI:  https://doi.org/10.1038/s41598-025-11990-z
Sci Rep. 2025 Jul 24. 15(1): 26918

Impact of the PD-1/PD-L1 inhibitor SCL-1 on MDA-MB231 tumor growth in a humanized MHC-double knockout NOG mouse model.

Tomoatsu Ikeya, Tadashi Ashizawa, Akari Kanematsu, Chie Maeda, Akira Iizuka, Kazue Yamashita, Haruo Miyata, Yasufumi Kikuchi, Kouji Maruyama, Mamoru Ito, Ken Yamaguchi, Yasuto Akiyama.

  Although triple-negative breast cancers are still challenging to treat, the development of novel neoadjuvant chemotherapy combined with immune checkpoint antibodies is promising. Our group developed the small compound-based anti-PD-1/PD-L1 inhibitor SCL-1 and reported its potent anti-tumor effects on various syngeneic mouse tumors. We herein investigated the efficacy of SCL-1 using an in vivo humanized NOG mouse system. We established a humanized mouse system using double major histocompatibility complex-knockout NOG mice transplanted with MDA-MB231 breast cancer cells and HLA-matched human PBMCs. Tumor-infiltrating lymphocytes (TILs) were analyzed using flow cytometry and real-time PCR. An RNA-sequencing analysis (RNA-seq) of SCL-1-treated MDA-MB231 tumors was performed to identify differentially expressed genes. Orally administered SCL-1 exerted potent anti-tumor effects with > 50% reduction in tumor sizes, which were dependent on PD-L1 expression and T-cell infiltration. Its effects were significantly stronger than those of nivolumab or atezolizumab. A TIL analysis revealed effector CD8+ T cells expressing cytotoxic markers and exhausted markers as well as increases in NK cells and B cells. RNA-seq showed the up-regulated expression of tumor-specific long non-coding (lnc) RNAs in SCL-1-treated tumor tissues, some of which exhibited high HLA-binding activity. SCL-1 exerted strong tumor growth inhibitory effects that were mediated by effector T-cell induction inside tumors and the up-regulated expression of lncRNAs as neoantigens leading to CTL activation. The up-regulated expression of lncRNAs in SCL-1-treated MDA-MB231 tumors is a novel result and may be one of the mechanisms responsible for the anti-tumor efficacy of SCL-1.

Keywords:  Humanized mouse; Immune checkpoint inhibitor; NOG mouse; PD-1/PD-L1; Triple-negative breast cancer

DOI:  https://doi.org/10.1038/s41598-025-12103-6
Cancer Commun (Lond). 2025 Jul 22.

Lifileucel tumor-infiltrating lymphocyte cell therapy in patients with unresectable or metastatic mucosal melanoma after disease progression on immune checkpoint inhibitors.

Harriet Kluger, Götz Ulrich Grigoleit, Sajeve Thomas, Evidio Domingo-Musibay, Jason A Chesney, Miguel F Sanmamed, Theresa Medina, Mirjana Ziemer, Eric Whitman, Friedrich Graf Finckenstein, Brian Gastman, Jeffrey Chou, Xiao Wu, Giri Sulur, Rana Fiaz, Rongsu Qi, Amod A Sarnaik.

DOI: https://doi.org/10.1002/cac2.70050
Ann Oncol. 2025 Jul 21. pii: S0923-7534(25)00859-2. [Epub ahead of print]

Tumour-infiltrating lymphocytes in refractory melanoma - not as hard as we thought?

A Javaid, S P Patel, J Larkin.

DOI: https://doi.org/10.1016/j.annonc.2025.07.010
STAR Protoc. 2025 Jul 19. pii: S2666-1667(25)00363-6. [Epub ahead of print]6(3): 103957

Protocol for assessing pharmacokinetics and pharmacodynamics of human CAR-NKT cells in humanized mouse models using bioluminescence imaging.

Zibai Lyu, Yan-Ruide Li, Lili Yang.

  Human invariant natural killer T (NKT) cells exhibit strong tumor-killing ability and bridge innate and adaptive immunity. Peripheral blood mononuclear cell (PBMC)-derived chimeric antigen receptor (CAR)-engineered NKT (CAR-NKT) cells show potent anti-tumor activity. Here, we present a protocol for assessing the pharmacokinetics and pharmacodynamics (PK/PD) of PBMC-derived CAR-NKT cells in humanized mouse models using in vivo bioluminescence imaging (BLI). We describe steps for evaluating CAR-NKT cell distribution, persistence, and tumor infiltration across tumor-free and tumor-bearing models to support CAR-NKT cell therapy development. For complete details on the use and execution of this protocol, please refer to Li et al.1,2.

Keywords:  Biotechnology and bioengineering; Cancer; Immunology; Microscopy; Model Organisms

DOI:  https://doi.org/10.1016/j.xpro.2025.103957
Clin Cancer Res. 2025 Jul 25.

Phase 2, Open-Label, Multicenter Study of Nelitolimod in Combination with Pembrolizumab in Anti-PD-1 Treatment-Naive Advanced Melanoma.

Antoni Ribas, Mohammed M Milhem, Christopher J Hoimes, Asim Amin, Christopher D Lao, Robert M Conry, Jason P Hunt, Gregory A Daniels, Mohammed Almubarak, Montaser Shaheen, Theresa Medina, Minal Barve, Sarwan Bishnoi, Ehtesham Abdi, Michael J Chisamore, Cristiana Guiducci, Jose Gomez-Romo, Albert Candia, Erick Gamelin, Robert L Coffman, Robert S Janssen, Georgina V Long.

PURPOSE: Nelitolimod (previously SD-101) is a toll-like receptor 9 agonist. We assessed whether intratumoral nelitolimod plus pembrolizumab potentiates antitumor activity in patients with advanced melanoma who had not previously received anti-programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) therapy.
PATIENTS AND METHODS: Patients with advanced melanoma who were naive to anti-PD-1/PD-L1 therapy received either nelitolimod 2 mg injected into 1-4 lesions or nelitolimod 8 mg injected weekly into a single lesion for 4 weekly doses, then every 3 weeks. Pembrolizumab 200 mg was administered intravenously every 3 weeks.
RESULTS: Forty-five patients received nelitolimod 2-mg and 41 patients received nelitolimod 8-mg per injection. The objective response rate (ORR) was 76% in the 2-mg group and 49% in the 8-mg group. In those with distant metastases, ORRs in both treatment groups were similar to the overall ORRs. In the 2-mg group, treatment responses were similar in those with PD-L1-positive tumors and those with PD-L1-negative tumors. Progression-free survival rate at 18 months (landmark) was 62% in the 2-mg group and 40% in the 8-mg group. Forty-four patients (100%) in the 2-mg group and 37 patients (95%) in the 8-mg group experienced a treatment-related adverse event (TEAE) with either drug; overall, 31 patients (37%) had a grade 3 or 4 TEAE related to either study drug.
CONCLUSIONS: In patients with anti-PD-1/PD-L1 treatment-naive advanced melanoma, nelitolimod plus pembrolizumab induced objective responses, including in PD-L1-negative tumors. The treatment combination warrants further study in advanced melanoma.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-0987
Nat Immunol. 2025 Jul 22.

LARP4-mediated hypertranslation drives T cell dysfunction in tumors.

Yi Liu, Haochen Ni, Jie Li, Jing Yang, Ivann Sekielyk, Bryan E Snow, Zihao Zhang, Feifan Zhang, Michael St Paul, Jinyi Han, Meghan Kates, Shaofeng Liu, Yawei Zhang, Zurui Huang, Yin Xu, Samuel D Saibil, Tak W Mak, Dali Han, Meng Michelle Xu.

Adoptive T cell therapies have therapeutic potential for treating solid tumors, but long-term efficacy is limited by reduced functional fitness and poor persistence within the tumor microenvironment. Here we show that intratumoral T cells undergo translatome remodeling, transitioning into a hypertranslational state as they acquire dysfunctional traits. The RNA-binding protein LARP4 is a translation regulator that drives hypertranslation and dysfunction by selectively enhancing the translation of nuclear-encoded oxidative phosphorylation (OXPHOS) mRNAs in exhausted T cells, disrupting OXPHOS subunit balance and causing mitochondrial dysfunction. Knockout of Larp4 in tumor-specific CD8+ T cells reduces hypertranslation, restores mitochondrial function, mitigates exhaustion and enhances effector persistence, resulting in enhanced anti-tumor responses. Additionally, LARP4 knockdown in chimeric antigen receptor T cells prevents terminal exhaustion and improves the response to liquid and solid tumors. This study highlights translation dysregulation as a determinant of T cell dysfunction in tumors.

DOI: https://doi.org/10.1038/s41590-025-02232-5