bims-tuinly 2024-10-13 papers

Immunity. 2024 Oct 08. pii: S1074-7613(24)00456-4. [Epub ahead of print]57(10): 2260-2262

TIL the end: Tracking T cell clonotype dynamics during adoptive cell therapy.

Understanding the factors that lead to the therapeutic success of adoptive cell therapies using tumor-infiltrating lymphocytes (TIL-ACT) will improve current treatment protocols. In this issue of Immunity, Chiffelle et al. comprehensively compare the dynamics of CD8+ T cell clonotypes during the course of ACT between responding and non-responding patients.

DOI: https://doi.org/10.1016/j.immuni.2024.09.012

Cancer Lett. 2024 Oct 04. pii: S0304-3835(24)00676-1. [Epub ahead of print] 217281

Therapeutic potential of tumor-infiltrating lymphocytes in non-small cell lung cancer.

Daniel R Plaugher, Avery R Childress, Christian M Gosser, Dave-Preston Esoe, Kassandra J Naughton, Zhonglin Hao, Christine F Brainson.

Lung cancer is the leading cause of cancer-related death worldwide, with poor outcomes even for those diagnosed at early stages. Current standard-of-care for most non-small cell lung cancer (NSCLC) patients involves an array of chemotherapy, radiotherapy, immunotherapy, targeted therapy, and surgical resection depending on the stage and location of the cancer. While patient outcomes have certainly improved, advances in highly personalized care remain limited. However, there is growing excitement around harnessing the power of tumor-infiltrating lymphocytes (TILs) through the use of adoptive cell transfer (ACT) therapy. These TILs are naturally occurring, may already recognize tumor-specific antigens, and can have direct anti-cancer effect. In this review, we highlight comparisons of various ACTs, including a brief TIL history, show current advances and successes of TIL therapy in NSCLC, discuss the potential roles for epigenetics in T cell expansion, and highlight challenges and future directions of the field to combat NSCLC in a personalized manner.

Keywords: Tumor-infiltrating lymphocytes; adoptive cell transfer; non-small cell lung cancer

DOI: https://doi.org/10.1016/j.canlet.2024.217281

Front Immunol. 2024 ;15 1476365

Prognostic implications of tumor-infiltrating lymphocytes in non-small cell lung cancer: a systematic review and meta-analysis.

Qin Yan, Shuai Li, Lang He, Nianyong Chen.

Background: Tumor-infiltrating lymphocytes (TILs) have demonstrated potential as prognostic biomarkers across various cancer types. However, their prognostic implications in non-small cell lung cancer (NSCLC) remain ambiguous.
Methods: An exhaustive electronic search was executed across the Pubmed, EMBASE, Web of Science, and Cochrane Library databases to locate relevant studies published up until December 19, 2023. Studies were eligible if they assessed the association between TILs and overall survival (OS) and disease-free survival (DFS) in NSCLC patients. The OS and DFS were subsequently extracted for analysis. The prognostic significance of TILs was evaluated by calculating the Pooled Hazard Ratios (HRs) and their corresponding 95% Confidence Intervals (CIs).
Results: The meta-analysis incorporated 60 studies, which collectively included 15829 NSCLC patients. The collective analysis indicated that NSCLC patients exhibiting TILs infiltration demonstrated a significantly improved OS(HR: 0.67; 95%CI: 0.55-0.81). Subgroup analyses, based on TIL subtypes (CD8+, CD3+ and CD4+), consistently revealed a favorable prognostic impact on OS. However, it was observed that FOXP3+ was correlated with a poor OS (HR: 1.35; 95% CI: 0.87-2.11).
Conclusion: This comprehensive systematic review and meta-analysis substantiate the prognostic significance of TILs in patients diagnosed with NSCLC. Notably, elevated TILs infiltration correlates with a favorable prognosis, particularly among CD8+, CD3+ and CD4+ subtypes.
Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023468089 PROSPERO, identifier CRD42023468089.

Keywords: meta-analysis; non-small cell lung cancer; prognostic implication; systematic review; tumor-infiltrating lymphocytes

DOI: https://doi.org/10.3389/fimmu.2024.1476365

Front Immunol. 2024 ;15 1328368

Automated manufacturing and characterization of clinical grade autologous CD20 CAR T cells for the treatment of patients with stage III/IV melanoma.

Introduction: Point-of-care (POC) manufacturing of chimeric antigen receptor (CAR) modified T cell has expanded rapidly over the last decade. In addition to the use of CD19 CAR T cells for hematological diseases, there is a growing interest in targeting a variety of tumor-associated epitopes.
Methods: Here, we report the manufacturing and characterization of autologous anti-CD20 CAR T cells from melanoma patients within phase I clinical trial (NCT03893019). Using a second-generation lentiviral vector for the production of the CD20 CAR T cells on the CliniMACS Prodigy®.
Results: We demonstrated consistency in cell composition and functionality of the products manufactured at two different production sites. The T cell purity was >98.5%, a CD4/CD8 ratio between 2.5 and 5.5 and transduction rate between 34% and 61% on day 12 (harvest). Median expansion rate was 53-fold (range, 42-65-fold) with 1.7-3.8×109 CAR T cells at harvest, a sufficient number for the planned dose escalation steps (1×105/kg, 1×106/kg, 1×107/kg BW). Complementary research of some of the products pointed out that the CAR+ cells expressed mainly central memory T-cell phenotype. All tested CAR T cell products were capable to translate into T cell activation upon engagement of CAR target cells, indicated by the increase in pro-inflammatory cytokine release and by the increase in CAR T cell amplification. Notably, there were some interindividual, cell-intrinsic differences at the level of cytokine release and amplification. CAR-mediated T cell activation depended on the level of CAR cognate antigen.
Discussion: In conclusion, the CliniMACS Prodigy® platform is well suited for decentralized POC manufacturing of anti-CD20 CAR T cells and may be likewise applicable for the rapid and automated manufacturing of CAR T cells directed against other targets.
Clinical trial registration: https://clinicaltrials.gov/study/NCT03893019?cond=Melanoma&term=NCT03893019&rank=1, identifier NCT03893019.

Keywords: CD20 CAR investigational medicinal product; automated manufacturing of engineered T cell products; cell composition of CAR T cell products; clinical CD20 CAR T cell trial; ex vivo expansion

DOI: https://doi.org/10.3389/fimmu.2024.1328368

Front Oncol. 2024 ;14 1414900

PD-1 expression in tumor infiltrating lymphocytes as a prognostic marker in early-stage non-small cell lung cancer.

Asaf Dan, Ozan Aricak, Konstantinos Rounis, M Angeles Montero-Fernandez, Ricardo Guijarro, Simon Ekman, Cristian Ortiz-Villalón, Luigi De Petris.

Introduction: Programmed death ligand - 1 (PD-L1) expression is a well-established predictive biomarker for immunotherapy in non-small cell lung cancer (NSCLC). Programmed death - 1 (PD-1) serves as the target protein to PD-L1 and their interaction serves as a crucial pathway for immune evasion. This study aimed to investigate the expression pattern of PD-1 on Tumor-infiltrating lymphocytes (TILs) in early-stage NSCLC, and its potential role as prognostic biomarker.
Materials & methods: PD-1 was evaluated in 474 surgical resected early-stage NSCLC specimens, using Tissue microarray and immunohistochemical staining. Expression was scored as negative (<1%) or positive. Positive PD-1 expression was further divided into low (<10%) and high (≥10%). None of the patients had received treatment with PD-1/PD-L1 inhibitors.
Results: PD-1 expression ≥1% in TILs was observed in 83.5% of cases and was associated with pT stage (p=0.02), grade 3 (p=0.004), and adenocarcinoma subtype (p=0.05). Individuals with high PD-1 expression (≥10%) experienced reduced 10-year overall survival (Log-Rank test = 0.005). In addition, high PD-1 expression emerged as an independent factor associated with reduced survival on multivariate analysis (HR: 1.328 (95% CI: 1.074-1.641).
Conclusions: Patients with early-stage NSCLC who exhibited PD-1 expression of ≥10% on TILs had an unfavorable 10-year OS rate. These findings indicate that elevated PD-1 expression on TILs can be associated with immune evasion during the early stages of malignancy evolution in the NSCLC setting and further research is required to further delineate the role of PD-1/PD-L1 pathway on tumor immune senescence. These results underline the potential role of PD-1/PD-L1 inhibitors in the treatment of early-stage NSCLC.

Keywords: PD-1; TILs; Tissue microarray; early-stage NSCLC; immunotherapy; prognosis

DOI: https://doi.org/10.3389/fonc.2024.1414900

Paediatr Drugs. 2024 Oct 09.

Developing CAR T-Cell Therapies for Pediatric Solid Tumors.

Gabriele Canciani, Francesco Fabozzi, Claudia Pinacchio, Manuela Ceccarelli, Francesca Del Bufalo.

Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of hematological malignancies, inducing notable and durable clinical responses. However, for solid tumors, including but not limited to pediatric tumors, several peculiar biological features posed substantial challenges for achieving comparable results. Despite sound pre-clinical evidence of the ability of CAR T cells to eradicate solid malignancies, their activity remains suboptimal when facing the in vivo complexity of solid tumors, characterized by antigen heterogeneity, scarce T-cell infiltration, and an immunosuppressive microenvironment. Neuroblastoma was amongst the first tumors to be evaluated as a potential candidate for GD2-targeting CAR T cells, which recently documented promising results in high-risk, heavily pre-treated patients. Moreover, innovative engineering strategies for generating more potent and persistent CAR T cells suggest the possibility to reproduce, and potentially improve, these promising results on a larger scale. In the next years, harnessing the full therapeutic potential of CAR T cells and other immunotherapeutic strategies may open new possibilities for effectively treating the most aggressive forms of pediatric tumors.

DOI: https://doi.org/10.1007/s40272-024-00653-7

Methods Cell Biol. 2024 ;pii: S0091-679X(24)00149-3. [Epub ahead of print]189 55-69

Tumor slice culture system for ex vivo immunotherapy studies.

Leire Arrizabalaga, Joan Salvador Russo-Cabrera, Virginia Belsúe, Pedro Berraondo, Ignacio Melero, Fernando Aranda.

Personalized immunotherapy is emerging as a promising approach for cancer treatment, aiming to harness the patient's own immune system to target and eliminate tumor cells. One key aspect of developing effective personalized immunotherapies is the utilization of tumor slices derived from individual patient tumors. Tumor slice models retain the complexity and heterogeneity of the original tumor microenvironment, including interactions with immune cells, stromal elements, and vasculature. These ex vivo models serve as valuable tools for studying tumor-immune interactions and for testing the efficacy of immunotherapeutic agents tailored to the specific characteristics of each patient's tumor. In this chapter, we set up a protocol for immunotherapy strategies in mouse models highlighting their translational potential to guide treatment decisions and improve therapeutic outcomes in cancer patients.

Keywords: Ex vivo; Organotypic cultures; Personalized immunotherapy; Tumor microenvironment; Tumor slice

DOI: https://doi.org/10.1016/bs.mcb.2024.05.007