bims-tuinly 2025-03-02 papers

J Immunother Cancer. 2025 Feb 25. pii: e009367. [Epub ahead of print]13(2):

Tumor-specific CD8+ T cells from the bone marrow resist exhaustion and exhibit increased persistence in tumor-bearing hosts as compared with tumor-infiltrating lymphocytes.

Elizabeth M Zawidzka, Luca Biavati, Amy Thomas, Claudio Zanettini, Luigi Marchionni, Robert Leone, Ivan Borrello.

BACKGROUND: Immunotherapy is now an integral aspect of cancer therapy. Strategies employing adoptive cell therapy (ACT) have seen the establishment of chimeric antigen receptor (CAR)-T cells using peripheral blood lymphocytes as well as tumor-infiltrating lymphocytes (TILs) with significant clinical results. The bone marrow (BM) is an immunological niche housing T cells with specificity for previously encountered antigens, including tumor-associated antigens from certain solid cancers. This study sought to improve our understanding of tumor-specific BM T cells in the context of solid tumors by comparing them with TILs, and to assess whether there is a rationale for using the BM as a source of T cells for ACT against solid malignancies.
METHODS: We used the murine B16 melanoma model examining both the endogenous OVA-specific T cell response using an OVA-specific tetramer or examining the OVA-specific response with OVA-specific transgenic CD8+ (OT-1) T cells. Specifically, we compared baseline intrinsic properties of TILs or BM T cells from tumor-bearing mice and their changes following adoptive transfer in the tumor and bone marrow (as well as other compartments when indicated).
RESULTS: In tumor-bearing mice, endogenous tumor-specific T cells could be detected in the BM early in the course of tumor progression and possessed a more stem-cell-like and memory phenotype in an unsupervised cluster analysis compared with TILs which appeared more exhausted. The BM and tumor microenvironments significantly impact the fate of T cells. Naïve OT-1 transferred T cells acquired an exhausted phenotype in the tumor but maintained a more memory-like phenotype in the BM with tumor progression. Importantly, in a competitive transfer experiment, BM T cells infiltrated the tumor more efficiently than TILs, displayed a higher polyfunctionality with interleukin-2, interferon-γ, tumor necrosis factor-α production and showed greater persistence compared with TILs.
CONCLUSIONS: T cells from the BM appear superior to TILs as a source of cells for cellular therapy. They possess a memory-enriched phenotype and exhibit improved effector function, greater persistence within a tumor-bearing host, and the capacity for increased tumor infiltration. These data provide a foundation for further exploring the BM as a source of tumor-specific T cells for ACT in solid malignancies.

Keywords: Adoptive cell therapy - ACT; Tumor infiltrating lymphocyte - TIL

DOI: https://doi.org/10.1136/jitc-2024-009367

Cancers (Basel). 2025 Feb 09. pii: 589. [Epub ahead of print]17(4):

Advancing Immunotherapy in Pancreatic Cancer: A Brief Review of Emerging Adoptive Cell Therapies.

Deepak Sherpally, Ashish Manne.

Pancreatic cancer has the lowest 5-year survival rate (13%) among major cancers and is the third leading cause of cancer-related deaths in the United States. The high lethality of this cancer is attributed to its insidious onset, late-stage diagnosis, rapid progression, and limited treatment options. Addressing these challenges requires a deeper understanding of the complex tumor microenvironment to identify novel therapeutic targets. Newer approaches like adoptive cell therapy have shown remarkable success in treating hematological malignancies, but their application in solid tumors, particularly pancreatic cancer, is still in the early stages of development. ACT broadly involves isolating immune cells (T lymphocytes, Natural Killer cells, and macrophages) from the patient, followed by genetic engineering to enhance and mount a specific anti-tumor response. Various ACT modalities are under investigation for pancreatic cancer, including chimeric antigen receptor T cells (CAR-T), chimeric antigen receptor NK cells (CAR-NK), tumor-infiltrating lymphocytes (TIL), T-cell receptor (TCR)-engineered T cells, and cytokine-induced killer cells (CIK). Major hurdles have been identifying actionable tumor antigens and delivering focused cellular therapies to overcome the immunosuppressive and dense fibrotic stroma surrounding the pancreatic cancer. Further studies are needed to explore the limitations faced by cellular therapy in pancreatic cancer and identify novel combination treatment approaches in order to improve clinical outcomes.

Keywords: T-cell receptor (TCR)-engineered T cells; adoptive cell therapy; chimeric antigen receptor NK cells (CAR-NK); chimeric antigen receptor T cells (CAR-T); cytokine-induced killer cells (CIK); pancreatic ductal adenocarcinoma; tumor-infiltrating lymphocytes (TIL)

DOI: https://doi.org/10.3390/cancers17040589

J Clin Med. 2025 Feb 12. pii: 1200. [Epub ahead of print]14(4):

Advancements in Melanoma Treatment: A Review of PD-1 Inhibitors, T-VEC, mRNA Vaccines, and Tumor-Infiltrating Lymphocyte Therapy in an Evolving Landscape of Immunotherapy.

Apoorva Mehta, Mateen Motavaf, Ikenna Nebo, Sophia Luyten, Kofi D Osei-Opare, Alejandro A Gru.

Melanoma, an aggressive skin cancer, presents significant therapeutic challenges. Consequently, innovative treatment strategies beyond conventional chemotherapy, radiation, and surgery are actively explored. This review discusses the evolution of immunotherapy in advanced melanoma, highlighting PD-1/PD-L1 inhibitors, mRNA vaccines, Talimogene Laherparepvec (T-VEC), and tumor-infiltrating lymphocyte (TIL) therapies. PD-1/PD-L1 inhibitors such as pembrolizumab and nivolumab block immune checkpoints, promoting T-cell cytotoxic activity and improving overall survival in patients with advanced melanoma. T-VEC, a modified oncolytic herpes virus, promotes a systemic anti-tumor response while simultaneously lysing malignant cells. mRNA vaccines, such as Moderna's mRNA-4157/V940, take advantage of malignant-cell-specific neoantigens to amplify the adaptive immune response while protecting healthy tissue. TIL therapy is a form of therapy involving ex vivo expansion and reinfusion of the patient's tumor-specific lymphocytes and has been shown to provide durable tumor control. While these therapies have demonstrated promising clinical outcomes, challenges such as tumor resistance, high financial burden, and limited accessibility pose challenges to their widespread use. This review explores combination therapies such as PD-L1 inhibitors with mRNA vaccines, or TIL therapy, which aim to enhance treatment through synergistic approaches. Further research is required to optimize these combinations, address barriers preventing their use, and control adverse events.

Keywords: CAR-T; PD-1 inhibitors; PD-L1 inhibitors; T-VEC; T-cell; TIL; advancement; immunotherapy; mRNA vaccine; melanoma; therapy; treatment

DOI: https://doi.org/10.3390/jcm14041200

Nat Med. 2025 Feb 27.

Neoadjuvant triplet immune checkpoint blockade in newly diagnosed glioblastoma.

Glioblastoma (GBM) is an aggressive primary adult brain tumor that rapidly recurs after standard-of-care treatments, including surgery, chemotherapy and radiotherapy. While immune checkpoint inhibitor therapies have transformed outcomes in many tumor types, particularly when used neoadjuvantly or as a first-line treatment, including in melanoma brain metastases, they have shown limited efficacy in patients with resected or recurrent GBM. The lack of efficacy has been attributed to the scarcity of tumor-infiltrating lymphocytes (TILs), an immunosuppressive tumor microenvironment and low tumor mutation burden typical of GBM tumors, plus exclusion of large molecules from the brain parenchyma. We hypothesized that upfront neoadjuvant combination immunotherapy, administered with disease in situ, could induce a stronger immune response than treatment given after resection or after recurrence. Here, we present a case of newly diagnosed IDH-wild-type, MGMT promoter unmethylated GBM, treated with a single dose of neoadjuvant triplet immunotherapy (anti-programmed cell death protein 1 plus anti-cytotoxic T-lymphocyte protein 4 plus anti-lymphocyte-activation gene 3) followed by maximal safe resection 12 days later. The anti-programmed cell death protein 1 drug was bound to TILs in the resected GBM and there was marked TIL infiltration and activation compared with the baseline biopsy. After 17 months, there is no definitive sign of recurrence. If used first line, before safe maximal resection, checkpoint inhibitors are capable of immune activation in GBM and may induce a response. A clinical trial of first-line neoadjuvant combination checkpoint inhibitor therapy in newly diagnosed GBM is planned (GIANT; trial registration no. NCT06816927 ).

DOI: https://doi.org/10.1038/s41591-025-03512-1

J Immunother Cancer. 2025 Feb 25. pii: e010153. [Epub ahead of print]13(2):

Effector T cells under hypoxia have an altered transcriptome similar to tumor-stressed T cells found in non-responsive melanoma patients.

Mate Z Nagy, Lourdes B Plaza-Rojas, Justin C Boucher, Elena Kostenko, Anna L Austin, Ahmad A Tarhini, Zhihua Chen, Dongliang Du, Awino Maureiq E Ojwang', Joshua Davis, Alyssa Obermayer, Katarzyna A Rejniak, Timothy I Shaw, Jose A Guevara-Patino.

BACKGROUND: In the tumor microenvironment (TME), hypoxia stands as a significant factor that modulates immune responses, especially those driven by T cells. As T cell-based therapies often fail to work in solid tumors, this study aims to investigate the effects of hypoxia on T cell topo-distribution in the TME, gene expression association with T cell states, and clinical responses in melanoma.
METHODS: To generate detailed information on tumor oxygenation and T cell accessibility, we used mathematical modeling of human melanoma tissue microarrays that incorporate oxygen supply from vessels, intratumoral diffusion, and cellular uptake. We created tumor maps and derived plots showing the fraction of CD4 and CD8 T cells against the distance to the nearest vessel and oxygen pressure. To assess their function and transcriptional changes caused by hypoxia, effector T cells were generated and cultured under hypoxia (0.5% oxygen) or normoxia (21% oxygen). The T cell hypoxia-transcriptional signature was compared against datasets from msigDB, iATLAS (clinical trials of melanoma patients treated with immune checkpoint inhibitors (ICIs)), ORIEN AVATAR (real-world melanoma patients treated with ICIs), and a single-cell atlas of tumor-infiltrating lymphocytes.
RESULTS: We made three specific observations: (1) in melanoma T cells preferentially accumulated in oxygenated areas close to blood vessels (50-100 µm from the vasculature in the regions of high oxygen availability) but not in hypoxic areas far from blood vessels. (2) Our analysis confirmed that under hypoxia, T cell functions were significantly reduced compared with normoxic conditions and accompanied by a unique gene signature. Furthermore, this hypoxic gene signature was prevalent in resting and non-activated T cells. Notably and clinically relevant, the hypoxic T cell gene set was found to correlate with reduced overall survival and reduced progression-free survival in melanoma patients, which was more pronounced in non-responder patients undergoing ICI therapy. (3) Finally, compared with a single-cell atlas of tumor-infiltrating T cells, our hypoxia signature aligned with a population of cells at a state termed stress response state (TSTR).
CONCLUSIONS: Our study highlights the critical role of hypoxia in shaping T cell distribution and its correlation with clinical outcomes in melanoma. We revealed a preferential accumulation of T cells in oxygenated areas. Moreover, hypoxic T cells develop a distinct hypoxic gene signature prevalent in resting, non-activated T cells and TSTR that was also associated with poorer outcomes, particularly pronounced among non-responders to ICIs.

Keywords: Gene expression profiling - GEP; Immune Checkpoint Inhibitor; Melanoma; Tumor infiltrating lymphocyte - TIL; Tumor microenvironment - TME

DOI: https://doi.org/10.1136/jitc-2024-010153

Cancer Immunol Res. 2025 Feb 25. OF1-OF7

The Problem with Syngeneic Mouse Tumor Models.

Nils Lonberg.

The advent of syngeneic mouse tumor models provided the scientific foundation for cancer immunotherapies now in widespread use. However, in many respects, these models do not faithfully recapitulate the interactions between cancer cells and the immune systems of human patients who have solid tumors because they represent a very early stage in the immune response to the newly transplanted cancer cells compared with the relatively mature stage found in human patients at the time of treatment. The lack of translatability of syngeneic models is probably responsible for many failed clinical trials conducted at considerable expense, involving far too many patients with cancer who received no benefit. Better mouse models would substantially accelerate the pace of discovery of new immunotherapies. Until these models emerge, a better understanding of the differences between the existing syngeneic models and human cancers may provide a more efficient path for moving experimental drugs into clinical development. To accomplish this, we must consider mice transplanted with syngeneic tumor cells to be in vivo assays, potentially useful for understanding the mechanism of action of immunotherapies rather than disease models.

DOI: https://doi.org/10.1158/2326-6066.CIR-24-1046