bims-tuinly Biomed News
on Tumor-infiltrating lymphocytes therapy
Issue of 2024‒11‒10
nine papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Prognostic significance of the tumor budding and tumor-infiltrating lymphocytes in survival of hepatocellular carcinoma patients.
  2. T cell receptor repertoire characteristics and therapeutic potential of tumor infiltrating lymphocytes (TILs) derived from metastatic lymph node in cervical cancer.
  3. Anti-CTLA-4 antibody self-presented dendritic cell nanovesicles boost the immunotherapy of hepatocellular carcinoma after microwave ablation.
  4. Evaluation of Tumor-Infiltrating Lymphocytes as Predictors of Response to Neoadjuvant Chemotherapy in Patients With Locally Advanced Breast Cancer.
  5. T cell landscape in the microenvironment of human solid tumors.
  6. A tumor-conditional IL-15 safely synergizes with immunotherapy to enhance antitumor immune responses.
  7. Applying metabolic control strategies to engineered T cell cancer therapies.
  8. CAR T Cells and T-Cell Therapies for Cancer: A Translational Science Review.
  9. Italy tests first gene-edited vines for winemaking.
  1. Int J Health Sci (Qassim). 2024 Nov-Dec;18(6):18(6): 10-19
    Prognostic significance of the tumor budding and tumor-infiltrating lymphocytes in survival of hepatocellular carcinoma patients.
    Ahmed Mahran Shafiq, Noura Ali Taha, Amen Hamdy Zaky, Abdallah Hedia Mohammed, Ola M Omran, Lobaina Abozaid, Hagir H T Ahmed, Mahmoud Gamal Ameen.
      Objective: In spite of great advance in the management of hepatocellular carcinoma (HCC), the prognostic factors are still obviously not understood. The role of tumor budding (TB) and tumor-infiltrating lymphocytes (TILs) in HCC as pathological parameters affecting prognosis stands principally unknown.Methods: Seventy-four surgical resection pathology specimens of HCC patients were used. Assessment of TB and TILs were performed using hematoxylin-eosin-stained slides. Follow-up data were collected over a 5-year period to determine disease-free survival rates, overall survival (OS) rates, and how they related to TB, TILs, and other clinicopathological factors.
    Results: There was a significant statistical association between high-grade TB and lymphovascular embolization (LVE), tumor necrosis, and grade of HCC with P = 0.003, 0.036, and 0.017, respectively. The positive TILs group showed a statistically significant correlation with histological grade, LVE, and serum alpha-fetoprotein (AFP) level with P = 0.002, 0.006, and 0.043, respectively. Multivariate analysis using the Cox proportional hazard model revealed that TILs are not an independent pathological factor for disease-free and OS, although TB is an independent pathological factor for both.
    Conclusions: In all HCC patients, TB was seen, and there was a significant link between the grade of the HCC and the presence of tumor necrosis, LVE, and high-grade TB. The majority (92%) of HCC patients had TILs, and there was a strong relationship between the histological grade, LVE, and serum AFP level. While TILs show variation of the immunologic reaction to the tumor, TB tends to suggest a hostile biologic nature and a bad prognosis.
    Keywords:  Hepatocellular carcinoma; overall survival; tumor budding; tumor-infiltrating lymphocytes
  2. Mol Biomed. 2024 Nov 04. 5(1): 51
    T cell receptor repertoire characteristics and therapeutic potential of tumor infiltrating lymphocytes (TILs) derived from metastatic lymph node in cervical cancer.
    Xuan Zhao, Zhenjiang Liu, Haifeng Qin, Yarong Liu, Yi Zhang.
      
    DOI:  https://doi.org/10.1186/s43556-024-00215-w
  3. J Control Release. 2024 Nov 06. pii: S0168-3659(24)00742-9. [Epub ahead of print]376 913-929
    Anti-CTLA-4 antibody self-presented dendritic cell nanovesicles boost the immunotherapy of hepatocellular carcinoma after microwave ablation.
    Tan Li, Bo Li, Liteng Lin, Gengjia Chen, Xiaobin Wang, Ye Chen, Wensou Huang, Mingyue Cai, Xintao Shuai, Kangshun Zhu.
      Microwave ablation (MWA) is a frequently adopted regional therapy for treating hepatocellular carcinoma (HCC) in clinic. However, incomplete microwave ablation (IMWA) is often inevitable due to the restraint of ablating large tumors or tumors in special locations, resulting in a high recurrence rate of HCC. Moreover, the most promising immune checkpoint blockade (ICB)-based immunotherapy is raising hindered by the toxicity and insufficient immune response. To overcome these barriers, we conjugate small nanovesicle (smDV)-derived from matured dendritic cells (mDCs) with anti-CTLA-4 antibody (smDV-aCTLA-4) using a metabolic tagging technology, which could trigger the infiltration of cytotoxic T cells (CTLs) and adopted tumor-infiltrating lymphocytes (TILs) in residual HCC after IMWA. In HCC microenvironment, the administration of smDV-aCTLA-4 could promote antigen presentation and immune checkpoint suppression to activate CTLs and improve the safety of anti-CTLA-4 antibody. Moreover, the anti-tumor efficacy of CTLs elicited by smDV-aCTLA-4 could also be further enhanced by anti-programmed death 1 (aPD-1) antibody. In addition, compared to the adoptive TILs therapy, the treatment using smDV-aCTLA-4-bonded TILs (smDV-aCTLA-4@TILs) could promote the proliferation and infiltration of cytotoxic TILs in residual HCC after IMWA. Our results clearly evidenced the potency of a new type of engineered DC nanovesicles in reducing HCC recurrence after IMWA.
    Keywords:  Anti-CTLA-4 antibody; Click chemistry; Dendritic cell nanovesicle; Hepatocellular carcinoma; Microwave ablation
    DOI:  https://doi.org/10.1016/j.jconrel.2024.10.069
  4. Cureus. 2024 Nov;16(11): e73133
    Evaluation of Tumor-Infiltrating Lymphocytes as Predictors of Response to Neoadjuvant Chemotherapy in Patients With Locally Advanced Breast Cancer.
    Deepak Kumar, Shivani B Paruthy, Amit Yadav, Soni Pal, Vikas Pandurangappa, Sushant Tanwar, Sajith K Mohan, Rajguru Siwach, Tulsi Appat, Prudhvi Raju Trs.
      Background This study aimed to evaluate tumor-infiltrating lymphocytes (TILs) as predictors of response to neoadjuvant chemotherapy (NACT) in patients with locally advanced breast cancer (LABC). Methods Overall, 35 patients with LABC were included in the study. Information on demographic profile, medical history, and signs and symptoms was collected for each patient, and a complete clinical evaluation was conducted, which involved physical examination, imaging studies (mammogram/ultrasound imaging), biopsy of each patient, and a metastatic workup. Patient consent was obtained for core-needle biopsy under local anesthesia, followed by a pathologic assessment of the type of breast cancer, before NACT and after mastectomy. Patients treated with NACT were followed up for response using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and were scheduled for modified radical mastectomy (MRM) on completion of NACT. MRM specimens were sent for immunohistopathologic analysis for CD3 and CD5, and for grading. Subsequently, correlations between TILs and grading with NACT response and type of cancer were analyzed. Results Of the 35 patients, 24 were positive for CD3. A correlation was identified between NACT in LABC patients and CD3 TILs, as 68.6% of patients were CD3-positive, with 54.3% showing stromal CD3 variants and 14.3% showing intramural CD3 variants. This result indicates that CD3 TILs can be an indicator of response to NACT in LABC patients. In the sample, 48.6% of patients showed CD5 positivity, with stromal predominance. Overall, 17 patients (48.6%) had a RECIST complete response to NACT, 16 (45.7%) had a partial response, and 1 (2.9%) had progressive disease. Therefore, the study showed a significant response to NACT in LABC patients (p-value < 0.0001), and reductions in tumor size could be evaluated using RECIST criteria. Conclusions NACT had a significant effect on tumors, as shown by RECIST assessments in patients with LABC. TILs can be used as promising prognostic markers to evaluate and predict patients' responses to NACT. Evaluating TILs is expensive but may be useful for the diagnosis and prediction of immunologic responses in breast cancer and other types of carcinomas following chemotherapy.
    Keywords:  breast cancer research; complete clinical response; locally advanced breast-cancer; neoadjuvant chemotherapy(nact); prospective observational study; recist criteria; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.7759/cureus.73133
  5. Immunol Lett. 2024 Oct 31. pii: S0165-2478(24)00116-0. [Epub ahead of print]270 106942
    T cell landscape in the microenvironment of human solid tumors.
    Enrico Maggi, Enrico Munari, Nadine Landolina, Francesca Romana Mariotti, Bruno Azzarone, Lorenzo Moretta.
      T cells are the main effectors involved in anti-tumor immunity, mediating most of the adaptive response towards cancer. After priming in lymph nodes, tumor antigens-specific naïve T lymphocytes proliferate and differentiate into effector CD4+ and CD8+ T cells that migrate from periphery into tumor sites aiming to eliminate cancer cells. Then while most effector T cells die, a small fraction persists and recirculates as long-lived memory T cells which generate enhanced immune responses when re-encountering the same antigen. A number of T (and non-T) cell subsets, stably resides in non-lymphoid peripheral tissues and may provide rapid immune response independently of T cells recruited from blood, against the reemergence of cancer cells. When tumor grows, however, tumor cells have evaded immune surveillance of effector cells (NK and CTL cells) which are exhausted, thus favoring the local expansion of T (and non-T) regulatory cells. In this review, the current knowledge of features of T cells present in the tumor microenvironment (TME) of solid adult and pediatric tumors, the mechanisms upregulating immune-checkpoint molecules and transcriptional and epigenetic landscapes leading to dysfunction and exhaustion of T effector cells are reviewed. The interaction of T cells with cancer- or TME non-neoplastic cells and their secreted molecules shape the T cell profile compromising the intrinsic plasticity of T cells and, therefore, favoring immune evasion. In this phase regulatory T cells contribute to maintain a high immunosuppressive TME thus facilitating tumor cell proliferation and metastatic spread. Despite the advancements of cancer immunotherapy, many tumors are unresponsive to immune checkpoint inhibitors, or therapeutical vaccines or CAR T cell-based adoptive therapy: some novel strategies to improve these T cell-based treatments are lastly proposed.
    Keywords:  Immunosuppression; Immunotherapy of tumors; Pediatric and adult Solid tumors; T effector cells; T regulatory cells; Tumor infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.imlet.2024.106942
  6. Mol Ther. 2024 Oct 25. pii: S1525-0016(24)00681-6. [Epub ahead of print]
    A tumor-conditional IL-15 safely synergizes with immunotherapy to enhance antitumor immune responses.
    Wenqiang Shi, Wei Xu, Luyao Song, Qiongya Zeng, Gen Qi, Ying Qin, Zhikun Li, Xianglei Liu, Zheng Jiao, Yonggang Zhao, Nan Liu, Huili Lu.
      It is a challenge to invigorate tumor-infiltrating lymphocytes without causing immune-related adverse events, which also stands as a primary factor contributing to resistance against cancer immunotherapies. IL-15 can potently promote expansion and activation of T cells, but its clinical use has been limited by dose-limiting toxicities. In this study, we develop a tumor-conditional IL-15 (pro-IL-15), which masks IL-15 with steric hindrance caused by Fc fragment and IL-15Rα-sushi domain. Upon reaching the tumor site, it can be cleaved by tumor-associated proteases to release an IL-15 superagonist, resulting in potent antitumor activities. Systemic delivery of pro-IL-15 demonstrates significantly reduced toxicity but uncompromised antitumor efficacy. Pro-IL-15 can yield better effectors and vitalize terminally exhausted CD8+ T cells to overcome checkpoint blockade resistance. Moreover, pro-IL-15 promotes chemotaxis and activation of adoptive T cells, leading to eradication of advanced solid tumors and durable cures. Furthermore, pro-IL-15 shows promise for synergizing with other immunotherapies like IL-12 and oncolytic virus by improving CD8/Treg ratio and IFN-γ levels, resulting in substantial regression of both local and metastatic cold tumors. Collectively, our results suggest that pro-IL-15 represents a compelling strategy for overcoming resistance to current immunotherapies while avoiding toxicities.
    DOI:  https://doi.org/10.1016/j.ymthe.2024.10.021
  7. Metab Eng. 2024 Oct 25. pii: S1096-7176(24)00137-X. [Epub ahead of print]
    Applying metabolic control strategies to engineered T cell cancer therapies.
    Andrea C Fox, John Blazeck.
      Chimeric antigen receptor (CAR) T cells are an engineered immunotherapy that express synthetic receptors to recognize and kill cancer cells. Despite their success in treating hematologic cancers, CAR T cells have limited efficacy against solid tumors, in part due to the altered immunometabolic profile within the tumor environment, which hinders T cell proliferation, infiltration, and anti-tumor activity. For instance, CAR T cells must compete for essential nutrients within tumors, while resisting the impacts of immunosuppressive metabolic byproducts. In this review, we will describe the altered metabolic features within solid tumors that contribute to immunosuppression of CAR T cells. We'll discuss how overexpression of key metabolic enzymes can enhance the ability of CAR T cells to resist corresponding tumoral metabolic changes or even revert the metabolic profile of a tumor to a less inhibitory state. In addition, metabolic remodeling is intrinsically linked to T cell activity, differentiation, and function, such that metabolic engineering strategies can also promote establishment of more or less efficacious CAR T cell phenotypes. Overall, we will show how applying metabolic engineering strategies holds significant promise to improve CAR T cells for the treatment of solid tumors.
    Keywords:  CAR T cell therapies; Cellular engineering; Immunotherapy; Metabolic engineering; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ymben.2024.10.009
  8. JAMA. 2024 Nov 04.
    CAR T Cells and T-Cell Therapies for Cancer: A Translational Science Review.
    Jennifer N Brudno, Marcela V Maus, Christian S Hinrichs.
      Importance: Chimeric antigen receptor (CAR) T cells are T lymphocytes that are genetically engineered to express a synthetic receptor that recognizes a tumor cell surface antigen and causes the T cell to kill the tumor cell. CAR T treatments improve overall survival for patients with large B-cell lymphoma and progression-free survival for patients with multiple myeloma.Observations: Six CAR T-cell products are approved by the US Food and Drug Administration (FDA) for 6 hematologic malignancies: B-cell acute lymphoblastic leukemia, large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, and multiple myeloma. Compared with standard chemotherapy followed by stem cell transplant, CAR T cells improved 4-year overall survival in patients with large B-cell lymphoma (54.6% vs 46.0%). Patients with pediatric acute lymphoblastic leukemia achieved durable remission after CAR T-cell therapy. At 3-year follow-up, 48% of patients were alive and relapse free. In people with multiple myeloma treated previously with 1 to 4 types of non-CAR T-cell therapy, CAR T-cell therapy prolonged treatment-free remissions compared with standard treatments (in 1 trial, CAR T-cell therapy was associated with progression-free survival of 13.3 months compared with 4.4 months with standard therapy). CAR T-cell therapy is associated with reversible acute toxicities, such as cytokine release syndrome in approximately 40% to 95% of patients, and neurologic disorders in approximately 15% to 65%. New CAR T-cell therapies in development aim to increase efficacy, decrease adverse effects, and treat other types of cancer. No CAR T-cell therapies are FDA approved for solid tumors, but recently, 2 other T lymphocyte-based treatments gained approvals: 1 for melanoma and 1 for synovial cell sarcoma. Additional cellular therapies have attained responses for certain solid tumors, including pediatric neuroblastoma, synovial cell sarcoma, melanoma, and human papillomavirus-associated cancers. A common adverse effect occurring with these T lymphocyte-based therapies is capillary leak syndrome, which is characterized by fluid retention, pulmonary edema, and kidney dysfunction.
    Conclusions and Relevance: CAR T-cell therapy is an FDA-approved therapy that has improved progression-free survival for multiple myeloma, improved overall survival for large B-cell lymphoma, and attained high rates of cancer remission for other hematologic malignancies such as acute lymphoblastic leukemia, follicular lymphoma, and mantle cell lymphoma. Recently approved T lymphocyte-based therapies demonstrated the potential for improved outcomes in solid tumor malignancies.
    DOI:  https://doi.org/10.1001/jama.2024.19462
  9. Nat Biotechnol. 2024 Nov 06.
    Italy tests first gene-edited vines for winemaking.
    Anna Meldolesi.
      
    DOI:  https://doi.org/10.1038/s41587-024-02478-8
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