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Empowering exhausted T cells of Glioblastoma patients by Neurotransmitters and Neuropeptides: decreasing immune checkpoint inhibitors, and increasing CD3zeta, proliferation and Glioblastoma arrest

Published on Friday, 27 February 2026

Abstract

Background: Glioblastoma is the most common malignant brain tumor, with extremely poor prognosis, and patient's T cells are exhausted, dysfunctional, and unable to eliminate Glioblastoma. To our knowledge, there is no effective and safe treatment for rejuvenating and improving multiple functions of exhausted T cells. We previously found that specific Neurotransmitters and Neuropeptides induce direct, potent and beneficial effects on human T cells.

Method: We studied if Dopamine, Glutamate, GnRH-II, Neuropeptide Y or their combinations, can rejuvenate and improve peripheral T cells of four Glioblastoma patients.

Results: The Glioblastoma patients had abnormally low numbers of T cells, and mostly small T cells. Single Ex-vivo treatment (24 h) of Glioblastoma patient's T cells with either Dopamine, Glutamate, GnRH-II, or Neuropeptide Y, or their combinations (10-8 M, without any antigen/mitogen/cytokine/growth factor), induced multiple beneficial effects: 1. increased the number of live T cells; 2. decreased simultaneously all tested exhaustion-related immune checkpoint inhibitors: PD-1, Tim-3, LAG-3, TIGIT and CD160; 3. increased expression of TCR-associated CD3zeta; 4. increased proliferation of patient's T cells in response to human Glioblastoma cells; and 5. dramatically increased arrest of Glioblastoma cells by Glioblastoma patient's T cells.

Conclusions: Dopamine, Glutamate, Neuropeptide Y or GnRH-II, and the most beneficial being Dopamine + Neuropeptide Y, and Glutamate + Neuropeptide Y, can rejuvenate and improve Glioblastoma patient's T cells. They simultaneously decrease multiple immune checkpoint imhibitory receptors, and increase CD3zeta, T cell proliferation, and T cell anti-cancer activity. A novel 'Personalized Adoptive Neuro-Immunotherapy' was invented for Ex vivo rejuvenation and empowerment of patient's exhausted peripheral T cells by physiological Neurotransmitters/Neuropeptides, and their repeated infusion to patients.

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About this publication.

The Di Bella's Method: Use of Somatostatin/Octreotide analogues and/or derivatives, Cabergoline and/or Bromocriptine associated with pseudo-Metronomic Chemotherapy Cyclophosphamide and/or Hydroxyurea (together with others chemical compounds) in Glioma/Glioblastoma:

- Recurrent Glioblastoma Multiforme (grade IV – WHO 2007): a case of complete objective response achieved by means of the concomitant administration of Somatostatin and Octreotide – Retinoids – Vitamin E – Vitamin D3 – Vitamin C – Melatonin – D2 R agonists (Di Bella Method – DBM) associated with Temozolomide;

- A retrospective observational study on cases of anaplastic brain tumors treated with the Di Bella Method: A rationale and effectiveness;

- The Di Bella Method (A Fixed Part - Somatostatin, Octreotide, Sandostatin LAR, analogues and/or derivatives);

- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;

- Publication, 2018 Jul: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);

- Publication, 2018 Sep: The over-expression of GH/GHR in tumour tissues with respect to healthy ones confirms its oncogenic role and the consequent oncosuppressor role of its physiological inhibitor, somatostatin: a review of the literature (from Di Bella's Foundation);

- Publication, 2019 Aug: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of Somatostatin and Vitamin C on the Fatty Acid Profile of Breast Cancer Cell Membranes (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of somatostatin, curcumin, and quercetin on the fatty acid profile of breast cancer cell membranes (from Di Bella's Foundation);

- Publication, 2020 Sep: Two neuroendocrine G protein-coupled receptor molecules, somatostatin and melatonin: Physiology of signal transduction and therapeutic perspectives (from Di Bella's Foundation);

- The Di Bella Method (A Fixed Part - Bromocriptine and/or Cabergoline);

- Prolactin inhibitors in oncology - In vitro, review and in vivo publications;

- The Di Bella Method (A Fixed Part - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);

The Di Bella's Method: Use of Somatostatin/Octreotide analogues and/or derivatives since 1977 with Cabergoline and/or Bromocriptine associated with pseudo-Metronomic Chemotherapy Cyclophosphamide and/or Hydroxyurea - together with others chemical compounds - in several Oncological Pathologies:

- The Di Bella Method DBM improved survival objective response and performance status in a retrospective observational clinical study on 23 tumours of the head and neck;

- Chronic Lymphocytic Leukemia: Long-Lasting Remission with Combination of Cyclophosphamide, Somatostatin, Bromocriptine, Retinoids, Melatonin, and ACTH;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in advanced non-small-cell lung cancer patients with low performance status;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in chemotherapy-pretreated patients with advanced lung adenocarcinoma and low performance status;

- Observations on the Report of a case of pulmonary adenocarcinoma with lymph node, hepatic and osseus metastasis;

- Pleural Mesothelioma: clinical records on 11 patients treated with Di Bella's Method;

- Malignant pleural mesothelioma, stage T3-T4. Consideration of a case study;

- Excellent result in a Mesothelioma case treated exclusively with Di Bella Method for over 4 years and still treatment with positive results;

- A case of advanced Multiple Myeloma treated with Di Bella Method (DBM) into total remission for 13 years;

- Neuroblastoma: Complete objective response to biological treatment;

- Cyclophosphamide plus Somatostatin, Bromocriptin, Retinoids, Melatonin and ACTH in the Treatment of Low-grade Non-Hodgkin’s Lymphomas at Advanced Stage: Results of a Phase II Trial;

- Relapse of High-Grade Non-Hodgkin’s Lymphoma After Autologous Stem Cell Transplantation: A Case Successfully Treated With Cyclophosphamide Plus Somatostatin, Bromocriptine, Melatonin, Retinoids, and ACTH;