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

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.