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The psychoneuroendocrine-immunotherapy of cancer: Historical evolution and clinical results
Paolo Lissoni, Giusy Messina, Arianna Lissoni, Rovelli Franco
Department of Clinical Oncology, International Institute of Psychoneuroendocrineimmunology, Milan, Italy
| Date of Submission | 13-Apr-2016 |
| Date of Decision | 27-Nov-2016 |
| Date of Acceptance | 31-Jan-2017 |
| Date of Web Publication | 26-Apr-2017 |
Correspondence Address:
Giusy Messina
International Institute of Psychoneuroendocrineimmunology, Via Mauro Macchi, 10 Milan 124
Italy
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jrms.JRMS_255_16
The prognosis of the neoplastic diseases depends not only on the biogenetic characteristics of cancer cells but also on the immunological response of patients, which may influence the biological features of cancer cells themselves as well as the angiogenic processes. Moreover, the immune system in vivo is under a physiological psychoneuroendocrine (PNE) regulation, mainly mediated by the brain opioid system and the pineal gland. In more detail, the anticancer immunity is stimulated by the pineal hormone melatonin (MLT) and inhibited by the opioid system, namely, through a mu-opioid receptor. Several alterations involving the pineal endocrine function and the opioid system have been described in cancer patients, which could play a role in tumor progression itself. Therefore, the pharmacological correction of cancer progression-related anomalies could contribute to control cancer diffusion, namely, the pineal endocrine deficiency and the hyperactivity of brain opioid system. In fact, the administration of pharmacological doses of the only MLT has already been proven to prolong the 1-year survival in untreatable metastatic cancer patients. Better results may be achieved by associating other pineal indoles to MLT, mu-opioid antagonists, cannabinoids, beta-carbolines. Moreover, these neuroendocrine combinations may be successfully associated with antitumor cytokines, such as interleukin (IL)-2 and IL-12, as a PNE-immune cancer therapy as well as with antitumor plants as PNE-phytotherapy of cancer in an attempt to propose possible anticancer treatments also to patients with disseminated cancer and untreatable according to the standard oncology. Keywords: Cancer disease, psychoneuroimmunology, pineal glande
How to cite this article:
Lissoni P, Messina G, Lissoni A, Franco R. The psychoneuroendocrine-immunotherapy of cancer: Historical evolution and clinical results. J Res Med Sci 2017;22:45 |
How to cite this URL:
Lissoni P, Messina G, Lissoni A, Franco R. The psychoneuroendocrine-immunotherapy of cancer: Historical evolution and clinical results. J Res Med Sci [serial online] 2017 [cited 2018 Dec 18];22:45. Available from: http://www.jmsjournal.net/text.asp?2017/22/1/45/205234 |
| Introduction | |  |
The all medical oncological strategies available up to now in the treatment of human neoplasms have been elaborated in an attempt to counteract cancer dissemination through an inhibition of cancer cell proliferation by inducing the apoptosis of by blocking the angiogenetic processes, which are essential for tumor biological malignancy. However, it has to be remarked that tumor growth does not depend only on the genetic characteristics of cancer cells but also on the immune status of cancer patients.[1],[2],[3] Then, the limit of the conventional anticancer therapies available up to now, including the more recent target therapies, is consisting of the exclusion of the importance of the immune status of cancer patients in determining their prognosis. In fact, a great number of immune alterations have been described in cancer patients, which would play a role in influencing the clinical history of the neoplastic disease.[1],[2],[3],[4] Moreover, because of the existence of a neuroendocrine regulation of the immune system, as shown by the recent advances in the knowledge of the psychoneuroendocrine-immunology (PNEI),[5],[6] cancer-associated immune alterations occurring at the beginning of the disease could be due at least in part to an altered psychoneuroendocrine (PNE) control of the antitumor immune response. Then, at least from a theoretical point of view, it could be possible to correct cancer-related immune alterations by acting on the PNE regulation of the immune system.
The PNE therapy of cancer consists of the replacement of the psychoneuroimmune conditions of the status of health by a pharmacological correction of the major cancer progression-related alterations involving the neuroendocrine regulation of the anticancer immunity. This project is justified by the fact that cancer-related immunosuppressive status would depend, at least at the beginning of cancer development, on an altered neuroendocrine regulation of the immune system since it is only with cancer dissemination that tumor mass itself may produce immunosuppressive substances, such as interleukin IL-10 and transforming growth factor (TGF)-beta,[7] which further suppress the already altered function of the immune system. Then, a pharmacological correction of cancer-related neuroendocrine alterations involved in the control of the antitumor immunity could improve the immune functionless of cancer patients. Several neuroendocrine alterations have been described in advanced cancer patients, such as the disappearance of cortisol circadian rhythm in many tumor histotypes [8] and abnormally high levels of prolactin, namely, in breast and prostate carcinomas,[9] but the main cancer progression-related neuroendocrine deficiency consists of a progressive decline in the nocturnal production of melatonin (MLT),[10] which represents the most investigated, but not the only, indole hormone provided by anticancer activity produced by the pineal gland. The mechanisms of the antitumor action of MLT have been well investigated, and at present, MLT would represent the only molecule existing in the nature, which is potentially able to inhibit the overall phases of cancer development and progression,[11],[12],[13],[14],[15] consisting of (1) the existence of a previous immunosuppressive status due to an altered neuroendocrine control of the immune system related to stress and depression; (2) spontaneous or carcinogen-induced malignant transformation of a single cell; (3) the alteration of intracellular junctions; (4) the change in the intercellular matrix following an alteration of intercellular junctions, which stimulates the angiogenesis; (5) angiogenesis-induced cancer invasion and dissemination, with tumor production of immunosuppressive substances; (6) tumor expression of FAS-ligand, which may induce apoptosis of FAS-expressing T-lymphocytes.
Methods
In this review article, we used keywords such as “MLT,” “neuroimmunomodulation,” or “pineal gland” in PubMed to evaluate possible anticancer treatments for patients with disseminated cancer and untreatable according to the standard oncology.
| The Physiopathology of the Anticancer Immunity | | |
It is known that immune system-induced destruction of cancer cells is mainly mediated by T cytotoxic lymphocytes (CD8+) and NK cells (CD16+), respectively, through an antigen-specific and an antigen nonspecific cytotoxicity.[16] NK cells are mainly stimulated by IL -2 released by T helper-1 (TH1) lymphocytes (CD4+) while T cytotoxic lymphocytes (CD8+) are namely under a stimulatory control released by IL-12 produced by the dendritic cells.[17] On the other hand, the anticancer immunity is inhibited by the activation of the macrophage system through the production of suppressive cytokines, such as IL-6 and T regulatory (T reg) lymphocytes (CD4+CD25+), which counteract the anticancer immunity by producing immunosuppressive cytokines inhibiting the secretion of both IL-2 and IL-12, including TGF-beta and IL-10, or by a direct cell-cell contact.[18],[19],[20] Therefore, the knowledge of the mechanisms responsible for the anticancer immunity is essential to identify which immunobiological alterations may have a prognostic significance in influencing the clinical history of the neoplastic disease.
| The Psychoneuroendocrine Control of Cancer Growth and Antitumor Immunity | | |
During the long history of the human war against cancer, several experimental strategies have been elaborated to promote both spontaneous and carcinogen-induced cancer onset and to stimulate cancer dissemination in tumor-bearing animals, the most important of them would be represented by stress conditions [21] and by pinealectomy.[22] Each hormone, neurohormone and neurotransmitter may potentially influence the immune system, but the recent discoveries of PNEI [23],[24],[25] have allowed to identify three main anatomic structures responsible for the physiological PNE regulation of the immune responses, consisting of brain opioid system, brain cannabinergic system, and the pineal gland. Pineal gland and cannabinergic system would constitute a functional axis,[23] which plays an important role in the stimulation of the anticancer immunity, namely, by directly promoting IL-2 production by TH-1 lymphocytes.[24] In contrast, brain opioid system may inhibit the anticancer immune response by stimulating the immunosuppressive function of T reg lymphocytes.[25] Stress condition - promotion of cancer growth would be due to a chronic-enhanced production of cortisol, whose immunosuppressive effects are well known, and to an enhanced brain opioid system activity,[21] which may be abrogated by the administration of mu-opioid antagonists. At the other side, it is known since more than 50 years that the surgical removal of the pineal gland or its pharmacological inhibition may enhance the frequency of both spontaneous or carcinogen-induced tumors.[22],[26] The promoting effect of pinealectomy on tumor growth may be only partially abrogated by the administration of MLT,[27] by suggesting that pineal hormones other than MLT are involved in the anticancer activity of the pineal gland.[28] The importance of the neuroendocrine status of patients in cancer progression is confirmed by the fact that in experimental conditions, the pharmacological neutralization of cancer development-associated changes in neurotransmission may oppose tumor onset.[29] Therefore, cancer-related neuroendocrine alterations would not represent a simple epiphenomenon, but they could play a physiopathological role in cancer progression.
| Pineal Endocrine Deficiency and Cancer Progression | | |
The most frequent neuroendocrine alteration occurring with cancer progression is represented by the progressive decline in the nocturnal production of MLT,[30] with a following disappearance of its physiological light/dark circadian rhythm. Because of its antitumor activity,[11],[12],[13],[14],[15] cancer progression-related MLT deficiency could contribute at least in part to tumor dissemination itself. The progressive decline in MLT blood levels would depend on tumor production of the enzyme indoleamine-2,3-dioxygenase,[31] which may induce a depletion of tryptophan, that is, essential for both MLT synthesis and the anticancer immunity since tryptophan deficiency inhibits TH1-lymphocyte functions and stimulates T reg lymphocyte activation, with a following suppression of the anticancer immune response. In addition, histological alterations of the pineal gland had been already described in patients died from cancer since more than 50 years ago.[32] Therefore, MLT deficiency would not constitute the only pineal endocrine defect occurring during the clinical history of the neoplastic disease. In fact, the pineal gland has been proven to produce several anticancer natural molecules other than MLT; in particular, the indole hormone 5-methoxytryptamine, which in vitro has appeared to exert an anticancer antiproliferative activity superior to that of MLT itself,[33] and a great variety of beta-carbolines, which may play both antitumor and psychotropic effects in terms of expansion of mind, the most active of them is the 6-methoxy-1, 2, 3, 4 tetrahydro-beta-carboline, also called pinoline or pinealine.[34] At present, however, the only well-investigated anticancer properties are those of MLT.[11],[12],[13],[14],[15]
| The Clinical History of the Psychoneuroendocrine Therapy of Cancer | | |
On the basis of the fact that cancer growth is inhibited by the pineal gland and is stimulated by brain opioid system, namely, through the activation of mu-opioid receptors,[21],[22],[23],[24],[25],[26],[27] the PNE therapy of cancer is consisting of the administration of endogenous human neuroendocrine molecules provided by anticancer activity, due to a direct antiproliferative action and/or a stimulation of the anticancer immunity, in association with pharmacological strategies performed to counteract its suppression, such as the use of the mu-opioid antagonist naltrexone (NTX).
From a historical point of view, the evolution of PNE approach in cancer therapy may be summarized into 5 main consecutive clinical phases, consisting of (1) the oral administration of pharmacological doses of the only MLT during the dark period of the day [35] as shown by Bartsch and Bartsch [36] corresponding to the daily period of its maximal endogenous production; (2) the administration of other pineal antitumor indole hormones in association with MLT, namely, the 5-methoxy-tryptamine (5-MTT) during the light phase of the day in an attempt to pharmacologically reproduce the physiological light/dark rhythm of the pineal gland;[37] (3) the administration of the mu-opioid antagonist NTX to block the opioid system, which plays a stimulatory role on cancer growth and an inhibitory one on the anticancer immunity;[38] (4) the administration of cannabinoid agonists to counteract cancer-related hyperactivity of the macrophage system,[39] which may suppress the anticancer immunity and stimulate cancer growth by producing tumor growth factors and angiogenic molecules; (5) the administration of beta-carbolines, such as the pinoline.
All clinical data are referred to untreatable metastatic cancer patients, for whom no other antitumor standard treatment was available, and with life expectancy <1 year.[40] Moreover, most studies have been performed with MLT alone and at a mild pharmacological dose consisting of 20 mg/day in the dark phase of the day.[35],[40] MLT at a daily dose of 20 mg has appeared to induce a survival time longer than 1 year in about 30% of advanced cancer patients with life expectancy <1 year,[35] in association with an improvement in their clinical status, in particular in the treatment of cachexia, depression, and thrombocytopenia. The antidepressant and the thrombopoietic properties of MLT have appeared to be enhanced by a concomitant administration of the other pineal indole 5-MTT.[37] Moreover, it has been recently demonstrated that the anticancer activity of MLT in humans is a dose-dependent phenomenon since MLT at 100 mg/day has appeared to induce a disease stabilization in cancer patients, who had progressed under a dose of 20 mg, and to determine a survival time >1 year in about 50% of patients with life expectancy <1 year,[41] in association with a percent of objective tumor regressions of about 10%, whereas they are extremely rare at a dose of 20 mg/day. On the contrary, the therapeutic role of the mu-opioid antagonists in cancer therapy is still controversial, since two different schedules have been proposed, consisting of low-dose and high-dose NTX.[42],[43] Preliminary clinical results would suggest the concomitant administration of high-dose NTX may enhance the anticancer activity of MLT, at least in the treatment of brain tumors.[44] As far as, the clinical use of cannabinoids in cancer therapy is concerned, it is still at the beginning. However, preliminary data would suggest that cannabinoids may be effective in the palliative therapy of tumors to cure cachexia, anorexia, vomiting, and also pain in association with opioids.[45] Moreover, preliminary data would seem to show that cannabinoid agonists may increase the efficacy of MLT in the therapy of brain glioblastoma.[44] Finally, the administration of beta-carbolines, such as the pinoline, in association with MLT and the other pineal indoles would further improve the consciousness status of the untreatable metastatic cancer patients and their mode (unpublished data).
| The Future Evolutions of the Psychoneuroendocrine Therapy of Cancer | | |
The anticancer efficacy of a PNE approach to cancer therapy may be further enhanced by at least two main strategies, consisting of its association with anticancer cytokines, namely, with IL-2 and IL-12, as a PNEI therapy of cancer, or with the administration of anticancer natural plants, namely, Aloe vera and Arborescens, Myrrh, Magnolia, Boswellia, Curcuma, and Annona muricata as a PNE-phytotherapy of tumors. The main anticancer molecules are represented by aloe-emodin for Aloe, Guggulsterone for Myrrh, and Honokiol for Magnolia.[45],[46],[47] MLT has appeared to enhance the antitumor efficacy of low-dose IL-2 in terms of both tumor response and survival time with respect to IL-2 alone,[48] with potential activity in most tumor histotypes, whereas IL-2 is generally effective only in the treatment of renal cancer and melanoma. Moreover, at present, the maximum lymphocytosis achieved on treatment has been obtained with IL-2 plus IL-12 under a neuroendocrine modulation with MLT.[49] On the same way, the antitumor efficacy of MLT in untreatable cancer patients with life expectancy <1 year may be increased by the concomitant administration of Aloe, Myrrh, Magnolia, and Boswellia, with a greater percentage of tumor regressions and a 1-year survival of about 50% of patients.[50]
Finally because of its fundamental immunoregulatory role,[5],[6] MLT could be successfully associated with the recent immunotherapies with checkpoint inhibitors [51] to pilot the immune response in an antitumor way by stimulating lymphocyte proliferation and counteract that of monocytes which in contrast may suppress the antitumor immunity, with a consequent increase in lymphocyte-to-monocyte ratio that represents one of the most simple clinical parameters, able to predict the efficacy of the various anticancer therapies.[52]
Therefore, in conclusion, it is possible to affirm that the PNEI approach in cancer therapy may offer new therapeutic strategies in patients with disseminated cancer, for whom no other standard anticancer therapy is available.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Riley V. Psychoneuroendocrine influences on immunocompetence and neoplasia. Science 1981;212:1100-9.  |
| 2. | Foon KA. Biological response modifiers: The new immunotherapy. Cancer Res 1989;49:1621-39. |
| 3. | Lissoni P, Barni S, Rovelli F, Tancini G. Lower survival in metastatic cancer patients with reduced interleukin-2 blood concentrations. Preliminary report. Oncology 1991;48:125-7. |
| 4. | Antoni MH. Psychoneuroendocrinology and psychoneuroimmunology of cancer: Plausible mechanisms worth pursuing? Brain Behav Immun 2003;17 Suppl 1:S84-91. |
| 5. | Maestroni GJ. The immunoneuroendocrine role of melatonin. J Pineal Res 1993;14:1-10. |
| 6. | Lissoni P. The pineal gland as a central regulator of cytokine network. Neuro Endocrinol Lett 1999;20:343-9. |
| 7. | Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006;6:295-307. |
| 8. | Mormont MC, Lévi F. Circadian-system alterations during cancer processes: A review. Int J Cancer 1997;70:241-7. |
| 9. | Holtkamp W, Nagel GA, Wander HE, Rauschecker HF, von Heyden D. Hyperprolactinemia is an indicator of progressive disease and poor prognosis in advanced breast cancer. Int J Cancer 1984;34:323-8. |
| 10. | Maestroni GJ, Conti A, Pierpaoli W. Pineal melatonin, its fundamental immunoregulatory role in aging and cancer. Ann N Y Acad Sci 1988;521:140-8. |
| 11. | Danielczyk K, Dziegiel P. MT1 melatonin receptors and their role in the oncostatic action of melatonin. Postepy Hig Med Dosw 2009;63:425-34. |
| 12. | Cos S, Fernández R. Melatonin effects on intercellular junctional communication in MCF-7 human breast cancer cells. J Pineal Res 2000;29:166-71. |
| 13. | Hill SM, Frasch T, Xiang S, Yuan L, Duplessis T, Mao L. Molecular mechanisms of melatonin anticancer effects. Integr Cancer Ther 2009;8:337-46. |
| 14. | Park SY, Jang WJ, Yi EY, Jang JY, Jung Y, Jeong JW, et al. Melatonin suppresses tumor angiogenesis by inhibiting HIF-1alpha stabilization under hypoxia. J Pineal Res 2010;48:178-84. |
| 15. | Reiter RJ, Tan DX, Fuentes-Broto L. Melatonin: A multitasking molecule. Prog Brain Res 2010;181:127-51. |
| 16. | Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med 1982;155:1823-41. |
| 17. | King IL, Segal BM. Cutting edge: IL-12 induces CD4 + CD25 - T cell activation in the presence of T regulatory cells. J Immunol 2005;175:641-5. |
| 18. | Thornton AM, Shevach EM. Suppressor effector function of CD4 + CD25 + immunoregulatory T cells is antigen nonspecific. J Immunol 2000;164:183-90. |
| 19. | Shevach EM. CD4 + CD25 + suppressor T cells: More questions than answers. Nat Rev Immunol 2002;2:389-400. |
| 20. | Gallimore AM, Simon AK. Positive and negative influences of regulatory T cells on tumour immunity. Oncogene 2008;27:5886-93. |
| 21. | Lewis JW, Shavit Y, Terman GW, Nelson LR, Gale RP, Liebeskind JC. Apparent involvement of opioid peptides in stress-induced enhancement of tumor growth. Peptides 1983;4:635-8. |
| 22. | Buswell RS. Letter: The pineal and neoplasia. Lancet 1975;1:34-5. |
| 23. | Guerrero JM, Reiter RJ. Melatonin-immune system relationships. Curr Top Med Chem 2002;2:167-79. |
| 24. | Lissoni P, Resentini M, Mauri R, Esposti D, Esposti G, Rossi D, et al. Effects of tetrahydrocannabinol on melatonin secretion in man. Horm Metab Res 1986;18:77-8. |
| 25. | Sacerdote P, Panerai AE. Role of opioids in the modulation of the TH1/TH2 responses. Neuroimmunomodulation 1999;6:422-3. |
| 26. | Lapin V. Pineal gland and malignancy. Osterr Z Onkol 1976;3:51-60. |
| 27. | El-Domeiri AA, Das Gupta TK. Reversal by melatonin of the effect of pinealectomy on tumor growth. Cancer Res 1973;33:2830-3. |
| 28. | Starr KW. Growth and new growth: Environmental carcinogens in the process of human ontogeny. Prog Clin Cancer 1970;4:1-29. |
| 29. | Jankovic BD. Neuroimmunomodulation. From phenomenology to molecular evidence. Ann N Y Acad Sci 1994;741:1-38. |
| 30. | Brzezinski A. Melatonin in humans. N Engl J Med 1997;336:186-95. |
| 31. | Carbone DP, Gandara DR, Antonia SJ, Zielinski C, Paz-Ares L. Non-small-cell lung cancer: Role of the immune system and potential for immunotherapy. J Thorac Oncol 2015;10:974-84. |
| 32. | Regelson W, Pierpaoli W. Melatonin: A rediscovered antitumor hormone? Its relation to surface receptors; sex steroid metabolism, immunologic response, and chronobiologic factors in tumor growth and therapy. Cancer Invest 1987;5:379-85. |
| 33. | Sze SF, Ng TB, Liu WK. Antiproliferative effect of pineal indoles on cultured tumor cell lines. J Pineal Res 1993;14:27-33. |
| 34. | Cao R, Peng W, Wang Z, Xu A. Beta-carboline alkaloids: Biochemical and pharmacological functions. Curr Med Chem 2007;14:479-500. |
| 35. | Lissoni P. Is there a role for melatonin in supportive care? Support Care Cancer 2002;10:110-6. |
| 36. | Bartsch H, Bartsch C. Effect of melatonin on experimental tumors under different photoperiods and times of administration. J Neural Transm 1981;52:269-79. |
| 37. | Lissoni P, Mandalà M, Mandelli A, Fumagalli L. Neuroimmunotherapy with subcutaneous low-dose interleukin-2 plus the pineal oncostatic hormones melatonin and 5-methoxytryptamine in untreatable advanced solid neoplasm patients with very poor clinical status. Int J Immunother 1999;XV: 35-8. |
| 38. | Plotnikoff NP, Miller GC. Enkephalins as immunomodulators. Int J Immunopharmacol 1983;5:437-41. |
| 39. | Grotenhermen F. Pharmacology of cannabinoids. Neuro Endocrinol Lett 2004;25:14-23. |
| 40. | Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer: A systematic review of randomized controlled trials and meta-analysis. J Pineal Res 2005;39:360-6. |
| 41. | Lissoni P, Porro G, Messina G, Porta E, Rovelli F, Roselli MG, et al. Morphine, melatoninm marijuana, magnolia and myrrh as the five M schedule in the treatment of cancer pain and the possible dose-dependency of the antitumor and analgesic effects of the pineal hormone melatonin. Anticancer Res 2014;34:6033-4. |
| 42. | Berkson BM, Rubin DM, Berkson AJ. Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: A report of 3 new cases. Integr Cancer Ther 2009;8:416-22. |
| 43. | Lissoni P, Malugani F, Bordin V, Conti A, Maestroni G, Tancini G. A new neuroimmunotherapeutic strategy of subcutaneous low-dose interleukin-2 plus the long-acting opioid antagonist naltrexone in metastatic cancer patients progressing on interleukin-2 alone. Neuro Endocrinol Lett 2002;23:255-8. |
| 44. | Lissoni P, Meregalli S, Nosetto L, Barni S, Tancini G, Fossati V, et al. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology 1996;53:43-6. |
| 45. | Guo JM, Xiao BX, Liu Q, Zhang S, Liu DH, Gong ZH. Anticancer effect of aloe-emodin on cervical cancer cells involves G2/M arrest and induction of differentiation. Acta Pharmacol Sin 2007;28:1991-5. |
| 46. | Hanus LO, Rezanka T, Dembitsky VM, Moussaieff A. Myrrh – Commiphora chemistry. Biomed Pap 2005;149:3-27. |
| 47. | Fried LE, Arbiser JL. Honokiol, a multifunctional antiangiogenic and antitumor agent. Antioxid Redox Signal 2009;11:1139-48. |
| 48. | Lissoni P, Brivio F, Fumagalli L, Messina G, Vigoré L, Parolini D, et al. Neuroimmunomodulation in medical oncology: Application of psychoneuroimmunology with subcutaneous low-dose IL-2 and the pineal hormone melatonin in patients with untreatable metastatic solid tumors. Anticancer Res 2008;28:1377-81. |
| 49. | Lissoni P, Pittalis S, Rovelli F, Vigorè L, Roselli MG, Brivio F. Interleukin-2, melatonin and interleukin-12 as a possible neuroimmune combination in the biotherapy of cancer. J Biol Regul Homeost Agents 1995;9:63-6. |
| 50. | Lissoni P, Giani L, Zerbini S, Trabattoni P, Rovelli F. Biotherapy with the pineal immunomodulating hormone melatonin versus melatonin plus Aloe vera in untreatable advanced solid neoplasms. Nat Immun 1998;16:27-33. |
| 51. | Sundar R, Cho BC, Brahmer JR, Soo RA. Nivolumab in NSCLC: Latest evidence and clinical potential. Ther Adv Med Oncol 2015;7:85-96. |
| 52. | Manson G, Norwood J, Marabelle A, Kohrt H, Houot R. Biomarkers associated with checkpoint inhibitors. Ann Oncol 2016;27:1199-206. |
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