Immunotherapy (recombinant interleukin 2), hormone therapy (medroxyprogesterone acetate) and antioxidant agents as combined maintenance treatment of responders to previous chemotherapy

Mantovani, Giovanni; Macciò, Antonio; Madeddu, Clelia; Massa, Elena; Mudu, Maria Caterina; Mulas, Carlo; Gramignano, Giulia; Massidda, Stefania; Murgia, V.; Lusso, Maria Rita; Mura, Loredana

doi:10.3892/ijo.18.2.383

Cited by 7 publications

(7 citation statements)

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“…This supports combining immunotherapy with drugs that modulate chronic inflammation, counteracting oxidative stress and correcting derangements of energy and iron metabolism (Fig ). Some studies by our groups have already tested the efficacy of a combination treatment approach with immunotherapy (recombinant IL‐2), anti‐inflammatory agents (medroxyprogesterone acetate) and antioxidants in patients with advanced cancer . More recently, we demonstrated the effectiveness of combination therapy with the anti‐PD‐1 antibody, nivolumab, and cyclophosphamide, an immunomodulatory chemotherapy agent that down‐regulates macrophage activity and inhibits pro‐inflammatory cytokine synthesis, thereby synergistically enhancing the action of immunotherapy .…”

Section: Rationale For a Combination Immunotherapy Approachmentioning

confidence: 99%

“…Some studies by our groups have already tested the efficacy of a combination treatment approach with immunotherapy (recombinant IL-2), antiinflammatory agents (medroxyprogesterone acetate) and antioxidants in patients with advanced cancer. 58,59 More recently, we demonstrated the effectiveness of combination therapy with the anti-PD-1 antibody, nivolumab, and cyclophosphamide, an immunomodulatory chemotherapy agent that down-regulates macrophage activity and inhibits pro-inflammatory cytokine synthesis, 60 thereby synergistically enhancing the action of immunotherapy. 61 Of note, low-dose cyclophosphamide can also induce Treg depletion by inhibiting their proliferation and intratumoral migration and to dampen their activity by decreasing the FOXP3 and GITR expression.…”

Section: Rationale For a Combination Immunotherapy Approachmentioning

confidence: 99%

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Blocking inflammation to improve immunotherapy of advanced cancer

Macciò

Madeddu

2019

Immunology

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The ability to induce functional reprogramming of regulatory T (Treg) cells in the tumor microenvironment is an extremely important therapeutic opportunity. However, when discussing such an approach, the opposing effect that the activation of the Treg cell compartments may have in inducing the immune inflammatory response and its link with the efficacy of immunotherapy should be considered. In fact, Treg reprogramming has a dual effect: immediate, with mechanisms that activate immunosurveillance, and late, mediated by the macrophage activation that yields an inflammatory status that is deleterious for the antineoplastic efficiency of the immune system response. Persistence of the inflammatory response is associated with specific changes of oxidative and glycolytic metabolic pathways that interfere with conventional T‐cell activation and function and may be one of the reasons for the failure of immunotherapy in advanced cancer patients. Therefore, in addition to modulating Treg cell action, the combined use of drugs able to block chronic inflammation mediated mainly by macrophages, to counteract the oxidative stress, and to positively regulate the metabolic derangements, could improve the effectiveness of modern immunotherapy. In conclusion, reprogramming of Treg cells may be an appropriate strategy for treating early stages of neoplastic diseases, whereas other immunosuppressive mechanisms should be the target of a combined immunotherapy approach in more advanced phases of cancer.

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Section: Rationale For a Combination Immunotherapy Approachmentioning

confidence: 99%

Section: Rationale For a Combination Immunotherapy Approachmentioning

confidence: 99%

Blocking inflammation to improve immunotherapy of advanced cancer

Macciò

Madeddu

2019

Immunology

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“…In an earlier nonrandomized trial, the same investigators administered IL-2, medroxyprogesterone, and the antioxidants ␣-lipoic acid and N-acetylcysteine to 16 cancer patients. 161 Body weight and body mass index increased significantly, whereas appetite did not change. It is unclear which components of the treatment were responsible for the beneficial effects.…”

Section: Combination Treatmentsmentioning

confidence: 94%

Nutrition Modulation of Cachexia/Proteolysis

et al. 2006

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Cachexia represents progressive wasting of muscle and adipose tissue and is associated with increased morbidity and mortality. Although anorexia usually accompanies cachexia, cachexia rarely responds to increased food intake alone. Our knowledge of the underlying mechanisms responsible for cachexia remains incomplete. However, most states of cachexia are associated with underlying inflammatory processes and/or cancer. These processes activate protein degradation and lipolytic pathways, resulting in tissue loss. In this article, we briefly review the pathophysiology of cachexia and discuss the role of specific nutrient supplements for the treatment of cachexia. The branched chain amino acid leucine, the leucine metabolite beta-hydroxy-beta-methylbutyrate, arginine, glutamine, omega-3 long chain fatty acids, conjugated linoleic acid, and polyphenols have demonstrated some efficacy in animal and/or human studies. Optimal treatment for cachexia is likely aimed at maximizing muscle and adipose synthesis while minimizing degradation.

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“…rIL‐2 (PROLEUKIN ® , Chiron, Milan, Italy) was administered at a dose of 1.8 MIU subcutaneously three times/week (every other day) for the first 2 weeks of every month for 1 year (31 patients) or at the same dose five times/week for the first and third week of every month for 1 year (the last 11 patients enrolled). This dose was established on the basis of previously reported studies by Recchia et al (phase IB)(30) and by ourselves (21,22). Paracetamol medication was administered orally 1 h before and 2 h after the rIL‐2 administration to prevent flu‐like symptoms.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, we have carried out two subsequent studies, the first one pilot and the second phase II non‐randomized which included all patients treated with whatever chemotherapy or combined modality regimen for whatever cancer who were in clinical objective response (complete response, CR, or partial response, PR) or SD to receive a maintenance treatment with rIL‐2 plus MPA plus antioxidant agents ALA and NAC (21,22). The results of these two previous studies prompted us to carry out a mature phase II study, which is presented here.…”

Section: Introductionmentioning

confidence: 99%

Subcutaneous interleukin‐2 in combination with medroxyprogesterone acetate and antioxidants in advanced cancer responders to previous chemotherapy: phase II study evaluating clinical, quality of life, and laboratory parameters

et al. 2003

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We carried out an open, non-randomized phase II study including all patients treated with whatever chemotherapy or combined modality regimen for whatever cancer who were in clinical objective response (complete response, CR, or partial response, PR) or stable disease (SD). The treatment consisted of administration of recombinant interleukin-2 (rIL-2) at a dose of 1.8 MIU subcutaneously three times/week (every other day) for the first 2 weeks of every month plus medroxyprogesterone acetate (MPA) 500 mg/day every other day plus antioxidant agents alpha-lipoic acid 300 mg/day and N-acetyl cysteine 1800 mg/day or carbocysteine lysine salt oral solution 2.7 g/day. The treatment was administered for 1 year except when progression of disease occurred. The primary study endpoints were to define clinical outcome, i.e. duration of response, survival (overall survival, OS and progression-free survival, PFS), the toxicity profile, and the evaluation of quality of life (QL). As secondary endpoints, we measured the changes of lymphocyte count, serum levels of proinflammatory cytokines, IL-2, C-reactive protein (CRP) and leptin, blood levels of reactive oxygen species (ROS) and antioxidant enzymes (glutathione peroxidase, GPx and superoxide dismertase, SOD). From July 1998 to June 2003, 42 patients were enrolled in the study (M/F ratio, 39/3; mean age, 62.5 years). Twenty (47.6%) patients were elderly (> 65 years). The majority of patients had either head and neck cancer or lung cancer, 88% had locally advanced or metastatic disease at diagnosis, and 76% had ECOG 0. Forty patients were previously treated with chemotherapy (27 also with radiotherapy), two with IL-2 and interfiron (IFN), one with endocrine therapy and one with only surgery. We obtained an objective response to maintenance treatment of 50%. Median duration of response was 19 months and median PFS was 33 months. Median duration of maintenance treatment was 12 months, median follow-up duration from diagnosis to June 2003 was 40 months, and median follow-up duration from study entry to June 2003 was 17 months. The median overall survival has not been reached. Toxicity was negligible. As for QL, a significant improvement of cognitive functions was observed, whereas all other functioning and symptom scales did not change significantly. As for laboratory parameters, absolute lymphocyte count increased significantly, IL-6, IL-1 beta, tumor necrosis factor-alpha, CRP, and fibrinogen decreased significantly whereas IL-2 and leptin increased significantly after treatment. ROS decreased significantly, whereas GPx increased significantly after treatment. Patients alive at study end showed a significant increase in absolute lymphocyte count, IL-2, leptin, and GPx and a significant decrease of proinflammatory cytokines, CRP, fibrinogen, and ROS, whereas patients who died before study end exhibited only a significant increase in absolute lymphocyte count, IL-2, and GPx and a significant decrease of ROS. Long-term combined maintenance therapy with rIL-2 + MPA + antioxidant agents...

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Immunotherapy (recombinant interleukin 2), hormone therapy (medroxyprogesterone acetate) and antioxidant agents as combined maintenance treatment of responders to previous chemotherapy

Cited by 7 publications

References 0 publications

Blocking inflammation to improve immunotherapy of advanced cancer

Blocking inflammation to improve immunotherapy of advanced cancer

Nutrition Modulation of Cachexia/Proteolysis

Subcutaneous interleukin‐2 in combination with medroxyprogesterone acetate and antioxidants in advanced cancer responders to previous chemotherapy: phase II study evaluating clinical, quality of life, and laboratory parameters

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