Use of rhu-GM-CSF in pulmonary tuberculosis patients: results of a randomized clinical trial

Abstract

It has been postulated that deficient or incomplete clinical and/or microbiological response to tuberculosis treatment is associated with cell-mediated immunological dysfunction involving monocytes and macrophages. A phase 2 safety trial was conducted by treating patients with either recombinant human granulocyte-macrophage colony-stimulating factor (rhu-GM-CSF) or a placebo, both in combination with anti-tuberculosis chemotherapy. Thirty-one patients with documented pulmonary tuberculosis were treated with rifampin/isoniazid for six months, plus pyrazinamide for the first two months. At the beginning of treatment, rhu-GM-CSF (125mg/M(2)) was randomly assigned to 16 patients and injected subcutaneously twice weekly for four weeks; the other 15 patients received a placebo. The patients were accompanied in the hospital for two weeks, then monthly on an out patient basis, for 12 months. Clinical outcomes were similar in both groups, with no difference in acid-fast bacilli (AFB) clearance in sputum at the end of the fourth week of treatment. Nevertheless, a trend to faster conversion to negative was observed in the rhu-GM-CSF group until the eighth week of treatment (p=0.07), after which all patients converted to AFB negative. Adverse events in the rhu-GM-CSF group were local skin inflammation and an increase in the leukocyte count after each injection, returning to normal 72 hours after rhu-GM-CSF injection. Three patients developed SGOP and SGPT > 2.5 times the normal values. All patients included in the GM-CSF group were culture negative at six months, except one who had primary TB resistance. None of the patients had to discontinue the treatment in either group. We conclude that rhu-GM-CSF adjuvant immunotherapy could be safely explored in a phase 3 trial with patients who have active tuberculosis.

Modulation of pulmonary DC function by vaccine‐encoded GM‐CSF enhances protective immunity against Mycobacterium tuberculosis infection

“…Recombinant human GM-CSF has been used in humans to improve the immunological function of patients with various infectious diseases. A recent trial of GM-CSF co-delivery with antibiotic chemotherapy of patients with active tuberculosis revealed that, with the exception of one patient with primary tuberculosis resistance, all patients in the GM-CSF group were culture negative at six months [33]. Our data indicate that delivery of GM-CSF via BCG does not significantly alter the in vivo replication kinetics of parental BCG in mice (Fig.…”

Cytokines as Immunomodulators in Tuberculosis Therapy

“…Thus far, one phase-II controlled clinical trial of GM-CSF used in conjunction with chemotherapy has been performed. Results showed no major differences between the treatment and control groups, although faster clearance of acidfast bacilli in sputum was observed in the GM-CSF treatment group [84].…”

Improved Protection against Disseminated Tuberculosis by Mycobacterium bovis Bacillus Calmette-Guérin Secreting Murine GM-CSF Is Associated with Expansion and Activation of APCs

“…In humans, however, the use of tumor cells engineered to over-express GM-CSF have extensively been tested in clinical trials, and for the most part the regime is well tolerated (44). Further, recombinant human GM-CSF has been tested in combination with rifampin/isoniazid to treat patients with active tuberculosis with no adverse effects (45). Thus the capacity to deliver transiently low levels of immunostimulatory cytokines via BCG may be advantageous in invoking protective immune responses without negatively influencing pathology.…”

“…Murine and human GM-CSF display limited biological cross-reactivity (49), which suggests modification of the recombinant strain would be required for use in humans. However the potent activity of human GM-CSF on APC function (44), coupled with the favorable safety profile of studies employing human GM-CSF in clinical trials (44,45), suggests further study of this vaccine as a candidate to protect against tuberculosis in human populations is warranted. …”