Co-administration of plasmid-encoded granulocyte-macrophage colony-stimulating factor increases human immunodeficiency virus-1 DNA vaccine-induced polyfunctional CD4+ T-cell responses

T-cell based vaccines against human immunodeficiency virus (HIV) generate specific responses that may limit both transmission and disease progression by controlling viral load. Broad, polyfunctional, and cytotoxic CD4+T-cell responses have been associated with control of simian immunodeficiency virus/HIV-1 replication, supporting the inclusion of CD4+ T-cell epitopes in vaccine formulations. Plasmid-encoded granulocyte-macrophage colony-stimulating factor (pGM-CSF) co-administration has been shown to induce potent CD4+ T-cell responses and to promote accelerated priming and increased migration of antigen-specific CD4+ T-cells. However, no study has shown whether co-immunisation with pGM-CSF enhances the number of vaccine-induced polyfunctional CD4+ T-cells. Our group has previously developed a DNA vaccine encoding conserved, multiple human leukocyte antigen (HLA)-DR binding HIV-1 subtype B peptides, which elicited broad, polyfunctional and long-lived CD4+ T-cell responses. Here, we show that pGM-CSF co-immunisation improved both magnitude and quality of vaccine-induced T-cell responses, particularly by increasing proliferating CD4+ T-cells that produce simultaneously interferon-γ, tumour necrosis factor-α and interleukin-2. Thus, we believe that the use of pGM-CSF may be helpful for vaccine strategies focused on the activation of anti-HIV CD4+ T-cell immunity.

Phase II study of ifosfamide, carboplatin, etoposide and GM-CSF in small cell lung cancer.

Twenty patients with small cell lung cancer (SCLC) were entered to the study. Fourteen cases were male and six cases were female. Twelve cases were extensive disease, eight cases were limited disease. Median age was 60 years (range = 40-72 years), median performance status was 70 per cent (range = 60-80%). All patients were treated with combination chemotherapy consisting of ifosfamide 5 g/m2 intravenous infusion over 4 hours with mesna uroprotection, carboplatin 300 mg/m2 intravenous infusion over 2 hours on day 1, and etoposide 120 mg/m2 intravenous infusion over 4 hours on day 1-3. Chemotherapy was re-cycled every 28 days. Assessment of hematologic toxicity (CBC) was performed two times per week. If there was grade 3 or 4 neutropenia on any cycle of chemotherapy, GM-CSF was administered for febrile neutropenia and on the next cycle it was administered prophylactically on day 4-14. RESULTS: Seventeen cases were evaluable for response and toxicity (three cases were inevaluable due to loss to follow-up after the first cycle of chemotherapy). Fourteen cases (five limited disease, nine extensive disease) achieved partial response (82.5%). Two cases had stable disease, one case died on day 7. One year survival was 23.5 per cent. Seventy and a half percent grade 3 and 4 neutropenia was seen during the first cycle. One patient had febrile neutropenia. After being prophylactically treated with GM-CSF, grade 3 and 4 neutropenia was reduced from 70.5 per cent to 56.2 per cent, 46.7 per cent, 63.6 per cent, 42.8 per cent and 0 per cent in cycle 2-6 respectively. Major toxicity of GM-CSF consisted of transient chest distress, chills, sweating and hypotension which subsided in 5-10 minutes. No fever or skin rash was observed. CONCLUSION: Combination of ifosfamide, carboplatin and etoposide (ICE) is an active regimen for small cell lung cancer. However, because of its severe myelosuppression, this regimen needs hematopoietic growth factor support, and GM-CSF was used in this study. The administration of GM-CSF rendered ICE chemotherapy to be given safely.

Effect of granulocyte macrophage colony stimulating factor on hepatitis-B vaccination in haemodialysis patients.

OBJECTIVES: Haemodialysis patients often fail to respond to hepatitis B vaccination. There are various agents that can be used as vaccine adjuvant in chronic renal failure patients on haemodialysis. In this study, the adjuvant effect of granulocyte macrophage colony stimulating factor (GMCSF) is compared with that of control subjects. METHODS: In this study, eight patients were started on 150 mcg of GMCSF subcutaneously 24 hours prior to intramuscular hepatitis B vaccination (20 mcg of genetically engineered vaccine at the same site). The antibody response to surface antigen (anti HBsAg) in these patients were compared with those of eight control subjects who received standard three doses of monthly 40 mcg of same hepatitis B vaccine. RESULTS: In the control study, only two patients developed significant antibody response to surface antigen whereas seven of eight patients in GMCSF group developed significant antibody titres (> 10 IU/L). The sero-protection rate was 87.5% in GMCSF group and 25% in control group. CONCLUSION: This study shows that GMCSF offers significantly better seroprotection against hepatitis B compared to standard dose of vaccination in patients with chronic renal failure on haemodialysis.

Ciclofosfamida a dosis escaladas en tumores sólidos malignos en población pediátrica: Experiencia en el Hospital Infantil de México Federico Gómez / Cyclophosphamide dose escalation in solid tumors in children

Introducción. La ciclofosfamida a dosis escaladas incrementó su citotoxicidad en tumores sensibles a ésta, sin aumento de sus efectos tóxicos. Material y métodos. Se evaluaron 50 pacientes con tumores sólidos, en los que se utilizó ciclofosfamida en dosis escaladas de 2.5 g hasta 4.5 g/m² de superficie corporal como esquema de primera línea o de rescate, con uroprotector y factor estimulante de colonia en cada ciclo. La toxicidad y la respuesta fueron basadas en criterios de la Organización Mundial de la Salud. Resultados. Los diagnósticos más frecuentes fueron tumores del sistema nervioso central y retinoblastoma con 18 y 9 pacientes respectivamente. Cuarenta y cinco pacientes (90 por ciento) presentaron respuesta a quimioterapia, ya sea completa (72 por ciento) o parcial. Sólo en 5 pacientes no hubo respuesta. Se presentaron 3 episodios de cistitis hemorrágica. Conclusiones. Se comprobó que la ciclofosfamida a dosis escalada es activa en un grupo heterogéneo de pacientes con tumores sólidos y que esta modalidad terapéutica no incrementa el riesgo de toxicidad

Neutrophil recovery time and adverse side effects in acute leukemia patients treated with intensive chemotherapy and concomitant G or GM-CSF

Objetivo. Comparar la velocidad de recuperación de neutrófilos y los efectos secundarios indeseables en dos grupos de pacientes con leucemia aguda con quimioterapia intensiva y factor estimulante de colonias de granulocitos (G-CSF) o de granulocitos y macrófagos (GM-CSF). Pacientes y métodos. Los pacientes fueron asignados de manera aleatoria para recibir, por vía subcutánea y junto con el inicio de la quimioterapia, G-CSF 300 µg en adultos y 150 µg en niños o GM-CSF 400 y 200 µg, respectivamente. Los factores se administraron hasta que la cuenta total de neutrófilos alcanzó 500/µL. Los efectos secundarios fueron atribuidos a los factores sólo cuando no fueron coincidentes con infección, quimioterapia o transfusión de hemoderivados. Resultados. Se incluyeron 34 pacientes con G-CSF y 37 con GM-CSF. La distribución por sexo, edad, tipo de leucemia, tipo de quimioterapia recibida (inducción o postinducción), cifra inicial de leucocitos y plaquetas fue similar entre los dos grupos. El tiempo promedio para alcanzar 500 neutrófilos/µL fue 19 días para el grupo de G-CSF y 16 días para el grupo de GM-CSF (p=0.08). No existieron diferencias estadísticamente significativas entre los efectos secundarios indeseables de los dos grupos. Se registraron dos casos de fiebre asociada a G-CSF y 5 a GM-CSF (p=0.25). Hubo un caso de reacción sistémica en el grupo G-CSF. Veintinueve pacientes de cada grupo presentaron episodios de neutropenia febril (p=0.45). El único factor que mostró influencia significativa en la velocidad de recuperación de neutrófilos fue el tipo de leucemia, siendo más rápido en el caso de leucemia aguda linfoblástica (p=0.04). Conclusiones. No encontramos diferencias significativas entre los dos factores para esta indicación

A Role for granulocyte-macrophage colony-stimulating factor (GM-CSF) in the treatment of neutropenic patients with pneumonia

Pneumonia is a serious, difficult to manage, and often fatal infection in neutropenic patients. The availability of hematopoietic growth factors has made it possible to evaluate the role of reversing the neutropenic state. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used in an investigator-initiated, open-label clinical trial in approximately 1200 patients. Data colleted on each patient was reviewed to identify all patients who had the combination of neutropenia and pneumonia. Sixty-eight patients (5 percent of the patients for whom GM-CSF was requested) met the criteria for having neutropenic peneumonia. In this patient population there were 45 males and 20females (gender was not indicated in 3). Ages ranged from 3 to 83 years (mean 39 ñ 18 years). The underlying diseases included: 7 patients who were receiving chemotherapy for solid malignant tumors, 14 for lymphoma, and 22 for leukemia; 15 post bone marrow transplantation primarily for hematologic malignancy; 3 idiosyncratic drug-induced neutropenia; and 7 with other causes of neutropenia. The type of pneumonia was predominantly fungal in 21 patients, bacterial in 23, viral in 2, protozoal in 1, and uncertain in 21 (presumed to be bacterial in 19 and viral in 2). Patients received a mean of 5µg/kg GM-CSF (range 1.3-12.5µg/kg) daily for a mean of 13 ñ 10 (range 2-57) days. The mean leukocyte count at start of treatment was 600 ñ 500 cells/mmü, and at the end of treatment was 5600 ñ 9200 cells/mmü (P=0.001). The time between start of GM-CSF and a leukocyte level in excess of 1500/mmü was a median of 13 days. Hematopoietic recovery was showm in 46/62 (74 percent), 40/64 (63 percent) showed good clinical and/or radiologic improvement, and 41/68 (60 percent) survived. Four illustrative case reports are provided. By comparing the hematologic responders to non-responders, it is clear that persistent neutropenia contributed significantly to poor clinical outcome and mortality. Only 3/22 (13 percent) of non-responders survived, whereas 38/46 (83 percent) of responders survived. There were 7 adverse events (rash 1, fever/chills 2, malaise 1, myalgia/bone pain 2, increased myeloblasts 1) which were considered to be related to use of the cytokine. Aggravation of the pulmonary inflammation or sepis syndrome was not observed. Tolerability was good or very good in 89 percent of patients. Based on this open-label study, the use of GM-CSF in combination with appropiate antibiotics ...