Cytokines and molecular therapy最新文献

In this study, effective antitumour immunity was transferred by autologous short activated killer (SHAK) cells induced over four hours with lymphocyte conditioned medium (LCM) and recombinant interleukin-2 (rIL-2). Among eight patients with progressive metastatic renal cell carcinoma refractory to standard therapy, there were six objective tumour responses to SHAKs. Progression-free survival ranged from 0 to 8+ months, and overall survival ranged from 2 to 14+ months, with a median of 9+ months. Systemic toxicity of SHAKs was limited to flulike symptoms. Patient SHAKs provided a tumour-specific immunity, both cellular and humoral (expression and secretion of secondary cytokines, including IL-2, GM-CSF, INF-gamma and TNF-alpha), far superior to rIL-2 activated killer cells.

This study evaluates (i) constitutive levels of oncogene and p53 transcripts in chronic phase CML patients and (ii) their modulations subsequent to in vivo therapy with rIFN-alpha 2c. Peripheral blood mononuclear cells (pbmc) and bone marrow cells of 26 patients were examined for c-fos, c-myc, p53 and the hybrid bcr/abl mRNA levels. Results indicated that (i) constitutive c-fos transcript levels are significantly higher in patients subsequently responding to IFN-alpha therapy (p < 0.01) and positively correlated with the proportion of lymphocytes (r = 0.6895, p < 0.01) and negatively with the proportion of immature cells (r = -0.568, p < 0.01) contained in the pbmc preparations tested, (ii) constitutive mRNA levels of the hybrid bcr/abl, c-myc and p53 are positively correlated with each other, but failed to relate to disease parameters, and (iii) acute and chronic in vivo exposure to IFN-alpha is accompanied by upregulation of c-fos and downregulation of c-myc mRNA levels in responder patients.

The polymerase chain reaction (PCR) has been applied to detect occult leukemia (ALL) cells in patients with acute lymphoblastic leukemia who are otherwise considered in complete remission by traditional morphological examination of bone marrow specimens. The combined data from the clinical studies published to date suggest that a consistent pattern for residual disease disappearance over many months exists for patients who remain in complete remission for an extended period of time. Conversely, a pattern of residual disease persistence and reappearance preceding clinical findings exists for the majority of patients who ultimately relapse. The ability to detect residual ALL disease near the end of chemotherapy or after the completion of treatment in some patients who otherwise are deemed likely to be cured of their malignancy raises the possibility that mechanisms other than leukemia cell cytotoxicity are influencing the outcome for this disease.

We have explored the effect of IL-3 and IL-6, each alone and in combination with G-CSF, GM-CSF or IL-1, on neutrophil and platelet recovery in BALB/c mice (H-2d) given 10 Gy total body irradiation followed by 10(7) bone marrow cells and 10(6) spleen cells from C57BL6 donors (H-2b), as well as the effect of IL-3 alone and IL-6 alone on graft-versus-host disease (GVHD) and survival. Neither IL-3 alone nor IL-6 alone significantly increased the circulating absolute neutrophil count (ANC) at day 6 post transplant when compared with mice given saline injections (ANC 0.31 x 10(9)/l). G-CSF and IL-1, each alone, significantly raised the day-6 ANC (0.58 x 10(9)/l, p = 0.02; 0.67 x 10(9)/l, p = 0.007 respectively). However, IL-3, 200 ng twice daily, significantly increased the day-6 ANC when used in combination with GM-CSF (0.49 x 10(9)/l, p = 0.003) or with IL-6 (0.66 x 10(9)/l, p = 0.004), as well as with G-CSF (0.62 x 10(9)/l, p = 0.007) or with IL-1 (0.49 x 10(9)/l, p = 0.003). Apart from the combination with IL-3, IL-6 significantly raised the day-6 ANC only in combination with G-CSF (0.79 x 10(9)/l, p = 0.007). When used alone, both IL-6 and G-CSF raised the day-6 platelet count (312 x 10(9)/l, p = 0.02 and 309 x 10(9)/l, p = 0.01 respectively) compared with control mice (216 x 19(9)/l). IL-3 alone resulted in a platelet count of 303 x 10(9)/l (p = 0.06). In combination, only IL-3 with G-CSF significantly increased the value over that of saline control mice (328 x 10(9)/l, p = 0.02). IL-3 200 ng alone twice daily and IL-6 200 ng alone twice daily for 14 days post transplant resulted in survival not different from that of mice given saline injections. However, IL-3 500 ng twice daily for 14 days resulted in impaired survival and accelerated weight loss. In summary, while neither IL-3 nor IL-6 (nor GM-CSF) used alone accelerated neutrophil recovery post transplant, the combinations of IL-3 plus IL-6 and IL-3 plus GM-CSF did so. IL-6 (and G-CSF) accelerated platelet recovery post transplant, but combining IL-3 or IL-6 with the other cytokines was generally unsuccessful in this regard. Higher-dosage IL-3 appeared to accelerate graft-versus-host disease and impair survival, thus providing indirect evidence of the involvement of this cytokine in the mediation of GVHD.

A study was made to determine CR rate, response duration and survival in patients with RAEB or RAEB-t given AML-type chemotherapy, in particular the newer agents idarubicin and fludarabine. Eighty-five adults (58 RAEB-t, 27 RAEB) received either IA (idarubicin 12 mg/m2 daily on days 1-3, ara-C 1.5 g/m2 daily on days 1-4 CI), FA (fludarabine 30 mg/m2 daily on days 1-5, ara-C 2 g/m2 daily on days 1-5) or FLAG (FA + G-CSF 400 micrograms/m2 daily from day-1 until CR). IA was given exclusively to patients with better prognosis (as assessed by pretreatment karyotype), while FA and FLAG were given first to patients with worse and then to those with better prognosis. In remission, patients received lower doses of the same regimens for 6-12 months. The 85 patients comprise the largest reported series of RAEB or RAEB-t patients given AML-type chemotherapy. Their median age was 61 years, 33% had chromosome 5 or 7 abnormalities (-5/-7), and 55% were treated in laminar air flow rooms. The CR rate was 66%. While rates were highest in younger patients with a normal karyotype, CR rates in excess of 50% were also obtained in patients over age 60 (27/47; 57%) and in patients with -5/-7 (17/29; 59%). In 11 of the 14 cytogenetically abnormal patients in whom cytogenetic analysis was repeated at the time of CR, only normal metaphases were found. In the remaining 3 the number of abnormal metaphases was substantially reduced. However, the probability of continued CR was low (e.g. 452 +/- 0.08 at 12 months), and the only patients alive in CR beyond two years were patients under age 60 without -5/-7 and with RAEB-t. Survival probability was 0.35 +/- 0.05 at one year. Eight of 56 patients died in CR. While current AML-type chemotherapy can produce higher CR rates than is perhaps usually appreciated, in some patients with RAEB or RAEB-t (e.g. older patients with -5/-7) the brevity of the remissions and the risk entailed suggest that new post-remission therapies are needed to make this approach generally worthwhile.