The cancer journal from Scientific American最新文献

Purpose: Up to 80% of children with acute myelogenous leukemia treated with intensive chemotherapy achieve remission; however, a large proportion of patients develops recurrent disease. Because interleukin (IL)-2 can induce remission in patients with overt evidence of acute myelogenous leukemia, we hypothesized that it might prevent relapse when administered to patients in first remission after intensive consolidation chemotherapy. A pilot Children's Cancer Group (CCG) trial (CCG-0941) demonstrated the feasibility of this approach, and we initiated a prospective randomized trial (CCG-2961) to further evaluate the safety and potential efficacy of IL-2 therapy in preventing relapse of acute myelogenous leukemia.

Patients and methods: In trial CCG-0941, 21 pediatric patients in complete remission following induction and consolidation chemotherapy on protocol CCG-2941 received IL-2 therapy. In CCG-2961, 79 patients in complete remission were randomized as of February 1999 to receive either IL-2 (n = 39) or no further therapy. In both trials, recombinant IL-2 was given at a dose of 9 million IU/m2/d by continuous intravenous infusion for 4 days. After 4 days of rest, IL-2 was resumed at a dose of 1.6 million IU/m2/d for 10 days by continuous infusion. We monitored patients for toxicity and relapse.

Results: The majority of patients treated with IL-2 in these two trials experienced some degree of fever. Seven of 60 patients (12%) had clinically significant rashes, and grade 3 vascular leak syndrome and hypotension have each been observed in five patients (8%). Hypotension resolved promptly after treatment with intravenous fluids. No patients have experienced renal toxicity or required cardiac vasopressors or transfer to an intensive care unit; there have been no treatment-related deaths. Overall, the incidence and severity of adverse events remain similar in the two trials. Total projected accrual to the IL-2 randomization is anticipated to be 326 patients, and relapse and survival data remain blinded.

Conclusion: The dose and schedule of IL-2 used in these two trials continue to be reasonably well tolerated by children with acute myelogenous leukemia in first remission. Any conclusions with regard to efficacy must await completion of the randomized trial.

Purpose: Recombinant interleukin (IL)-2 administration can mediate regression of solid tumors in patients with melanoma and renal cell carcinoma. A better understanding of the mechanisms of IL-2-mediated antitumor effects has led to the investigation of novel immunotherapeutic approaches. The rationale for these immunotherapeutic approaches and the results of preliminary clinical studies are presented.

Patients and methods: The therapeutic potential of dendritic cells and the role of FLT3 ligand, a potent hematopoietic growth factor, was investigated in a variety of preclinical models. In addition, a clinical study with autologous dendritic cells pulsed with synthetic melanoma peptides derived from the MART1/ Melan A, gp100, and tyrosinase proteins was conducted. Twenty-eight human leukocyte antigen (HLA)-A2+ melanoma patients received an average of 106 dendritic cells a week for 4 weeks.

Results: In a murine liver metastases model, FLT3 ligand administration alone or in combination with IL-12 or IL-2 had significant antitumor effects and resulted in significant infiltration of the tumor border by lymphocytes and dendritic cells, which was associated with an increased number of apoptotic figures. Administration of melanoma peptide-pulsed dendritic cells to 28 patients with advanced metastatic melanoma produced a complete response in two patients and a partial response in one. Significant infiltration of T cells and dendritic cells into melanoma lesions was observed.

Conclusion: These studies confirm the feasibility of immunotherapeutic approaches using dendritic cells and FLT3 ligand and demonstrate their potential antitumor activity. These approaches may be effective for patients with metastatic melanoma and other solid tumors and will likely be used to improve the efficacy of IL-2-based immunotherapy.

Purpose: The development of an effective antitumor immune response is compromised in patients with renal cell carcinoma. Despite significant infiltration by T lymphocytes into renal tumors, no detectable induction of gene expression is associated with the generation of an antitumor immune response. Tumor-induced down-regulation of interleukin (IL)-2 expression may contribute to the impaired development of the T cell-mediated antitumor immune response. Within renal tumors, there is no detectable expression of IL-2 or the IL-2 receptor alpha chain, and only low levels of interferon gamma (IFN-gamma) mRNA are detected. Products in the tumor environment may suppress the expression of these genes, thus inhibiting production of type 1 helper T cell cytokines.

Methods: Peripheral blood lymphocytes obtained from healthy volunteers were exposed to supernatants from renal cell carcinoma explants, and the immunologic consequences of this were assessed using a variety of molecular assays.

Results: Soluble products from renal tumor explants can inhibit the production of IL-2 and IFN-gamma by peripheral blood lymphocytes and can suppress T-cell proliferation. Soluble products from renal cell carcinoma explants appear to block the nuclear translocation of nuclear factor kappa B (NFkappaB) proteins p50 and RelA without affecting cytoplasmic levels of these proteins. In some experiments, a reduction in the nuclear translocation of other transcription factors involved in IL-2 gene expression, including nuclear factor of activated T cells and accessory protein-1, was observed. Gangliosides isolated from tumor supernatants blocked the production of IL-2 and IFN-gamma in response to ionomycin plus phorbol myristate acetate stimulation. These gangliosides also inhibited stimulus-dependent activation and nuclear accumulation of NFkappaB. Coculture experiments demonstrated that renal cell carcinoma lines known to express gangliosides could inhibit the activation of NFkappaB in normal T cells and the Jurkat T-cell line. Supernatants from renal cell carcinoma explants and renal cell carcinoma cell lines can also suppress the proliferation of normal T cells, thus reproducing another defect observed in tumor-infiltrating lymphocytes. Supernatants from renal cell carcinoma tumors also appear to inhibit signaling through the IL-2 receptor. Although tumor supernatants had little effect on IL-2 receptor (alpha, beta or gamma) expression, they did block expression of JAK3, a key kinase involved in signaling through the IL-2 receptor pathway. Moreover, downstream events in IL-2 receptor signaling linked to JAK3 were impaired in T cells treated with tumor supernatants.

Conclusion: These findings suggest that soluble products from renal tumors may suppress T-cell responses by blocking both IL-2 production and normal IL-2 receptor signaling.

Purpose: The clinical utility of high-dose intravenous recombinant interleukin (IL)-2 therapy is limited by severe toxicity including hypotension, fever, chills, pulmonary edema, and oliguria Hypotension has been previously shown to result from excessive vascular relaxation due to overproduction of the endogenous vasodilator nitric oxide. Nitric oxide production can be decreased by administration of the competitive enzyme inhibitor NG-monomethyl-L-arginine (NMA). A clinical trial to investigate the dose-dependent effects of NMA on blood pressure was undertaken in patients with metastatic renal cell carcinoma.

Patients and methods: Patients with metastatic renal cell carcinoma receiving a 5-day continuous infusion of IL-2 (18 million IU/m2/d) who developed hypotension were treated with increasing doses of NMA, ranging from 3 to 36 mg/kg.

Results: Twenty-three patients received a total of 61 courses of IL-2; 18 of these patients developed hypotension and received NMA. Antihypotensive activity was observed at all dose levels, and the duration of the effect varied directly with the dose of NMA. At the higher dose levels tested (12 to 36 mg/kg), increased pulmonary vascular resistance and decreased cardiac output were observed. Patients experiencing a significant decrease in cardiac output received dobutamine (2.5 to 10 microg/kg/min). Pulmonary capillary wedge pressure was unaffected by administration of NMA. One patient treated at 24 mg/kg (bolus) experienced a major motor seizure, but no neurologic disorders were observed in other patients treated with NMA doses of 24 to 36 mg/kg. No other adverse events involving hepatic, renal, or hematologic systems were attributed to NMA. Three patients received NMA by an initial bolus followed by a continuous infusion. Similar antihypotensive effects were noted, and these patients were able to complete a full 5-day course of IL-2.

Conclusion: The antihypotensive effects of NMA appear to be optimal at a dose of 24 mg/kg, with maintenance doses of 8 mg/kg every 4 to 6 hours. At this dose level, blood pressure was restored, and IL-2-associated vasodilatation was fully reversed. Coincident with the reversal of hypotension, the state of high cardiac output was also reversed by NMA administration. These results suggest that NMA may be effective for alleviating the hypotensive effects of high-dose IL-2 therapy in cancer patients.

Purpose: The purpose of our efforts is to trigger the immune destruction of established cancer. Interleukin (IL)-2 can mediate the regression of tumors in patients with melanoma and renal cell carcinoma. In animal models, the antitumor effects of IL-2 are mediated by T lymphocytes. Stimulation with specific antigen can enhance the ability of T cells to respond to IL-2 by triggering the rapid upregulation of the high-affinity IL-2 receptor. We are seeking to design recombinant and synthetic vaccines capable of preferentially priming T cells with specificity for tumor cells.

Methods: The antitumor activity of experimental vaccines is being studied preclinically using recently developed murine models that employ the mouse homologues of human tumor-associated antigens. Once the most effective experimental vaccines are optimized in experimental animals, clinical trials can be conducted. Vaccines are being evaluated for their ability to mediate the regression of established tumors, and a variety of immunologic correlates are being measured.

Results: In animal models, vaccines based on molecularly defined tumor-associated antigens expressed in viral vectors or delivered as "naked" DNA stimulate the expansion of CD4+ and CD8+ tumor-specific T lymphocytes. Coadministration of IL-2 with these vaccines dramatically enhances their ability to mediate the regression of established cancer. In the clinic, treatment of melanoma patients with peptide vaccine and IL-2 resulted in objective responses in approximately 40% of patients, a response rate more than twice that typically achieved with IL-2 alone. Paradoxically, tumor-specific CD8+ T-cell levels were not increased in these patients.

Conclusion: The addition of recombinant and synthetic cancer vaccines to a regimen of IL-2 can result in improved antitumor responses in both animal models and melanoma patients. Vaccine-primed, tumor-specific T cells may preferentially proliferate upon administration of IL-2. The apparent lack of increase in CD8+ T-cell numbers in this setting suggests that the vaccine-primed T cells functionally disappear after a transient period of activation. Preventing the disappearance of activated T cells upon IL-2 administration-for example, by blocking proapoptotic signals-may enhance the therapeutic effectiveness of anticancer vaccines.

Purpose: The results of trials using interleukin (IL)-2-based therapy in leukemia and after hematopoietic stem cell transplant suggest that such therapy could have an impact on preventing disease relapse in patients with hematologic malignancy who achieve a minimal disease state. The use of immunotherapy in the autologous transplant setting is modeled in part on the well-characterized immunotherapeutic effect of the graft-versus-tumor response in patients undergoing allogeneic transplantation. The graft-versus-tumor response, mediated by donor cells, contributes to the higher cure rates seen in patients undergoing allogeneic transplant for the treatment of a variety of hematologic malignancies, including acute and chronic myelogenous and lymphoblastic leukemia, myeloma, and lymphoma

Patients and methods: The literature was reviewed, and we relate our own clinical experience with IL-2 therapy in this setting.

Results: Preclinical in vitro and animal data show a variety of leukemia cells are sensitive to autologous IL-2-activated effector cells. In addition, laboratory studies show that IL-2 can be used to activate antitumor cellular responses from bone marrow and peripheral blood without compromising hematopoiesis. Most importantly, in vitro studies show that chemoresistant malignant hematopoietic cells are sensitive to IL-2-induced cell death, thus emphasizing the lack of cross resistance to immunologic-based therapeutics. The results of phase I and II studies conducted in patients with acute myelogenous leukemia in first or subsequent remission suggest that autologous IL-2-activated cells may mediate an antitumor response and aid in preventing relapse after autologous transplantation. Clinical trials to determine the role of IL-2 after transplantation for the treatment of acute and chronic myelogenous leukemia, multiple myeloma, and lymphoma are ongoing.

Conclusion: These studies will help define the optimal dose and schedule of IL-2 and its role in augmenting therapeutic immune-mediated autologous responses.

Purpose: Dendritic cells (DC) can elicit potent immune responses to tumors through their capacity to efficiently process and present tumor-associated antigens. In a variety of animal tumor models, vaccines based on tumor lysate-pulsed DC (TP-DC) have been shown to effectively immunize against lethal tumor challenges as well as to treat established growing tumors at skin and organ sites. The antitumor effects elicited by TP-DC-based vaccines in vivo have been shown to be mediated by tumor-specific proliferative, cytotoxic, and cytokine-secreting host-derived T cells. Because of the critical involvement of T cells in the antitumor immune response, we have been investigating whether the systemic administration of recombinant interleukin (IL)-2 can enhance the therapeutic efficacy of TP-DC-based tumor vaccines.

Materials and methods: Immunization with TP-DC plus IL-2 administration was evaluated to determine if this combination could enhance protective immunity toward a weakly immunogenic sarcoma (MCA-207) and a poorly immunogenic subline (D5) of the B16 melanoma and mediate therapeutic rejection of established tumors in C57BL/6 (B6) mouse models.

Results: We have demonstrated in our murine models that the addition of IL-2 at relatively nontoxic doses can markedly augment the antitumor activity of TP-DC-based tumor vaccine therapies against both a weakly immunogenic sarcoma and a poorly immunogenic melanoma. Animals treated with the combination exhibited significantly greater protection from tumor-cell challenge, significantly greater regression of established tumors, and significantly longer mean survival time than with either TP-DC or IL-2 therapy alone. The mechanism operative in vivo appears to involve the enhancement of immune T-cell function.

Conclusion: These preclinical studies demonstrate the potential of this novel treatment strategy and support the rationale for planned phase I/II clinical trials of TP-DC-based vaccines plus IL-2 in patients with advanced melanoma and colorectal cancer.