A Phase Ib/II trial of granulocyte‐macrophage−colony stimulating factor and interleukin‐2 for renal cell carcinoma patients with pulmonary metastases

Hotton, Kirsten M.; Khorsand, Masoud; Hank, Jacquelyn A.; Albertini, Mark R.; Kim, Kyung Mann; Wilding, George; Salamat, M. Shahriar; Larson, Marilyn; Sondel, Paul M.; Schiller, Joan H.

doi:10.1002/(sici)1097-0142(20000415)88:8<1892::aid-cncr19>3.3.co;2-u

Cited by 4 publications

(5 citation statements)

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“…Moreover, GM-CSF blockade abolishes monocyte infiltration in the brain from APP/PS1 mice [58]. Also, GM-CSF administration in a phase Ib/II clinical trial on renal cell carcinoma has been associated with acute multifocal cerebral venous thrombosis and subdural and subarachnoid hemorrhage [63]. Since diabetes also affects vascular integrity and blood-brain barrier [64], it is feasible that the increased spontaneous central bleeding observed in APP/PS1xdb/db mice [17,31] is related, at least in part, to GM-CSF-glucose association.…”

Section: Discussionmentioning

confidence: 99%

Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer’s mouse model

Sankar

Infante-Garcia

Weinstock

et al. 2020

J Neuroinflammation

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Background: Diabetes is a risk factor for developing Alzheimer's disease (AD); however, the mechanism by which diabetes can promote AD pathology remains unknown. Diabetes results in diverse molecular changes in the brain, including dysregulation of glucose metabolism and loss of cerebrovascular homeostasis. Although these changes have been associated with increased Aβ pathology and increased expression of glial activation markers in APPswe/ PS1dE9 (APP/PS1) mice, there has been limited characterization, to date, of the neuroinflammatory changes associated with diabetic conditions. Methods: To more fully elucidate neuroinflammatory changes associated with diabetes that may drive AD pathology, we combined the APP/PS1 mouse model with either high-fat diet (HFD, a model of pre-diabetes), the genetic db/db model of type 2 diabetes, or the streptozotocin (STZ) model of type 1 diabetes. We then used a multiplexed immunoassay to quantify cortical changes in cytokine proteins. Results: Our analysis revealed that pathology associated with either db/db, HFD, or STZ models yielded upregulation of a broad profile of cytokines, including chemokines (e.g., MIP-1α, MIP-1β, and MCP-1) and proinflammatory cytokines, including IL-1α, IFN-γ, and IL-3. Moreover, multivariate partial least squares regression analysis showed that combined diabetic-APP/PS1 models yielded cooperatively enhanced expression of the cytokine profile associated with each diabetic model alone. Finally, in APP/PS1xdb/db mice, we found that circulating levels of Aβ1-40, Aβ1-42, glucose, and insulin all correlated with cytokine expression in the brain, suggesting a strong relationship between peripheral changes and brain pathology. Conclusions: Altogether, our multiplexed analysis of cytokines shows that Alzheimer's and diabetic pathologies cooperate to enhance profiles of cytokines reported to be involved in both diseases. Moreover, since many of the identified cytokines promote neuronal injury, Aβ and tau pathology, and breakdown of the blood-brain barrier, our data suggest that neuroinflammation may mediate the effects of diabetes on AD pathogenesis. Therefore, strategies targeting neuroinflammatory signaling, as well as metabolic control, may provide a promising strategy for intervening in the development of diabetes-associated AD.

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Section: Discussionmentioning

confidence: 99%

Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer’s mouse model

Sankar

Infante-Garcia

Weinstock

et al. 2020

J Neuroinflammation

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“…A combination of factors inherent to the biology of tumor and the treatment of these patients are likely to account for this form of hypercoagulability. The spectrum of such factors may include: increased ability of these cancers to invade adjacent major vessels; high potential for local and distant metastases; secretion of cancer procoagulant and, thrombogenic effect of chemotherapy and of other agents used in the treatment of these malignancies (5,(21)(22)(23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

Venous Thrombosis in Patients with Solid Tumors: Determination of Frequency and Characteristics

Sallah¹,

Wan²,

Nguyen³

2002

Thromb Haemost

355

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SummaryDeep venous thrombosis (DVT) and pulmonary embolism (PE) are well recognized complications of cancer. However, our current knowledge of this association is derived from studies conducted more than a decade ago. In light of the changes in medical practice and the improvement in cancer care in recent years, a re-evaluation of the relationship between malignancy and venous thrombosis is in order. Of a total of 1041 patients with solid tumors admitted to 3 major medical centers, there were 81 (7.8%) diagnosed with DVT/PE. Patients were more likely to develop DVT/PE during chemotherapy (p = .0001). Advanced malignancies (p = .001), renal carcinoma (p = .005), pancreatic (p = .001), gastric (p = .014) and brain tumors (p = .001) were independent variables strongly associated with the occurrence of venous thrombosis. The occurrence of thrombotic events in the population tested in this study did not adversely affect survival (p = .082).The study identifies subset of patients with cancer at high risk for venous thrombosis. Early prophylaxis with anticoagulants in these patients may be warranted. Most importantly, further clinical trials are desperately awaited to detect possible new trends in the frequency and types of thrombotic events and to better define prevention strategies in cancer patients at risk for thrombosis.The association between venous thromboembolic disease (VTD) and malignant neoplastic disorders is well known and has been the subject of several reports for more than a century (1–8). There is a general agreement among investigators that thrombotic complications in patients with cancer occur at a rather high frequency, and that other circumstantial factors such as surgery or chemotherapy potentiates this risk (9,10). However, several important considerations pertaining to cancer and thrombosis continue to be shrouded in controversy. For example, there are inexplicable differences in the proportion of patients with cancer diagnosed with deep venous thrombosis (DVT) or pulmonary embolism (PE) reported in the literature (2, 4, 5, 11). In the absence of large well-controlled studies, one may only postulate on the reasons that contributed to these differences. The inclusion of different types of VTD such as superficial, venous, arterial or vascular access device-induced thrombosis may have led to overestimation of the incidence of these events in patients with underlying malignancy. Another possible explanation for this discrepancy relates to the use of a variety of diagnostic and methodological criteria ranging from observation and clinical suspicion to more invasive procedures resulting in considerable differences in the rate of reported clotting events (12). Along the same line of discussion, one may argue whether VTD is a random event or constitutes a complication that occurs more commonly in patients with distinct characteristics and certain tumor types. To further investigate the association between malignancy and thrombosis, we evaluated 1041 patients with solid tumors for the risk of DVT/PE. The main objectives of the study were to determine the frequency of DVT/PE based on validated diagnostic criteria and to identify patients with cancer at high risk for developing these thrombotic episodes. Also, we evaluated the impact of VTD on the survival of these patients.

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“…The primary objective of this study was to evaluate the tolerability of combining hu14.18-IL2 with GM-CSF and isotretinoin in a schedule similar to the way dinutuximab is now given to high-risk neuroblastoma patients for minimal residual disease maintenance therapy as per the completed Children's Oncology Group Phase III trial ANBL0032 (8).We knew there may be risk of increased neurologic toxicity because of DLT seen in a phase Ib/II study where GM-CSF and IL2 were given concurrently to adults with renal cell cancer (18,19). For this reason, similar to what was tolerable in the renal cell carcinoma study, we dosed GM-CSF and the immunocytokine sequentially and did not see any grade 3 or 4 neurologic toxicities in this neuroblastoma trial.…”

Section: Discussionmentioning

confidence: 99%

“…GM-CSF was not given concurrently with Hu14.18-IL2 due to concern of neurotoxicity seen in a prior study when GM-CSF and IL2 were given concurrently (but not seen when IL2 and GM-CSF were given sequentially; refs. 18,19).…”

Section: Protocol Therapymentioning

confidence: 99%

Antitumor Activity and Tolerability of hu14.18-IL2 with GMCSF and Isotretinoin in Recurrent or Refractory Neuroblastoma: A Children's Oncology Group Phase II Study

Shusterman

Naranjo

Ryn

et al. 2019

Clinical Cancer Research

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Purpose: Combining anti-GD2 (disialoganglioside) mAb with GM-CSF, IL2, and isotretinoin is now FDA-approved for high-risk neuroblastoma minimal residual disease (MRD) therapy. The humanized anti-GD2 antibody conjugated to IL2 (hu14.18-IL2) has clinical activity in neuroblastoma and is more effective in neuroblastoma-bearing mice than antibody and cytokine given separately. We therefore evaluated the safety, tolerability, and antitumor activity of hu14.18-IL2 given with GM-CSF and isotretinoin in a schedule similar to standard MRD therapy.Patients and Methods: Hu14.18-IL2 was given at the recommended phase II dose of 12 mg/m 2 /day on days 4-6 of a 28-day cycle with GM-CSF (250 mg/m 2 /dose, days 1-2 and 8-14) and isotretinoin (160 mg/m 2 /day, days 11-25). Tolerability was determined on the basis of the number of unacceptable toxicities observed. Response was evaluated separately for patients with disease measurable by standard radiologic criteria (stratum 1), and for patients with disease evaluable only by I 123 -metaiodobenzylguanidine (I 123 -MIBG) scan and/or bone marrow histology (stratum 2).Results: Fifty-two patients with recurrent or refractory neuroblastoma were enrolled; 51 were evaluable for toxicity and 45 were evaluable for response. Four patients had unacceptable toxicities, well below the protocol-defined rule for tolerability. Other grade 3 and 4 nonhematologic toxicities were expected and reversible. No responses were seen in stratum 1 (n ¼ 14). In stratum 2 (n ¼ 31), 5 objective responses were confirmed by central review (3 complete, 2 partial).Conclusions: Hu14.18-IL2 given in combination with GM-CSF and isotretinoin is safe and tolerable. Patients with MIBG and/or bone marrow-only disease had a 16.1% response rate, confirming activity of the combination.

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A Phase Ib/II trial of granulocyte‐macrophage−colony stimulating factor and interleukin‐2 for renal cell carcinoma patients with pulmonary metastases

Cited by 4 publications

References 0 publications

Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer’s mouse model

Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer’s mouse model

Venous Thrombosis in Patients with Solid Tumors: Determination of Frequency and Characteristics

Antitumor Activity and Tolerability of hu14.18-IL2 with GMCSF and Isotretinoin in Recurrent or Refractory Neuroblastoma: A Children's Oncology Group Phase II Study

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