- Boosting Abscopal Response to Radiotherapy with Sargramostim: A Review of Data and Ongoing Studies. [Review]
- CCureus 2019 Mar 19; 11(3):e4276
- Drug development in oncology today routinely focuses on approaches that utilize the patients' immune system to destroy the malignancy. Combinatorial approaches of antineoplastic agents, both new and …
Drug development in oncology today routinely focuses on approaches that utilize the patients' immune system to destroy the malignancy. Combinatorial approaches of antineoplastic agents, both new and old, are being incorporated in the armamentarium of cancer treatments. The overarching goal of therapy remains the achievement of a complete and durable response with long term remission or cure. One approach in advancing treatment is aimed at strategies that improve immunological memory to induce long lasting immunity against the tumor. Although radiation therapy has not traditionally been thought to elicit an immunological effect, an increasing number of reports document the induction of an immune response against a tumor that kills cancer cells distant to the original site of treatment after local irradiation to a tumor. This phenomenon is called an abscopal effect. Since radiation alone is rarely associated with such a response, it is being combined with immuno-oncology drugs in an attempt to enhance response. One such strategy combines sargramostim, a recombinant human granulocyte macrophage colony stimulating factor (rhu GM-CSF), with radiotherapy. GM-CSF is a cytokine secreted by multiple cells types that promotes maturation of dendritic cells and enables the presentation of tumor-associated antigens to generate a T-cell response. This review article discusses the outcomes of clinical trials and case reports examining the efficacy and safety of combining radiation therapy with this immunomodulatory agent. We will also examine future studies and challenges facing the translation of this therapeutic approach.
- Romiplostim (Nplate®) as an effective radiation countermeasure to improve survival and platelet recovery in mice. [Journal Article]
- IJInt J Radiat Biol 2019 Apr 25; :1-10
- CONCLUSIONS: A single injection of romiplostim administered 24 h after TBI is a promising radiation medical countermeasure that dramatically increased survival, with or without pegfilgrastim, and hastened PLT recovery in mice.
- Monocytopenia in clozapine-induced agranulocytosis: insights into pathophysiology and treatment. [Case Reports]
- BCBMJ Case Rep 2019 Jan 18; 12(1)
- A 26-year-old man with history of schizophrenia was admitted for neutropaenia. He was started on clozapine 3 months prior to admission. As a result he had weekly monitoring of his blood counts and on…
A 26-year-old man with history of schizophrenia was admitted for neutropaenia. He was started on clozapine 3 months prior to admission. As a result he had weekly monitoring of his blood counts and on day of admission was noted to have an absolute neutrophil count (ANC) of 450 cells/μL. He was admitted for clozapine-induced agranulocytosis. Clozapine was held and the patient was started on granulocyte colony-stimulating factor (G-CSF) filgrastim and received two doses without any signs of ANC recovery. On further review, it was noted that the absolute monocyte count (AMC) was also low and tracked with the trend of ANC. We then theorised that the impact of clozapine was on a haematopoietic precursor (colony-forming unit granulocyte-macrophage, CFU-GM) which gives rise to both monocytic and myeloid lineages. Therefore, sargramostim GM-CSF was started. After two doses, the ANC and AMC started trending up and by the third dose, both counts had fully recovered. He was discharged from the hospital and there are no plans to rechallenge with clozapine. Thus, we demonstrate a case of monocytopenia accompanying clozapine-induced agranulocytosis with successful use of GM-CSF. At least in this case, the target of the clozapine injury appears to be the CFU-GM, explaining the rapid and full response to GM-CSF after lack of response to G-CSF.
- An update on sargramostim for treatment of acute radiation syndrome. [Review]
- DTDrugs Today (Barc) 2018; 54(11):679-693
- The potential use by terrorists of an improvised nuclear device, a radiological dispersal device, or an unintended nuclear/radiological accident in heavily populated areas is a national security thre…
The potential use by terrorists of an improvised nuclear device, a radiological dispersal device, or an unintended nuclear/radiological accident in heavily populated areas is a national security threat of major consequences. Although this type of security threat is considered to be low-risk, it would have a devastating impact. Health issues would be a major concern; medical care would be necessary for all those who received considerable radiation exposure (> 1 Gy) leading to hematopoietic acute radiation syndrome (ARS). In the past few years, the U.S. Food and Drug Administration (FDA) has approved for such radiation exposure contingencies recombinant human granulocyte colony-stimulating factor (rhG-CSF, filgrastim, Neupogen), PEGylated rhG-CSF (PEGylated filgrastim, Neulasta) and granulocyte-macrophage colony-stimulating factor (rhGM-CSF, sargramostim, Leukine) following the FDA's Animal Rule guidance. In this article, we have briefly reviewed the consequences of exposure to acute, potentially lethal doses of radiation and its pathologic sequelae, as well as ARS and the latest of the FDA-approved recombinant growth factors, namely sargramostim (Leukine), as a new treatment option for the subclinical, hematopoietic syndrome component of ARS. The nature of the recombinant and the preclinical and clinical research that preceded approval by the FDA are presented, as well as its use in the treatment of victims of radiation accidents.
- Phase II study of ERC1671 plus bevacizumab versus bevacizumab plus placebo in recurrent glioblastoma: interim results and correlations with CD4+ T-lymphocyte counts. [Randomized Controlled Trial]
- COCNS Oncol 2018 07 01; 7(3):CNS22
- CONCLUSIONS: The addition of ERC1671/GM-CSF/cyclophosphamide to bevacizumab resulted in a clinically meaningful survival benefit with minimal additional toxicity.
- Comparisons of therapeutic efficacy and safety of ipilimumab plus GM-CSF versus ipilimumab alone in patients with cancer: a meta-analysis of outcomes. [Meta-Analysis]
- DDDrug Des Devel Ther 2018; 12:2025-2038
- CONCLUSIONS: These data suggested that the combination of ipilimumab and GM-CSF was associated with a significant improvement in overall survival and lower high-grade toxicities, but there is no difference in overall response rate and progression-free survival among the cancer patients. Therefore, large-scale and well-designed studies are needed to summarize and analyze the data to draw a more convincing conclusion.
- Assay system development to measure the concentration of sargramostim with high specificity in patients with autoimmune pulmonary alveolar proteinosis after single-dose inhalation. [Journal Article]
- JIJ Immunol Methods 2018; 460:1-9
- During a clinical trial of a Saccharomyces cerviciae-derived recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF), sargramostim, in patients with autoimmune pulmonary alveola…
During a clinical trial of a Saccharomyces cerviciae-derived recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF), sargramostim, in patients with autoimmune pulmonary alveolar proteinosis (aPAP), we conducted a pharmacokinetic study of single-dose sargramostim inhalation. Several problems were encountered whereby sargramostim formed an immune-complex with GM-CSF autoantibodies (GMAbs) immediately after entering the body; thus, we could not measure the concentration of sargramostim using a commercial high sensitivity enzyme-linked immunosorbent assay (ELISA). Moreover, the ELISA could not discriminate inhaled sargramostim from intrinsic GM-CSF. To solve these problems, we developed a novel ELISA system with a capture antibody that is specific for sargramostim and a detection antibody capable of binding with GM-CSF. This system quantified the serum sargramostim concentration, but not E. coli-, CHO-, or HEK293T-derived human recombinant GM-CSF. Using this system, serum pharmacokinetics were estimated in five patients after inhalation of 250 μg sargramostim, with a mean Cmax of 9.7 ± 2.85 pg/ml at a Tmax of 2 ± 1.22 h.
- Comparative efficacy and safety of immune checkpoint inhibitor-related therapies for advanced melanoma: a Bayesian network analysis. [Journal Article]
- OOncotarget 2017 Oct 13; 8(48):83637-83649
- CONCLUSIONS: Nivolumab, pembrolizumab and ipilimumab plus sargramostim might be optimum treatments for advanced melanoma because they have the most favorable balance between benefits and acceptability. Ipilimumab plus nivolumab is the most effective in prolonging PFS, but is far more toxic than nivolumab and pembrolizumab.
- Assurance of Myeloid Growth Factor Administration in an Infusion Center: Pilot Quality Improvement Initiative. [Journal Article]
- JOJ Oncol Pract 2017; 13(12):e1040-e1045
- CONCLUSIONS: The establishment of simplified and standardized processes with safety checks for error prevention increased quality of care. Lean Six Sigma methodology can be applied by other institutions to produce positive outcomes and implement similar practice changes.
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- A phase 1 trial of 90Y-Zevalin radioimmunotherapy with autologous stem cell transplant for multiple myeloma. [Clinical Trial, Phase I]
- BMBone Marrow Transplant 2017; 52(10):1372-1377
- This phase 1 study (clinical trial NCT00477815) was conducted to determine the maximum tolerated dose (MTD) of yttrium-90 ibritumomab tiuxetan (90Y-Zevalin) with high dose melphalan (HDM) therapy in …
This phase 1 study (clinical trial NCT00477815) was conducted to determine the maximum tolerated dose (MTD) of yttrium-90 ibritumomab tiuxetan (90Y-Zevalin) with high dose melphalan (HDM) therapy in multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT). In a 3+3 trial design, 30 patients received rituximab 250 mg/m2 with indium-111 ibritumomab tiuxetan (111In-Zevalin) for dosimetry (day -22); rituximab 250 mg/m2 with escalating doses of 90Y-Zevalin (day -14); melphalan 100 mg/m2 (days -2,-1) followed by ASCT (day 0) and sargramostim (GM-CSF, day 0) until neutrophil engraftment. Each patient's 111In-Zevalin dosimetry data were used to calculate the dose of 90Y-Zevalin (in mCi) to deliver 10, 12, 14, 16, 18 or 20 Gy to the liver. Dose limiting toxicities were seen in 3 patients. The overall response rate was 73% (22/30) with stringent complete response in 2 patients; complete response, 5; very good partial response, 12; and partial response, 3. The median PFS was 16.5 months and the median overall survival was 63.4 months. In MM, the MTD of 90Y-Zevalin with HDM is 18 Gy to the liver. The addition of radiation with novel delivery methods such as radioimmunotherapy combined with standard transplant regimens warrants further study.