GM-CSF, G-CSF or no cytokine therapy with anti-GD2 immunotherapy for high-risk neuroblastoma.

Colony-stimulating factors have been shown to improve anti-disialoganglioside 2 (anti-GD2) monoclonal antibody response in high-risk neuroblastoma by enhancing antibody-dependent cell-mediated cytotoxicity (ADCC). A substantial amount of research has focused on recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant to anti-GD2 monoclonal antibodies. There may be a disparity in care among patients as access to GM-CSF therapy and anti-GD2 monoclonal antibodies is not uniform. Only select countries have approved these agents for use, and even with regulatory approvals, access to these agents can be complex and cost prohibitive. This comprehensive review summarizes clinical data regarding efficacy and safety of GM-CSF, recombinant human granulocyte colony-stimulating factor (G-CSF) or no cytokine in combination with anti-GD2 monoclonal antibodies (ie, dinutuximab, dinutuximab beta or naxitamab) for immunotherapy of patients with high-risk neuroblastoma. A substantial body of clinical data support the immunotherapy combination of anti-GD2 monoclonal antibodies and GM-CSF. In contrast, clinical data supporting the use of G-CSF are limited. No formal comparison between GM-CSF, G-CSF and no cytokine has been identified. The treatment of high-risk neuroblastoma with anti-GD2 therapy plus GM-CSF is well established. Suboptimal efficacy outcomes with G-CSF raise concerns about its suitability as an alternative to GM-CSF as an adjuvant in immunotherapy for patients with high-risk neuroblastoma. While programs exist to facilitate obtaining GM-CSF and anti-GD2 monoclonal antibodies in regions where they are not commercially available, continued work is needed to ensure equitable therapeutic options are available globally.

Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor (rhu GM-CSF) as Adjuvant Therapy for Invasive Fungal Diseases.

Background: Sargramostim (yeast-derived, glycosylated recombinant human granulocyte-macrophage colony-stimulating factor [rhu GM-CSF]) augments innate and adaptive immune responses and accelerates hematopoietic recovery of chemotherapy-induced neutropenia. However, considerably less is known about its efficacy as adjunctive immunotherapy against invasive fungal diseases (IFDs). Methods: The clinical courses of 15 patients with pediatric malignancies and IFDs treated adjunctively with sargramostim at a single institution were analyzed in a retrospective cohort review. Further, a systematic review of published reports of rhu GM-CSF for IFDs was also conducted. Results: Among 65 cases, 15 were newly described pediatric patients and 50 were previously published cases of IFDs treated with rhu GM-CSF. Among the newly reported pediatric patients, IFDs were caused by Candida spp., Trichosporon sp., and molds (Aspergillus spp., Rhizopus sp., Lichtheimia sp., and Scedosporium sp). Twelve (80%) were neutropenic at baseline, and 12 (80%) were refractory to antifungal therapy. Among 12 evaluable patients, the overall response rate was 92% (8 [67%] complete responses, 3 [25%] partial responses, and 1 [8%] stable). Treatment is ongoing in the remaining 3 patients. Among 50 published cases (15 Candida spp., 13 Mucorales, 11 Aspergillus spp., 11 other organisms), 20 (40%) had baseline neutropenia and 36 (72%) were refractory to standard therapy before rhu GM-CSF administration. Consistent with responses in the newly reported patients, the overall response rate in the literature review was 82% (40 [80%] complete responses, 1 [2%] partial response, and 9 [18%] no response). Conclusions: Sargramostim may be a potential adjunctive immunomodulator for selected patients with hematological malignancies and refractory IFDs.

Recombinant GM-CSF for diseases of GM-CSF insufficiency: Correcting dysfunctional mononuclear phagocyte disorders.

Introduction: Endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of myeloid cells, is now known to support maturation and maintain the metabolic capacity of mononuclear phagocytes including monocytes, macrophages, and dendritic cells. These cells sense and attack potential pathogens, present antigens to adaptive immune cells, and recruit other immune cells. Recombinant human (rhu) GM-CSF (e.g., sargramostim [glycosylated, yeast-derived rhu GM-CSF]) has immune modulating properties and can restore the normal function of mononuclear phagocytes rendered dysfunctional by deficient or insufficient endogenous GM-CSF. Methods: We reviewed the emerging biologic and cellular effects of GM-CSF. Experts in clinical disease areas caused by deficient or insufficient endogenous GM-CSF examined the role of GM-CSF in mononuclear phagocyte disorders including autoimmune pulmonary alveolar proteinosis (aPAP), diverse infections (including COVID-19), wound healing, and anti-cancer immune checkpoint inhibitor therapy. Results: We discuss emerging data for GM-CSF biology including the positive effects on mitochondrial function and cell metabolism, augmentation of phagocytosis and efferocytosis, and immune cell modulation. We further address how giving exogenous rhu GM-CSF may control or treat mononuclear phagocyte dysfunction disorders caused or exacerbated by GM-CSF deficiency or insufficiency. We discuss how rhu GM-CSF may augment the anti-cancer effects of immune checkpoint inhibitor immunotherapy as well as ameliorate immune-related adverse events. Discussion: We identify research gaps, opportunities, and the concept that rhu GM-CSF, by supporting and restoring the metabolic capacity and function of mononuclear phagocytes, can have significant therapeutic effects. rhu GM-CSF (e.g., sargramostim) might ameliorate multiple diseases of GM-CSF deficiency or insufficiency and address a high unmet medical need.

Sargramostim (rhu GM-CSF) as Cancer Therapy (Systematic Review) and An Immunomodulator. A Drug Before Its Time?

BACKGROUND: Sargramostim [recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF)] was approved by US FDA in 1991 to accelerate bone marrow recovery in diverse settings of bone marrow failure and is designated on the list of FDA Essential Medicines, Medical Countermeasures, and Critical Inputs. Other important biological activities including accelerating tissue repair and modulating host immunity to infection and cancer via the innate and adaptive immune systems are reported in pre-clinical models but incompletely studied in humans. OBJECTIVE: Assess safety and efficacy of sargramostim in cancer and other diverse experimental and clinical settings. METHODS AND RESULTS: We systematically reviewed PubMed, Cochrane and TRIP databases for clinical data on sargramostim in cancer. In a variety of settings, sargramostim after exposure to bone marrow-suppressing agents accelerated hematologic recovery resulting in fewer infections, less therapy-related toxicity and sometimes improved survival. As an immune modulator, sargramostim also enhanced anti-cancer responses in solid cancers when combined with conventional therapies, for example with immune checkpoint inhibitors and monoclonal antibodies. CONCLUSIONS: Sargramostim accelerates hematologic recovery in diverse clinical settings and enhances anti-cancer responses with a favorable safety profile. Uses other than in hematologic recovery are less-well studied; more data are needed on immune-enhancing benefits. We envision significantly expanded use of sargramostim in varied immune settings. Sargramostim has the potential to reverse the immune suppression associated with sepsis, trauma, acute respiratory distress syndrome (ARDS) and COVID-19. Further, sargramostim therapy has been promising in the adjuvant setting with vaccines and for anti-microbial-resistant infections and treating autoimmune pulmonary alveolar proteinosis and gastrointestinal, peripheral arterial and neuro-inflammatory diseases. It also may be useful as an adjuvant in anti-cancer immunotherapy.