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.

Clinical Characteristics and Outcomes of COVID-19 in Pediatric and Early Adolescent and Young Adult Hematopoietic Stem Cell Transplant Recipients: A Cohort Study.

Adult hematopoietic stem cell transplantation (HSCT) recipients are at a high risk of adverse outcomes after COVID-19. Although children have had better outcomes after COVID-19 compared to adults, data on risk factors and outcomes of COVID-19 among pediatric HSCT recipients are lacking. We describe outcomes of HSCT recipients who were ≤21 years of age at COVID-19 diagnosis and were reported to the Center for International Blood and Marrow Transplant Research between March 27, 2020, and May 7, 2021. The primary outcome was overall survival after COVID-19 diagnosis. We determined risk factors of COVID-19 as a secondary outcome in a subset of allogeneic HSCT recipients. A total of 167 pediatric HSCT recipients (135 allogeneic; 32 autologous HSCT recipients) were included. Median time from HSCT to COVID-19 was 15 months (interquartile range [IQR] 7-45) for allogeneic HSCT recipients and 16 months (IQR 6-59) for autologous HSCT recipients. Median follow-up from COVID-19 diagnosis was 53 days (range 1-270) and 37 days (1-179) for allogeneic and autologous HSCT recipients, respectively. Although COVID-19 was mild in 87% (n = 146/167), 10% (n = 16/167) of patients required supplemental oxygen or mechanical ventilation. The 45-day overall survival was 95% (95% confidence interval [CI], 90-99) and 90% (74-99) for allogeneic and autologous HSCT recipients, respectively. Cox regression analysis showed that patients with a hematopoietic cell transplant comorbidity index (HCT-CI) score of 1-2 were more likely to be diagnosed with COVID-19 (hazard ratio 1.95; 95% CI, 1.03-3.69, P = .042) compared to those with an HCT-CI of 0. Pediatric and early adolescent and young adult HSCT recipients with pre-HSCT comorbidities were more likely to be diagnosed with COVID-19. Overall mortality, albeit higher than the reported general population estimates, was lower when compared with previously published data focusing on adult HSCT recipients.

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.