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

Lazarus, Hillard M.; Ragsdale, Carolyn; Gale, Robert Peter; Lyman, Gary H.

doi:10.3389/fimmu.2021.706186

Cited by 35 publications

(40 citation statements)

References 144 publications

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“…Radiotherapy may cause multiple pro-immunogenic changes within the TME, which convert cancer into an in-situ vaccine via releasing abundant levels of tumor-derived antigens, and GM-CSF was often used as a vaccine adjuvant (24,25). GM-CSF can also enhance the antigen presentation by promoting the differentiation and activation of monocytes/M1 macrophages and DCs (26,27).…”

Section: Discussionmentioning

confidence: 99%

PD-1 Inhibitor Combined With Radiotherapy and GM-CSF (PRaG) in Patients With Metastatic Solid Tumors: An Open-Label Phase II Study

Kong

Zhao

et al. 2022

Front. Immunol.

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Patients with metastatic cancer refractory to standard systemic therapies have a poor prognosis and few therapeutic options. Radiotherapy can shape the tumor microenvironment (TME) by inducing immunogenic cell death and promoting tumor recognition by natural killer cells and T lymphocytes. Granulocyte macrophage-colony stimulating factor (GM-CSF) was known to promote dendric cell maturation and function, and might also induce the macrophage polarization with anti-tumor capabilities. A phase II trial (ChiCTR1900026175) was conducted to assess the clinical efficacy and safety of radiotherapy, PD-1 inhibitor and GM-CSF (PRaG regimen). This trial was registered at http://www.chictr.org.cn/index.aspx. A PRaG cycle consisted of 3 fractions of 5 or 8 Gy delivered for one metastatic lesion from day 1, followed by 200 μg subcutaneous injection of GM-CSF once daily for 2 weeks, and intravenous infusion of PD-1 inhibitor once within one week after completion of radiotherapy. The PRaG regimen was repeated every 21 days for at least two cycles. Once the PRaG therapy was completed, the patient continued PD-1 inhibitor monotherapy until confirmed disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). A total of 54 patients were enrolled with a median follow-up time of 16.4 months. The ORR was 16.7%, and the disease control rate was 46.3% in intent-to-treat patients. Median progression-free survival was 4.0 months (95% confidence interval [CI], 3.3 to 4.8), and median overall survival was 10.5 months (95% CI, 8.7 to 12.2). Grade 3 treatment-related adverse events occurred in five patients (10.0%) and grade 4 in one patient (2.0%). Therefore, the PRaG regimen was well tolerated with acceptable toxicity and may represent a promising salvage treatment for patients with chemotherapy-refractory solid tumors. It is likely that PRaG acts via heating upthe TME with radiotherapy and GM-CSF, which was further boosted by PD-1 inhibitors.

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Section: Discussionmentioning

confidence: 99%

PD-1 Inhibitor Combined With Radiotherapy and GM-CSF (PRaG) in Patients With Metastatic Solid Tumors: An Open-Label Phase II Study

Kong

Zhao

et al. 2022

Front. Immunol.

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“…In patients receiving chemotherapy for solid tumors, sargramostim (GM-CSF) has been shown to be beneficial as an immunostimulatory adjuvant to elicit antitumor immunity, and improve the overall condition of the patient ( 94 ). Subcutaneous administration of GM-CSF at a dose of 125 μg/m 2 for 14 days in different cycles for a year has been shown to prolong survival by two years in patients with surgically resected stage III/IV melanoma in comparison to patients who did not receive GM-CSF ( 95 , 96 ).…”

Section: Gm-csf Drives Both Tumor Suppression and Tumor Progressionmentioning

confidence: 99%

GM-CSF: A Double-Edged Sword in Cancer Immunotherapy

et al. 2022

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that drives the generation of myeloid cell subsets including neutrophils, monocytes, macrophages, and dendritic cells in response to stress, infections, and cancers. By modulating the functions of innate immune cells that serve as a bridge to activate adaptive immune responses, GM-CSF globally impacts host immune surveillance under pathologic conditions. As with other soluble mediators of immunity, too much or too little GM-CSF has been found to promote cancer aggressiveness. While too little GM-CSF prevents the appropriate production of innate immune cells and subsequent activation of adaptive anti-cancer immune responses, too much of GM-CSF can exhaust immune cells and promote cancer growth. The consequences of GM-CSF signaling in cancer progression are a function of the levels of GM-CSF, the cancer type, and the tumor microenvironment. In this review, we first discuss the secretion of GM-CSF, signaling downstream of the GM-CSF receptor, and GM-CSF’s role in modulating myeloid cell homeostasis. We then outline GM-CSF’s anti-tumorigenic and pro-tumorigenic effects both on the malignant cells and on the non-malignant immune and other cells in the tumor microenvironment. We provide examples of current clinical and preclinical strategies that harness GM-CSF’s anti-cancer potential while minimizing its deleterious effects. We describe the challenges in achieving the Goldilocks effect during administration of GM-CSF-based therapies to patients with cancer. Finally, we provide insights into how technologies that map the immune microenvironment spatially and temporally may be leveraged to intelligently harness GM-CSF for treatment of malignancies.

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“…, sargramostim) that orchestrate the immune system and behaviors of immune cells for optimal host immune response to different pathogens may be beneficial in improving outcomes for many patients ( 58 , 61 , 62 , 64 , 65 ). While the hematopoietic growth factor rhu G-CSF (discussed in the Introduction ) is more widely prescribed and comprises more than 95% of recombinant growth factor use, its use in infection has not demonstrated a mortality benefit in pneumonia when used in combination with antibiotic therapy ( 1 , 4 , 5 , 143 ). G-CSF recruits and increases the number of neutrophils, whereas GM-CSF orchestrates the behavior of many innate and adaptive immune cells to combat pathogens while avoiding an overwhelming systemic response ( 4 , 5 ).…”

Section: Immune Responses To Infections and Risk Of Gm-csf Insufficiencymentioning

confidence: 99%

“…Granulocyte-macrophage colony-stimulating factor (GM-CSF) was identified in the 1960s as a myeloid growth factor, purified in the 1970s, molecularly-cloned in the 1980s, and clinically developed in the 1990s ( 1 ). Sargramostim (Leukine ® ; Partner Therapeutics, Inc., Lexington, MA) is a glycosylated, yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF), FDA-approved for 6 disease indications based on its safe and efficacious hematopoietic growth factor function, differing from human GM-CSF by one amino acid at position 23, where leucine is substituted for arginine ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

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

Lazarus

Pitts²,

Wang

et al. 2023

Front. Immunol.

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IntroductionEndogenous 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.MethodsWe 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.ResultsWe 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.DiscussionWe 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.

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

Cited by 35 publications

References 144 publications

PD-1 Inhibitor Combined With Radiotherapy and GM-CSF (PRaG) in Patients With Metastatic Solid Tumors: An Open-Label Phase II Study

PD-1 Inhibitor Combined With Radiotherapy and GM-CSF (PRaG) in Patients With Metastatic Solid Tumors: An Open-Label Phase II Study

GM-CSF: A Double-Edged Sword in Cancer Immunotherapy

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

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