P3, N=72, Withdrawn, Peter MacCallum Cancer Centre | Not yet recruiting --> Withdrawn

P1, N=78, Completed, CSL Behring | Recruiting --> Completed

Interim analysis of the PREACH-M trial demonstrated that GM-CSF neutralization with LENZ/AZA, for the treatment of CMML with RAS-pathway mutations resulted in 55% CR, achieved early in treatment, durability up to 18 months, thus far, and no unexpected serious adverse events. These data suggest CMML is driven by a non-redundant cytokine that responds to immunotherapy. Xu Y, Guo R, Miao M, Zhang G, Lan J, Jin J. Real-world data on efficacy and safety of azacitidine therapy in chronic myelomonocytic leukemia in China: results from a multicenter, retrospective study.

Introduction: Chronic myelomonocytic leukemia (CMML) is characterized by accumulation of classical CD14+CD16- inflammatory monocytes driven in part by hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF), a pro-inflammatory cytokine. CMML is a disorder of profound innate immune activation, driven by GM-CSF and other pro-inflammatory cytokines. Early treatment with LENZ/AZA, a precision immunotherapeutic approach, leads to a) efficacy in INNATE-1 that exceeds historical CR rates for hypomethylating agents1,2; and b) evolving efficacy in INNATE-2, in which pro-inflammatory activity is more robust. Xu Y, Guo R, Miao M, Zhang G, Lan J, Jin J. Real-world data on efficacy and safety of azacitidine therapy in chronic myelomonocytic leukemia in China: results from a multicenter, retrospective study.

The PRaG 2.0 trial demonstrates that PD-1 inhibitors in combination with SBRT/HFRT, GM-CSF, and IL-2 could be a potential treatment regimen for patients with advanced refractory solid tumors, with an acceptable benefit/risk profile.

The PRaG 2.0 trial demonstrates that PD-1 inhibitors in combination with SBRT/HFRT, GM-CSF, and IL-2 could be a potential treatment regimen for patients with advanced refractory solid tumors, with an acceptable benefit/risk profile.

The schedule of RC48-ADC was changed from once every 2 weeks to once every 3 weeks, and was still effective with significantly reduced side effects. These preliminary results suggest that PRaG3.0 regimen has a manageable safety profile and enhancing potential sensitivity in pretreated patients with HER2-expressing cancers. Clinical trial information: NCT05115500.

These results reveal the immunosuppressive mechanism of tumorous BHLHE22 and provide a potential ICT combination therapy for patients with BHLHE22 PCa.

P2, N=56, Recruiting, Xiangpan Li

Siltuximab which binds to site I of IL-6 receptor and prevents IL-6 binding to it, is not FDA approved, however used in selective tocilizumab resistance cases or as an alternative therapy (Riegler et al., 2019). Anakinra is an IL-1 receptor antagonist, which was found to improve CRS in association with tocilizumab when compared to tocilizumab alone (Jatiani et al., 2020). Lenzilumab, is a monoclonal antibody that neutralizes granulocyte-monocyte colony stimulating factor (GM CSF), was also used in preclinical studies and found to be lessening the severity of CRS without dampening CAR-T cell function (Sterner et al., 2019).Infections: The factors which increase the risk of infection in MM patients post-BCMA therapy are >3 prior lines of therapy, B-cell aplasia, infections 30-days before CAR-T, and post CAR-T lymphopenia...In most cases cytopenia would improve over a period of 12-months.Conclusion : Given the recent use of BCMA therapy in RRMM, there is no standard guideline on how to manage the complications associated with it. Larger studies with longer follow up needs to be conducted, to address the safety of the therapy for better patient outcome

Within the last year alone, the FDA approved brexu-cel for adults w/ R/R B-ALL and expanded indications for liso-cel and axi-cel to include DLBCL w/ primary refractory disease or early first relapse...Anti-cytokine therapies beyond tocilizumab (anti-IL-6R mAb) are being investigated for prevention of CRS/ICANS, including lenzilumab (anti-GM-CSF mAb) and anakinra (IL-1R antagonist)...Accordingly, we designed and initiated a pilot study of Iomab-B w/ adoptive cellular therapy (Iomab-ACT; Fig 1A).Study design and Iomab-ACT is a single-institution pilot study of Iomab-B (w/o chemotherapy) as conditioning prior to 19-28z CAR-T in adults w/ R/R B-ALL or DLBCL (NCT04512716)...Unexpected toxicity (given low dose of ARC) observed in 1 pt included severe trilineage cytopenias lasting >8 wks (requiring RBC/PLT transfusion support, G-CSF, romiplostim) w/o marrow hypoplasia and w/o other apparent neoplastic or drug-induced etiology; this met criteria for dose-limiting toxicity and we will monitor in the next 3 pts...Key exploratory objectives include describing changes in circulating immune cells following ARC and 19-28z CAR T-cells w/spectral cytometry using a custom antibody panel (Fig 1B) and cytokine levels in cerebrospinal fluid. We hope to generate preliminary data to guide further study of CD45-targeted ARCs prior to CAR-T and other forms of adoptive cellular therapy.

All pts underwent lymphodepletion with cyclophosphamide 500 mg/m2/day and fludarabine 30 mg/m2/day before a single infusion of axi-cel at a target dose of 2 × 106 cells/kg. Conclusions No new safety signals or DLTs were observed in pts treated with axi-cel plus lenzilumab. Addition of lenzilumab to the axi-cel regimen appeared to dose-dependently suppress the GM-CSF axis and reduce markers of systemic inflammation.

In vitro, MDSCs were treated with PLY (0.67, 2 and 6 μM) or solcitinib (10 μM, positive control) for 48 or 96 h, and their proliferation, expansion, and differentiation into M-MDSCs were examined by flow cytometry...In mice, PLY (40 mg/kg) treatment alleviated EAE and inhibited inflammatory infiltration, demyelination, and MDSCs and Th17 cells infiltration into the spinal cord. PLY may be an excellent candidate for the treatment of MS and other autoimmune diseases.

Our preliminary results suggest that the PRaG regimen could improve clinical outcomes in mCRC patients with MSS/pMMR with acceptable toxicity. Radiotherapy could have radiosensitization effect on immunotherapy of mCRC with MSS/pMMR.

The treatment model of large split radiotherapy and PD-1 inhibitor and GM-CSF combined with or without IL-2 (PRaG treatment) was tolerable in terms of toxic side effects, and better clinical efficacy was observed. The Bragg treatment modality is expected to be a salvage treatment for patients with refractory advanced metastatic non-small cell lung cancer after failure of standard therapy and is expected to be a re-challenge regimen after failure of PD-1/PD-L1 inhibitor therapy.

The PRaG3.0 regimen is tolerated with acceptable toxicity. Our data suggest the PRaG3.0 regimen further improve the synergistic antitumor effects, this precise paradigm may provide a promising salvage treatment of HER2-expressing advanced solid tumors. This trial is registered with ClinicalTrials.gov, No.

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.

Taken together, these results indicated that CSF2 may regulate the phenotypic plasticity of SCLC through the phosphorylated STAT3/MYC pathway, thereby limiting the transformation between cell clones with different phenotypes and changing the sensitivity of specific cell clones to targeted drugs. Targeting CSF2 may be a potential therapeutic strategy to overcome drug resistance in SCLC treatment by influencing ITH.

The PRaG3.0 regimen manifested manageable safety profile and encouraging efficacy. So PRaG3.0 regimen is considered as a promising salvage treatment for patients with HER2-expressing advanced solid tumors. And the conclusion should be validated in more patients subsequently.

Given that GM-CSF was no more effective than Salt and Soda mouthwash for the prevention or treatment of OM, the readily available and cheaper mouthwash can be used at considerable cost savings.

GM-CSF modulates immune cells including monocytes and the innate immune response and has demonstrated safety and prolonged survival (OS) in combination with ipilimumab in melanoma. The combination of PEM plus GM-CSF was safe and well-tolerated with higher ORR than expected for PEM monotherapy in a predominantly MSS ABC population but did not meet target ORR threshold for efficacy. ORR and median PFS and OS were highest in patients with underlying HBV or HCV infection. Immune profiling of on-treatment biopsies and peripheral blood are ongoing to ascertain influence of both PEM and GM-CSF on circulating and tumor immune microenvironment.

Antigen specific T cells recognizing BCG, HY and PSA were identified. Thus, fewer intravesical instillations, with high dose BCG Tokyo or low dose BCG Tokyo with GMCSF + IFNα gene therapy, can induce effective systemic immunity.

In breast cancer patients, HIST1H1B expression is positively correlated with large tumor size, high grade, metastasis and poor survival. HIST1H1B contributes to basal-like breast cancer progression by modulating CSF2 expression, indicating a potential prognostic marker and therapeutic target for this disease.

Having demonstrated that GM-CSFRα is significantly upregulated on stimulated CART19 cells, we aimed to determine the impact of GM-CSF neutralization (clinical-grade anti-GM-CSF antibody, lenzilumab, 10 µg/mL) versus GM-CSFRα blockade (research-grade antibody, 10 µg/mL) on CART19 cell function and CART cell-monocyte interactions...In summary, our findings indicate significant differences on CART cell functions and CART cell-monocyte interactions when a specific cytokine, GM-CSF, is neutralized compared to blocking its receptor. Further mechanistic studies are ongoing to assess the functions of GM-CSFRα k/o and GM-CSF k/o CART cells.

All three approved CD19-directed CAR-T therapies (axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel) are associated with toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) that can be severe, resulting in non-relapse mortality, ICU admission, and significant non-drug related health resource utilization which represent barriers to access and adoption (Nabhan, et al...Blood 2016), which helps explain why the prophylactic administration of tocilizumab is not effective in reducing the overall incidence of CRS or ICANS, as this cytokine is downstream in the inflammatory cascade...Secondary endpoints include incidence of all grades and grade > 3 CRS and/or ICANS, respectively; ORR and CR at 1, 3, 6, 12 months; durability of CR; progression-free survival, overall survival and health related quality of life using validated patient reported outcome measures. In addition, the study will explore the CRS and ICANS grading criteria that have been utilized with each of the approved CAR-Ts.

Triple combination of XX, SBRT and GM-CSF is safe and shows promising efficacy as a novel second-line treatment for advanced EGFR/ALK negative NSCLC. The trial continues to recruit participants.

Triple combination of XX, SBRT and GM-CSF is safe and shows promising efficacy as a novel second-line treatment for advanced EGFR/ALK negative NSCLC. The trial continues to recruit participants.

We describe the disease burden and signal characteristics on MRI and correlate with the response reported in the patients' medical records. Given that the use of pexidartinib and other CSF inhibitors is likely to increase, musculoskeletal radiologists should be aware of this novel non-operative treatment and the MRI appearance of diffuse TSGCT during therapy.

Sintilimab, SBRT and GM-CSF for advanced NSCLC is safe with manageable TRAEs and the trial continues to recruit participants. Trial registration ClinicalTrials.gov, NCT04106180. Registered 26 September 2019, SBRT in Combination With Sintilimab and GM-CSF for the Treatment of Advanced NSCLC-Tabular View-ClinicalTrials.gov.

One patient suffered an exacerbation of GVHD. The 24-month relapse-free and overall survivals were 47 and 57%, respectively, with a median of 18.6 and 29 months.

There was a significant difference in the upregulation of sTRAIL and TNF-α level indicated by the increased annexin V, caspase-3, and caspase-8 expression binding between groups (p<0.05). MSCs Secretome and CSF-2 could significantly increase the activity of PBMCs through the improvement of sTRAIL and TNF-α levels which could lead to the escalation of OS-SCs apoptosis through an enhanced expression of caspase 3, caspase 8 and annexin V binding in vitro.

Consolidation with naxitamab and GM-CSF resulted in excellent survival rates for HR-NB patients in CR.

The combination therapy of radiotherapy and GM-CSF (200 µg subcutaneously q.o.d) is tolerable and safe. Further studies are warranted to confirm the effects and optimal total GM-CSF injection doses in the combination of radiotherapy in thoracic cancer patients.

While supportive care with red blood cell transfusions, erythropoiesis-stimulating agents, and iron chelation remains the mainstay of therapy for lower-risk (LR)-MDS patients, luspatercept has recently been approved for transfusion-dependent anemic LR-MDS patients ending a decade without any new drug approvals for MDS...For those patients, the hypomethylating agents (HMA) azacitidine and decitabine remain standard of care with azacitidine being the only agent that has shown an overall survival benefit in randomized trials. Although early results from novel molecularly driven agents such as IDH1/2 inhibitors, venetoclax, magrolimab, and APR-246 for MDS as well as tagraxofusp, tipifarnib, and lenzilumab for CMML appear encouraging, confirmatory randomized trials must be completed to fully assess their safety and efficacy prior to routine clinical use. Herein, we review the current management of MDS and CMML and conclude with a critical appraisal of novel therapies and general trends in this field.

P2, N=72, Not yet recruiting, South Australian Health & Medical Research Institute Ltd

Furthermore, higher intratumoral B7-H4 neutrophil percentage/number was found in GC patients with advanced tumor node metastasis stage and reduced overall survival following surgery. Our results illuminate a novel regulating mechanism of B7-H4 expression on tumor-activated neutrophils in GC, suggesting that functional inhibition of these novel GM-CSF-B7-H4 pathways may be a suitable therapeutic strategy to treat the immune tolerance feature of GC.

There was insignificant difference of STAT-3 epxression and IL-2 level between groups (P > 0.05). The co-cultivation of OS-MSCs and PBMSCs activated using secretome and GMCSF has a great ability to enhance OS-MSCs apoptosis.

P3, N=2282, Recruiting, Peter MacCallum Cancer Centre, Australia | Not yet recruiting --> Recruiting

hGMR-CAR T cells did not exert overt organ toxicities such as bone marrow suppression, monocytopenia and vasculitis, although they recognised and killed cynomolgus monocytes and macrophages in vitro. Although our model did not simulate a tumor-bearing model, it supports the safety of hGMR-CAR T cells and demonstrates the usefulness of a non-human primate model to evaluate the safety of T-cell products by assessing off-tumor/off-target toxicity before clinical trials.