An in vivo model to evaluate donor-dependent cytokine release in response to single-agent or combination immune-oncology therapies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3114-3114
Author(s):  
Kyle Draheim ◽  
Jing Jiao ◽  
Jiwon Yang ◽  
Danying Cai ◽  
Mingshan Cheng ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Tumor Burden ◽  
Cytokine Release ◽  
Humanized Mouse ◽  
Human Pbmc ◽  
Immune Oncology

3114 Background: Although immune-oncology therapies such as checkpoint inhibitor, bi-specific antibody and CAR-T cell therapies are successfully used for cancer therapy, they can have very severe adverse effects such as cytokine release syndrome (CRS). The animal models and in vitro human PBMC assays presently in use do not reliably predict CRS in patients. Currently, the only widely accepted predictors of CRS are cancer burden and therapeutic dose. Despite this, most pre-clinical assays that evaluate CRS do not incorporate cancer cells and the safety of drug combinations has not been widely explored. A predictive assay that identifies patient/cancer/therapy combinations at risk for developing CRS upfront in addition to treatment efficacy would improve the safety of immune-oncology drug development. Methods: We have developed sensitive in vivo humanized mouse models for quantitating CRS that are rapid, reproducible and able to show variation among PBMC donors. The NSG mouse and its derivatives are engrafted with cancer cells and human PBMCs. Mice are then dosed with checkpoint inhibitors or bi-specific antibodies as a single therapy or in combination. Cytokine release is evaluated 2-6 hours post dosing. This assay can be modified to also evaluate efficacy by using luciferase labeled cancer cells and monitoring tumor burden using the Xenogen IVIS imaging system. Results: For all therapy groups, each cytokine tested (including human IFN-γ, IL-2, IL-6, IL-10 and TNF) was upregulated 2-6 hours after drug treatment, but different PBMC donors had various cytokines release levels. Cytokine release levels correlated with a dose response, PBMC engraftment levels and tumor burden. We can demonstrate additive and synergistic cytokine release in the combination treated groups and compare efficacy versus single agents. Our in vivo method was able to determine CRS missed in the in vitro testing method. Conclusions: We have developed a rapid, sensitive and reproducible novel in vivo PBMC humanized mouse model that can differentiate human PBMC donors based on individual safety response to single agent and combination therapeutics of immune checkpoint inhibitors and bispecific T-cell-engaging antibodies. Additionally, this assay can utilize luciferase labelled cell lines to measure treatment efficacy. Using this assay, we can potentially evaluate both cytokine release and efficacy of current immune-oncology therapies as single agents and in combination. This assay has immediate utility in current and future drug development.

A donor-dependent in vivo model for single agent and drug combination cytokine release syndrome safety evaluation.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2612-2612
Author(s):  
James G. Keck ◽  
Mingshan Cheng ◽  
Michael Brehm ◽  
Dale Greiner ◽  
Lenny J. Shultz ◽  
...  
Keyword(s):  
Mouse Model ◽  
Single Agent ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Human Pbmc ◽  
Cytokine Levels

2612 Background: Although antibodies and CART cells therapies have been successfully used for cancer therapy, they can have lethal adverse effects such as cytokine release syndrome (CRS). The animal models and in vitro human PBMC assays presently in use can’t reliably predict the CRS in patients. A predictive marker for identifying patients at risk for developing CRS upfront would improve the safety of immune-oncology drug development. Methods: We have developed a rapid, sensitive and reproducible in vivo humanized mouse model for quantitating CRS. The NSG mouse and its derivatives are engrafted with human PBMCs. On day 6 we induced cytokines release with pembrolizumab, avelumab, atezolizumab, ipilimumab, anti-CD28, ATG and OKT3 in single dose; as well as combination treatments involving pembrolizumab, lenalidomide, ATG and anti-CD28. Furthermore, we compared our method versus the in vitro PBMC assay. The cytokine levels were also compared to the dose response. Results: There are about 10-15% CD45+ human cells on day 5 of engraftment; and among of them, there were approximately 70% CD3 T cells and 25% CD56 NK cells. All tested cytokines, human IFN-γ, IL-2, IL-4, IL-6, IL-10 and TNF were upregulated after 2 and 6 hours of OKT3, ATG, anti-CD28, pembrolizumab, avelumab and atezolizumab drug treatment. Mouse’s rectal temperatures dropped from 37-38 °C to about 36 °C at 6 hours’ time point in the treated groups. There is various cytokines release levels, low to high response in different donors with anti-CD28 treatment. All donors showed high response to OKT3. The cytokine release levels were consistent with a dose response or variable PBMC engraftment. The cytokine levels were also higher in some drug combination studies such as pembrolizumab combined with lenalidomide or ATG; anti-CD28 combined with ATG. Our in vivo method was able to determine CRS missed in the in vitro testing method. Conclusions: We have developed a rapid, sensitive and reproducible novel in vivo PBMC humanized mouse model that is able to differentiate human PBMC donors based on individual safety response to single agent and combination therapeutics of immune checkpoint inhibitors and possibly CAR-T therapy. This assay could be employed in future drug development.

scholarly journals Nano-encapsulated tryptanthrin derivative for combined anticancer therapy via inhibiting indoleamine 2,3-dioxygenase and inducing immunogenic cell death

Nanomedicine ◽  
2019 ◽  
Vol 14 (18) ◽  
pp. 2423-2440 ◽  
Author(s):  
Canyu Yang ◽  
Bing He ◽  
Qiang Zheng ◽  
Dakuan Wang ◽  
Mengmeng Qin ◽  
...  
Keyword(s):  
Cell Death ◽  
Single Agent ◽  
Tumor Burden ◽  
Antitumor Efficacy ◽  
In Vivo Studies ◽  
Immunogenic Cell Death ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tumor Tissues

Aim: We developed a polycaprolactone-based nanoparticle (NP) to encapsulate tryptanthrin derivative CY-1-4 and evaluated its antitumor efficacy. Materials & methods: CY-1-4 NPs were prepared and evaluated for their cytotoxicity and associated mechanisms, indoleamine 2,3-dioxygenase (IDO)-inhibitory ability, immunogenic cell death (ICD)-inducing ability and antitumor efficacy. Results: CY-1-4 NPs were 123 nm in size. In vitro experiments indicated that they could both induce ICD and inhibit IDO. In vivo studies indicated that a medium dose reduced 58% of the tumor burden in a B16-F10-bearing mouse model, decreased IDO expression in tumor tissues and regulated lymphocytes subsets in spleen and tumors. Conclusion: CY-1-4 is a potential antitumor candidate that could act as a single agent with combined functions of IDO inhibition and ICD induction.

Preclinical investigation of a small molecule inhibitor of p300/CBP reveals efficacy in patient-derived prostate tumor explants.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16534-e16534 ◽  
Author(s):  
Lisa Butler ◽  
Swati Irani ◽  
Margaret Centenera ◽  
Natalie Ryan ◽  
Neil Pegg ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Small Molecule ◽  
Single Agent ◽  
Specific Antigen ◽  
Resistance Mechanisms ◽  
Prostate Cancer Cells ◽  
In Vivo Models

e16534 Background: Growth and survival of prostate cancer cells are initially dependent upon androgens, and androgen deprivation therapy (ADT) is used to control tumor growth. Unfortunately, resistance to ADT inevitably occurs, and patients relapse with lethal castrate-resistant prostate cancer (CRPC). Increased expression of the androgen receptor (AR) and constitutively active AR variants are hallmarks of CRPC, and treatments targeting aberrant AR signaling are urgently required. CCS1477 is an inhibitor of p300/CBP currently in a Phase I/IIa study for CRPC. CCS1477 enhances degradation of numerous cellular proteins including the AR and AR variants in prostate cancer cells. Our preclinical studies with this compound demonstrated potent single-agent efficacy of CCS1477 using in vitro and in vivo models of prostate cancer and, when used in combination, CCS1477 enhances the efficacy of enzalutamide, a clinical AR antagonist. Understanding the response of clinical tumors to CCS1477, and their potential adaptive evolution, is essential to personalize treatment and predict potential resistance mechanisms. Methods: To assess CCS1477 in human disease, we used a unique model in which clinical prostate tumors from radical prostatectomy are cultured as explants with maintenance of tissue integrity, cell proliferation and androgen signaling. Tumors from 13 patients were cultured in the absence or presence of CCS1477 (10µM) or enzalutamide (10µM) for 48 or 72 hours; micromolar doses were selected to account for altered small molecule uptake and penetration into tissues compared to cell lines, as previously reported. Proliferation, apoptosis and androgen signaling were all analyzed post-culture. Results: Whereas the tumor explants exhibited highly heterogenous proliferative responses to enzalutamide, tumors from all patients exhibited a marked antiproliferative response to CCS1477 (mean reduction in Ki67 immunoreactivity of > 90% compared to vehicle control; p < 0.0005). Culture with CCS1477 was associated with repression of androgen signaling in the prostate tissues, measured by expression and secretion of the clinical biomarker prostate specific antigen (PSA). Conclusions: The consistent and pronounced efficacy of CCS1477 in this patient-derived model would support further investigation of this class of epigenetic agents in the castrate-sensitive prostate cancer setting.

scholarly journals Sulfisoxazole does not inhibit the secretion of small extracellular vesicles

2020 ◽  
Author(s):  
Pamali Fonseka ◽  
Sai V Chitti ◽  
Rahul Sanwlani ◽  
Suresh Mathivanan
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Breast Cancer Cells ◽  
Drug Repurposing ◽  
Tumor Burden ◽  
Immunocompetent Mouse ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractRecently, the study by Im et al. focused on blocking the release of extracellular vesicles (EVs) by cancer cells, as a strategy to block metastasis, by deploying a drug repurposing screen. Upon screening the library of FDA approved drugs in breast cancer cells in vitro, the authors reported the ability of the antibiotic Sulfisoxazole (SFX) in inhibiting EV biogenesis and secretion. SFX was also effective in reducing breast primary tumor burden and blocking metastasis in immunocompromised and immunocompetent mouse models. As we seek a compound to block EV biogenesis and secretion in our current in vivo studies, we intended to use SFX and hence performed in vitro characterization as the first step. However, treatment of two cancer cells with SFX did not reduce the amount of EVs as reported by the authors.

scholarly journals Dual-Function Anti-CD47mAbs Induce Tumor Cell Death and Promote Phagocytosis Resulting in Enhanced in Vivo Efficacy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 991-991
Author(s):  
Pamela T. Manning ◽  
Benjamin J. Capoccia ◽  
Michael P. Rettig ◽  
Ronald R. Hiebsch ◽  
Robert W. Karr ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Tumor Burden ◽  
Dual Function ◽  
Employment Equity ◽  
Hematologic Cancer ◽  
Equity Ownership

Abstract Recent success in immunomodulation of cancer has targeted immune checkpoints such as CTLA-4, PD-1 and PDL-1 to enhance adaptive immunity by stimulating production of tumor-selective, cytotoxic T cells. Anti-CD47mAbs enhance innate immunity by increasing the phagocytosis of tumor cells by macrophages leading to processing and presentation of tumor antigens to prime the adaptive T cell response. Many cancers, including hematologic cancers, up-regulate the expression of CD47 presumably to avoid immune destruction. Increased CD47 expression protects cancer cells from phagocytosis by sending a “don't eat me” signal to macrophages via SIRPalpha, an inhibitory receptor that prevents phagocytosis of CD47-bearing cells. CD47mAbs that block the CD47/SIRPalpha interaction (“blocking-only” mAbs) enhance phagocytosis of cancer cells in vitro. We have identified two CD47mAbs, Vx-1000 and Vx-1004, both of which block the CD47/SIRPalpha interaction and promote phagocytosis of tumor cells by macrophages equally well. However, Vx-1004 also has the unique property of killing cancer cells, but not normal blood cells, via a direct, cell-autonomous, cytotoxic mechanism. Therefore, Vx-1004 is a dual-function antibody. Vx-1004 selectively kills a variety of hematologic cancer cells in vitro, while Vx-1000, the blocking-only mAb, does not as assessed by annexin V staining and flow cytometry (Figure 1). In dose-response studies, cell death in leukemia cells was induced in 2 hrs by <1 ug="" vx-1004="" whereas="" normal="" peripheral="" blood="" mononuclear="" cells="" are="" resistant="" to="" the="" induction="" of="" cell="" death="" by="" following="" incubation="" with="" 10="" for="" 24="" hrs="" both="" these="" cd47mabs="" bind="" many="" species="" cd47="" including="" mouse="" and="" human="" p=""> To determine if the tumor-toxic activity of Vx-1004 confers enhanced efficacy in vivo compared to Vx-1000, we compared them in two mouse hematologic cancer models: murine acute promyelocytic leukemia (APL) and B cell lymphoma (BCL). Briefly, 1x106 GFP-labeled C57BL/6 APL cells were injected IV into wild-type C57BL/6 mice that were then treated IP with 0.4 mg/kg of either Vx-1000 or Vx-1004 on the day of tumor injection and on days 3 and 6 following tumor injection, a very low dose and limited dosing regimen. On day 25, the blood of these mice was analyzed for the number of circulating APL cells. As shown in Figure 2, Vx-1000 did not significantly reduce tumor burden compared to the control group. In contrast, Vx-1004 significantly reduced tumor burden compared to controls, demonstrating greater efficacy of the dual-function CD47mAb. In addition, enhanced efficacy of Vx-1004 compared to Vx-1000 was demonstrated in BCL (Figure 3). In this model, NSG mice were injected with 1x106 murine A20 lymphoma cells subcutaneously and then treated with 0.4mg/kg/day of the CD47mAbs IP for the first five days following tumor injection. In this model, Vx-1000 also failed to inhibit tumor growth compared to controls while Vx-1004 significantly reduced tumor burden at 35 days compared to both the control and Vx-1000 groups, nearly four weeks after treatment was stopped. These data demonstrate increased anti-cancer efficacy with a dual-function CD47mAb that not only blocks the CD47/SIRPalpha interaction to increase phagocytosis of cancer cells, but also selectively kills cancer cells. These studies indicate that dual-function CD47mAbs may have better anti-tumor activity in vivo and support their use in human clinical trials. Figure 1 Figure 1. Disclosures Manning: Corvus Pharmaceutical: Employment, Equity Ownership. Capoccia:Corvus Pharmaceutical: Employment, Equity Ownership. Hiebsch:Corvus Pharmaceutical: Employment, Equity Ownership. Karr:Corvus Pharmaceutical: Employment, Equity Ownership. Frazier:Corvus Pharmaceutical: Consultancy, Equity Ownership.

Impaired Anaplerosis Is a Major Contributor to Glycolysis Inhibitor Toxicity in Glioma

2020 ◽  
Author(s):  
Sunada Khadka ◽  
Kenisha Arthur ◽  
Mykia Washington ◽  
Yasaman Barekatain ◽  
Jeff Ackroyd ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Single Agent ◽  
Tca Cycle ◽  
Redox Status ◽  
Homozygous Deletion ◽  
Metabolomic Profiling ◽  
Selective Sensitivity ◽  
Homozygous Deletions

Abstract Reprogramming of metabolic pathways is crucial to satisfy the bioenergetic and biosynthetic demands and maintain the redox status of rapidly proliferating cancer cells. In tumors, the tricarboxylic acid (TCA) cycle generates biosynthetic intermediates by oxidation of anaplerotic substrates, such as glucose-derived pyruvate and glutamine20 derived glutamate. We have previously documented that a subset of tumors with 1p36 homozygous deletion exhibit co-deletion of ENO1, in turn becoming extremely dependent on its redundant isoform ENO2 and sensitive to an overall enzymatic deficiency of enolase. Metabolomic profiling of ENO1-deleted glioma cells treated with an enolase inhibitor revealed a profound decrease in TCA cycle metabolites, which correlated with cell-line specific sensitivity to enolase inhibition, highlighting the importance of glycolysis derived pyruvate for anaplerosis. Correspondingly, the toxicity of the enolase inhibitor was significantly attenuated by exogenous supplementation of supraphysiological levels of anaplerotic substrates including pyruvate. These findings led us to hypothesize that cancer cells with ENO1 homozygous deletions treated with an enolase inhibitor might show exceptional sensitivity to inhibition of glutaminolysis because of reduced anaplerotic flow from glycolysis. We found that ENO1-deleted cells indeed exhibited selective sensitivity to the glutaminase inhibitor CB-839, and this sensitivity was also attenuated by exogenous supplementation of anaplerotic substrates including pyruvate. Despite these promising in vitro results, the antineoplastic effects of CB-839 as a single agent in ENO1-deleted xenograft tumors in vivo were modest in both intracranial orthotopic tumors, where the limited efficacy could be attributed to the blood brain barrier (BBB), and subcutaneous xenografts, where BBB penetration is not an issue. This contrasts with the enolase inhibitor HEX, which, despite its negative charge, achieved antineoplastic effects in both intracranial and subcutaneous tumors. Together, these data suggest that at least for 1p36-deleted gliomas, tumors in vivo—unlike cells in culture—show limited dependence on glutaminolysis and instead primarily depend on glycolysis for anaplerosis. Our findings reinforce the previously reported metabolic idiosyncrasies of the in vitro and in vivo environments as the potential reasons for the differential efficacy of metabolism targeted therapies in in vitro and in vivo systems.

PTH- PTHR1 Axis Control on Anti-Myeloma Effect of Proteasome Inhibitors

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5017-5017
Author(s):  
Maurizio Zangari ◽  
Fang Xiao ◽  
Ye Yang ◽  
Hongwei Xu ◽  
Guido J. Tricot ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Conflicts Of Interest ◽  
Single Agent ◽  
Proteasome Inhibitors ◽  
In Vitro Study ◽  
Inhibitory Effect ◽  
Tumor Burden ◽  
Control Group

Abstract Abstract 5017 Multiple myeloma (MM) is a plasma cell malignancy with high osteolytic capacity and impaired bone formation. Our recent studies have demonstrated that PTH serum increases are associated with Bortezomib responses in multiple myeloma patients, indicating a possible role of PTH in anti myeloma effect of Bortezomib. We first tested the 5TGM1 cell line for sensitivity to bortezomib, PTH, and [TYR34]bPTH-(7-34) bovine (a specific PTHR1 inhibitor) in various combinations. In an in vitro study, 5TGM1 cells were sensitive to cytotoxicity of bortezomib and PTH in a dose dependent fashion. TYR compound was found to have no effect as single agent on 5TGM1 cell survival, but was able to partially block the inhibitory effect of bortezomib on cell growth (Figure 1). In an in vivo study using the 5TGM1 C 57BL/KaLwRijmice, we tested PTH-PTHR1 axis on bortezomib anti-myeloma activity. As shown in Figure 1, mice survival was positively affected by bortezomib administration (P = 0.04), and the combination of PTH + bortezomib showed a trend to further improve survival (P = 0.09). Interestingly, the concomitant use of [TYR] compound with bortezomib completely abrogated the efficacy of the proteasome inhibitor on survival. Tumor burden assessed by M-protein levels decreased consistently in mice treated with bortezomib alone, PTH alone, or a combination of PTH + bortezomib compared with the control group treated with PBS (P = 0.003, P = 0.05, P = 0.01 respectively). Importantly the tumor burden in the mice treated with bortezomib was significantly lower than in mice treated with bortezomib plus the PTH inhibitor (TYR), again indicating that the PTHR inhibitor abrogates the effect of Bortezomib on tumor growth. Similar results were obtained using the same systems for other commercially available proteasome inhibitors. Thus, we conclude that the PTH- PTHR1 pathway appears essential for proteasome inhibition activity in myeloma. Our observations may lead to novel treatment approaches in myeloma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals HGG-29. VENETOCLAX SYNERGIZES WITH RADIATION THERAPY FOR THE TREATMENT OF DIPG

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i23-i23
Author(s):  
Ilango Balakrishnan ◽  
Senthilnath Lakshmana Chetty ◽  
Krishna Madhavan ◽  
Susan Fosmire ◽  
Angela Pierce ◽  
...  
Keyword(s):  
Single Agent ◽  
Treatment Resistance ◽  
Pediatric Brain Tumors ◽  
Tumor Burden ◽  
Metabolic Reprogramming ◽  
In Vivo Studies ◽  
Significant Activity ◽  
Bcl2 Family

Abstract Background and Rationale Diffuse intrinsic pontine glioma (DIPG) is one of the most aggressive pediatric brain tumors. Currently, the main treatment for DIPG is radiation and it’s only a palliative care, as the tumor eventually becomes resistant to radiation. In this study we found that radiation leads to an increase in anti-apoptotic BH3 proteins mainly BCL2 in DIPG. Previous studies in other tumor types have shown that increase in these pro-survival BCL2 family members are associated with treatment resistance and poor prognosis. Therefore, we hypothesize that inhibition of BCL2 using a small-molecule inhibitor, venetoclax that crosses the blood-brain barrier, will represent a possible therapeutic strategy to overcome radiation resistance in DIPG. Approach: For in vitro studies, DIPG cells were exposed to different radiation doses (0–10 Gy) and the magnitude of the sensitizing effect of venetoclax (with IC15) was calculated by clonogenic assay. Evaluated BCL2 family proteins by western and cytotoxicity by cleaved caspase incucyte assays. For in vivo studies, NSG mice orthotopically engrafted with a human H3K27M-DIPG luciferase-expressing cells in the pons were exposed to a focal fractionated radiation of 2Gy/day for 3 days. Mice were randomized into 2 groups based on bioluminescence IVIS signal intensity; each group receiving either venetoclax (15 mg/kg, by i.p) 3 days/week for 10 weeks or vehicle. Decrease in tumor burden was measured by IVIS and survival was evaluated compared to vehicle treated mice. Results Single agent venetoclax showed no significant activity against DIPG tumors in in vitro and in vivo DIPG xenografts. Single-agent radiation cleared the tumor burden but only transiently. Combination of radiation with venetoclax showed considerable synergistic anti-tumor effect in vitro and in vivo leading to a significant increase in animal survival beyond either single agent treatments. The metabolic reprogramming that results in this enhanced cell-killing effect will be discussed.

Targeting KDM1A with iadademstat in combination with immunotherapy in an in vivo model of melanoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14248-e14248 ◽  
Author(s):  
Tamara Maes ◽  
Cristina Mascaró ◽  
Natalia Sacilotto ◽  
Michele MP Lufino ◽  
Filippo Ciceri
Keyword(s):  
Cancer Cells ◽  
Checkpoint Inhibitors ◽  
In Vivo Model ◽  
T Cell Apoptosis ◽  
Phase Ii Clinical Trials ◽  
Solid Malignancies ◽  
Melanoma Model ◽  
Immune Oncology ◽  
Host Inflammatory Response

e14248 Background: By recruiting the immune system against cancer cells, immunotherapy holds promise to achieve long-lasting responses in several malignant conditions. However, a therapeutic response is observed only in a subset of patients. The low mutational burden of “cold” tumors enables them to stay undetected from the host inflammatory response (innate resistance). Also, cancer cells develop a number of coping strategies in response to the selective pressure applied by the treatment with checkpoint inhibitors (recruitment of regulatory cells, defective antigen presentation, immunosuppressant mediators, reduced costimulation, and T cell apoptosis). Hence combinatorial treatments are being considered to tackle the problem of resistances and responsiveness. Iadademstat (ORY-1001) is a selective, orally-available KDM1A inhibitor with low nanomolar potency (Maes et al., 2018). KDM1A is a histone demethylase involved in transcription regulation and key to tumorigenicity in different hematological and solid malignancies. The tolerability and safety of iadademstat has been evaluated in Phase I studies in AML and SCLC and the drug is currently being investigated in combination with SoC in phase II clinical trials in AML and in SCLC. Methods: The combined efficacy of iadademstat administered orally at 10 µg/kg, a dose that does not provoke weight loss or thrombocytopenia, and an anti-Pd1 antibody was evaluated in the mice syngeneic B16F10 melanoma model. Results: Treatment with iadademstat and the checkpoint inhibitor anti-Pd1 monoclonal antibody was well tolerated. By Day 15, treatment with the anti-Pd1 antibody alone or in combo with iadademstat reduced tumor growth by 45% and 65% relative to vehicle controls. Control animals were sacrificed by day 19 due to progression. By day 22, 54% reduction was achieved in the animals treated with the combination compared to the animals treated with the anti-Pd1 antibody alone. Conclusions: This proof-of-concept in vivo experiment highlights the potential of iadademstat in combination with checkpoint inhibitors, prompting further investigation in other oncological indications, characterized by low or no response to the currently approved immune-oncology treatments.

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