Abstract C001: Prospective use of the single mouse experimental design for evaluation of PLX038A against pediatric solid tumor models

The lead compound, an ⍺-N-heterocyclic carboxaldehyde thiosemicarbazone HCT-13, was highly potent against a panel of pancreatic, small cell lung carcinoma, and prostate cancer models, with IC90 values in the low-to-mid nanomolar range. We show that the cytotoxicity of HCT-13 is copper-dependent, that it acts as a copper ionophore, induces production of reactive oxygen species (ROS), and promotes mitochondrial dysfunction and S-phase arrest. Lastly, DNA damage response/replication stress response (DDR/RSR) pathways, specifically Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase (ATR), were identified as actionable adaptive resistance mechanisms following HCT-13 treatment. Taken together, HCT-13 is potent against solid tumor models and warrants in vivo evaluation against aggressive tumor models, either as a single agent or as part of a combination therapy.

Download Full-text

Intravenous administration of the selective toll-like receptor 7 agonist DSR-29133 leads to anti-tumor efficacy in murine solid tumor models which can be potentiated by combination with fractionated radiotherapy

Oncotarget ◽

10.18632/oncotarget.7928 ◽

2016 ◽

Vol 7 (13) ◽

pp. 17035-17046 ◽

Cited By ~ 13

Author(s):

Simon J. Dovedi ◽

Amy L. Adlard ◽

Yosuke Ota ◽

Masashi Murata ◽

Eiji Sugaru ◽

...

Keyword(s):

Intravenous Administration ◽

Solid Tumor ◽

Toll Like Receptor ◽

Tumor Models ◽

Fractionated Radiotherapy

Download Full-text

208 E7777 (denileukin diftitox) enhances anti-tumor activity and significantly extends survival benefit of anti-PD-1 in syngeneic solid tumor models

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0208 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A224-A225

Author(s):

Mary Woodall-Jappe ◽

A Raghav Chari ◽

Anil Namboodiripad ◽

Chandrasekhar Goda

Keyword(s):

Overall Survival ◽

Tumor Growth ◽

Solid Tumor ◽

Therapeutic Benefit ◽

Tumor Models ◽

Treg Depletion ◽

Immune Biomarkers ◽

Group 5 ◽

Tumor Measurements ◽

Anti Tumor Activity

BackgroundRegulatory T cell (Tregs) inhibit activity of anti-tumor T cells, and have been shown to limit checkpoint inhibitor effectiveness. Depletion of Tregs seems desirable during immunotherapy, but chronic Treg depletion with antibody therapies can lead to serious autoimmune adverse events. Compared to antibodies, the fusion protein E7777 (IL-2/diphtheria toxin) has a relatively short half-life in circulation, which allows for transient and selective Treg depletion. The potential therapeutic benefit of combining E7777 with anti-PD-1 was tested in syngeneic solid tumor models.MethodsCT26 colon and H22 liver cancer tumors were implanted subcutaneously in immunocompetent BALB/c mice. E7777 (2.5 mcg/mouse, i.v.) was given on a Q7Dx3 schedule. Anti-murine PD-1 was given (100 mcg/mouse, i.v.) Q4Dx5. Groups of 16 mice received each agent as monotherapy or in combinations. Sequencing of combination administration was also varied: Group 4 started treatment on the same day; Group 5 received E7777 2 days prior to start of anti-PD-1; Group 6 received anti-PD-1 first. Tumor growth was compared across all groups. In survival studies, mice were treated for 3 weeks and observed with twice weekly tumor measurements. In other experiments, tumors, tumor-draining lymph nodes, and spleens were examined by IHC and by flow cytometry of immune cells from dissociated tissues at defined points, for immune biomarkers.ResultsFigure 1 shows additive benefit from the E7777 + anti-PD-1 combinations over either monotherapy. Most importantly, figure 2 and table 1 show significantly enhanced overall survival from a 3 week course of combinations compared to either agent alone (p<0.005) or to vehicle controls (p<0.000001). There was no clear distinction among different sequencing regimens. Benefit correlated with enhanced CD8:Treg ratios in tumors.Abstract 208 Figure 1Tumor growth in s.c. syngeneic solid tumors. N=16/groupAbstract 208 Figure 2Overall survival in s.c. syngeneic models. N=16/groupAbstract 208 Table 1Calculated median survivalConclusionsDepletion of Tregs by E7777 significantly increased anti-tumor activity and durably extended overall survival compared to treatment with anti-PD-1 alone in syngeneic solid tumor models. Clinical studies of a combination of the two agents are planned.Ethics ApprovalAll studies were conducted at Crown Bio, and were approved by the Crown Bio IACUC.

Download Full-text