Inhibition of tumor growth and metastasis by photoimmunotherapy targeting tumor-associated macrophage in a sorafenib-resistant tumor model

e15515 Background: Paclitaxel (PXL) was converted to paclitaxel orotate (PXLO). Different combinations of Carboxyamidotriazole orotate (CTO) and PXL or PXLO were first evaluated in female non-tumored athymic NCr-nu/nu mice to determine the tolerance of the combinations. The antiproliferative and antimetastatic effects of CTO are related to inhibition of receptor-operated calcium channel-mediated calcium influx. CTO can inhibit calcium sensitive signal transduction in the VEGF and the PI3K pathways, and inhibit FGF-2-induced tyrosine kinase. Methods: The antitumor effect of combinations was tested for: i) PXLO compared to PXL, ii) combinatorial effect of low (342mg/kg/dose) and high (513mg/kg/dose) doses of CTO (Q1Dx14, PO) with low (11.6 and 10mg/kg/inj, Q2Dx3/2 weeks, IV) and high (23.2 and 20mg/kg/inj, Q2Dx3/2 weeks, IV) respectively, doses of PXLO or PXL, against sc-implanted human OVCAR-5 ovarian tumor xenografts. Results: Results obtained in non-tumored mice show high PXLO plus CTO was better tolerated than high PXL plus CTO. In tumor bearing mice, oral CTO at doses of 513 or 342mg/kg/dose Q1Dx14 given alone resulted in slight inhibition of tumor growth, reaching statistical significance only when administered at a low dose (two tumor mass doubling: p=0.036 for 342mg/kg/dose). PXLO at 23.2 and 11.6mg/kg/inj. given alone inhibited tumor growth (p<0.001, 0.029, respectively). PXL at 20 and 10mg/kg/inj inhibited tumor growth (p<0.001 and 0.011, respectively). Since body weight loss was less with the orotate form of PXL, PXLO should be the preferred drug over PXL. Addition of oral CTO 513 or 342mg/kg/dose to PXLO 23.2 or PXL 20mg/kg/inj resulted in comparable tumor inhibition to PXLO or PXL alone. However, combination of PXLO 11.6 and PXL 10mg/kg/inj with CTO 513 or 342mg/kg/dose resulted in tumor inhibition suggesting that a low dose of PXL or PXLO may be combined with CTO to achieve tumor inhibition and to allow the use of the lower doses of PXL to reduce toxicity. Conclusions: Results suggest that PXLO is less toxic than PXL and CTO influences the sensitivity of PXL suggesting a role for combinatorial therapy with low doses of PXL and CTO in this ovarian tumor model.

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Combined OX40 agonist and PD-1 inhibitor immunotherapy improves the efficacy of vascular targeted photodynamic therapy in a urothelial tumor model.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e17004 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e17004-e17004 ◽

Cited By ~ 1

Author(s):

Ricardo Alvim ◽

Lucas Nogueira ◽

Petrina M Georgala ◽

Alexander Somma ◽

Karan Nagar ◽

...

Keyword(s):

Immune Responses ◽

Tumor Growth ◽

Suppressor Cells ◽

Tumor Model ◽

Treg Cells ◽

Low Grade ◽

Urothelial Tumor ◽

Ablative Therapies ◽

Tumor Growth And Metastasis ◽

Targeted Photodynamic Therapy

e17004 Background: In patients with low-grade, small upper tract urothelial carcinomas (UTUC), as well as those in whom preservation of kidney function is critical, local ablative therapies such as vascular targeted photodynamic (VTP) therapy have emerged as a means of reducing treatment-related morbidity. Toward increasing response rates to VTP, we evaluated its efficacy in combination with concurrent PD-1 inhibitor/OX40 agonist immunotherapy in a urothelial tumor-bearing model. Methods: In mice allografted with MB-49 UTUC cells, we compared the effects of combined VTP with PD-1 inhibitor/OX40 agonist with those of the component treatments on tumor growth, survival, lung metastasis, and antitumor immune responses. Results: The combination of VTP with both PD-1 inhibitor and OX40 agonist inhibited tumor growth and metastasis and prolonged survival to a much greater degree than VTP with either immunotherapeutic individually. These effects result from increased tumor infiltration and intratumoral proliferation of cytotoxic and helper T cells, depletion of Treg cells, and suppression of myeloid-derived suppressor cells. Conclusions: Our findings suggest that VTP synergizes with PD-1 blockade and OX40 agonist to promote strong antitumor immune responses, yielding therapeutic efficacy in an animal model of urothelial cancer.

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