Histamine dihydrochloride combinations and uses thereof

A technology of histamine receptors and subjects, which is applied in the directions of drug combinations, active ingredients of iodine compounds, and medical preparations containing active ingredients, etc., can solve the problems of cancer treatment not being the best effective, ineffective tumor cell killing, etc.

Inactive Publication Date: 2018-11-23
IMMUNE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Additionally, researchers realized that cancer treatments are often not optimally effective because although the immune system recognizes tumor cells, it can remain quiescent due to suppressive mechanisms that limit or shut down anti-tumor responses
For example, negative regulatory T cell surface molecules were found, which are upregulated in activated T cells to suppress their activity, resulting in less effective tumor cell killing

Method used

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  • Histamine dihydrochloride combinations and uses thereof
  • Histamine dihydrochloride combinations and uses thereof
  • Histamine dihydrochloride combinations and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0164] Combination of anti-PD-1 / anti-PDL1 and histamine - method

[0165] The EL-4 thymoma cell line (provided by Dr.Ingo Schmitz, Otto-von-Guericke-University, Magdeburg, Germany) was cultivated in DMEM medium (Sigma, Stockholm, Switzerland) supplemented with 10 % fetal bovine serum, 100 U / ml penicillin, 100 μg / ml streptomycin and 2 mM L-glutamine, as in Martner, A. et al. The Journal of Immunology, Vol. 194, No. 10, pp. 5014-5021 mentioned. C57BL / 6J mice (6-8 weeks old, purchased from Charles River Laboratories, Sulzfeld, Germany) were treated with 1.75-2x10 5 EL-4 tumor cells were inoculated subcutaneously and started on the day before cell inoculation by intraperitoneal injection three times a week with saline (control) or 1.5 mg histamine dihydrochloride diluted in saline (purchased from Sigma-Aldrich, Stockholm , Germany) for processing. Three, six and ten days after tumor inoculation, two hundred and forty μg of an antibody against the programmed cell death-1 recep...

example 2

[0167] Combination of anti-PD-1 / anti-PDL1 and histamine - results

[0168] Consistent with previous studies (Martner, A. et al. The Journal of Immunology, Vol. 194, No. 10, pp. 5014-5021), treatment of EL-4-bearing mice with histamine significantly reduced tumor growth rate ( Figure 1-3 ). Administration of α-PD1-+α-PDL1 inhibitory antibodies resulted in a comparable reduction in tumor growth. The combination of histamine and anti-PD1 / anti-PDL1 increased the reduction in EL-4 tumor growth over each treatment alone (histamine or α-PD1 / α-PDL1). exist Figure 1-3 In , tumor size is indicated as % of control, where 100% is the mean size of control tumors at the end of the experiment (ie, 2 weeks after tumor inoculation).

example 3

[0170] Dynamics of cytotoxic T cell subsets during immunotherapy predict outcome in acute myeloid leukemia

[0171] Materials and Methods

[0172] Patients, Study Design and Objectives

[0173] This single-arm, multicenter Phase IV study (Relapse:Remission, NCT01347996, registered at www.clinicaltrials.gov) enrolled 84 patients (ages 18-79) with AML in first CR. Such as Figure 4 As shown schematically in , patients received ten consecutive 21-day cycles of histamine dihydrochloride (HDC; Ceplene) in combination with low-dose IL-2 over an 18-month period or until relapse or death.

[0174] Treatment continued for a total of 18 months or until the patient relapsed, died, discontinued treatment due to an adverse event, withdrew consent, or became lost to follow-up. Cycles 1 to 3 consisted of 3 weeks on treatment and 3 weeks off treatment, and in cycles 4 to 10 the off treatment period was extended to 6 weeks. During each cycle, patients in the treatment arm received 0.5 ...

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Abstract

The present invention provides methods of treating cancer in a subject, preventing or delaying relapse to a cancer in a subject in remission, prolonging remission from cancer, increasing survival, anddecreasing or alleviating cancer symptoms comprising a) administering histamine dihydrochloride and an inhibitor of the Programmed cell Death protein 1 (PD-1) / Programmed Death Ligand 1 (PD-L1) or b)administering an agent that decreases reactive oxygen species (ROS) optionally, together with a histamine receptor agonist. The present invention also provides methods of predicting the efficacy of acancer treatment based on a re-distribution of cytotoxic T cells, frequency of NK cells, or other biochemical changes, and related methods of preventing relapse to cancer and for prolonging remissionfrom a cancer. Related kits and compositions are also provided.

Description

technical field [0001] The present invention provides methods of treating cancer in a subject, preventing or delaying recurrence of cancer in a subject in remission, prolonging remission of cancer, increasing survival and reducing or alleviating symptoms of cancer comprising a) administering histamine dihydrochloride and inhibitors of programmed cell death protein 1 (PD-1) / programmed death ligand 1 (PD-L1), or b) optionally together with a histamine receptor agonist to reduce reactive oxygen species (ROS) reagents. The present invention also provides methods for predicting the efficacy of cancer therapy based on redistribution of cytotoxic T cells, frequency of NK cells, or other biochemical changes, and related methods for preventing cancer recurrence and prolonging cancer remission. The invention also provides related kits and compositions. Background technique [0002] Histamine dihydrochloride is derived from the biogenic amine histamine. It inhibits the production of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/417A61K39/395C07K16/30A61P35/02A61P35/04
CPCA61K45/06A61K31/341A61K31/417A61K33/18A61K39/39541A61K39/39558C07K16/2818C07K16/2827A61K2039/507A61P35/00A61K2300/00A61P35/02
Inventor A·马特纳F·埃瓦德赛德F·伯格索伦K·海兰斯特H·维克托林格劳尔斯
Owner IMMUNE PHARMA
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