Immune memory induction by platinum based compounds

A compound, immune response technology, applied in the field of pharmaceutical science and medicinal chemistry, can solve the problems of anti-tumor response disorder, expression affecting immune response, deficiency, etc.

Inactive Publication Date: 2019-07-02
阿卡马拉医疗公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, barriers to antitumor responses, including lack of "signaling" from innate immune cells, poor recruitment of dendritic cells, and insufficient expression of co-stimulatory ligands on tumor cells or antigen-presenting cells (APCs) also affect immune responses

Method used

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  • Immune memory induction by platinum based compounds
  • Immune memory induction by platinum based compounds
  • Immune memory induction by platinum based compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0232] This example demonstrates that treatment with a compound of formula I (compound 1) induces a B cell-mediated immune response in tumors.

[0233] 4T1 cells were implanted subcutaneously into Balb / c mice to generate tumors. When the tumor reaches 100mm 3 These tumors were treated with compound 1 or oxaliplatin when the mean volume was . After one treatment cycle, after regression, tumors were harvested and a portion of tumors from each group was used for total RNA isolation. Relative mRNA expression levels of immune activation and immunosuppressive genes in tumor infiltrating immune cells were assessed (Denkert et al., Clin Oncol. 2015;33(9):983-91).

[0234] The results indicated that IGKC mRNA levels were significantly increased in tumors treated with Compound 1 ( figure 1 A). The prognostic impact of IGKC expression has been described in cancer, where IGKC expression has been shown to be a prognostic marker in human solid tumors (Schmidt et al., Clin Cancer Res 2...

Embodiment 2

[0238] This example demonstrates that treatment with a compound of formula I (compound 1) induces a T cell-mediated immune response in tumors.

[0239] Many clinical trials of cancer immunotherapy have shown tumor shrinkage and prolonged survival. The paradigm is that memory T cells remain inactive due to lack of T cell receptor (TCR) stimulation, where regulatory T (Treg) cells normally coordinate memory T cell quiescence (Kalia et al., Immunity 42, 1116-1129, June 2015 16). In addition to the activation of effector T cells and memory CD8+ T cells, the absence of Treg cells will also have a protective effect.

[0240] Treatment with compound 1 induced a significant activation of the TCR compared to oxaliplatin ( figure 2 A), and the infiltration of cytotoxic T cells, which was established by detecting CD8+ T cells ( figure 2 B).

Embodiment 3

[0242] This example demonstrates that treatment with a compound of Formula I (Compound 1) induces immune memory.

[0243] To stay cancer free in the long term, the immune system should remember how to recognize and attack cancer cells in case they return in the future. Thus, "immune memory" would enhance the body's ability to fight cancer recurrence.

[0244] 4T1 cells were implanted subcutaneously into Balb / c mice to generate tumors. When the tumor reaches 100mm 3 These tumors were treated with compound 1 when the mean volume of . Two groups of Balb / c mice (without tumors) were treated with Compound 1 or saline (designated as Group 1 and Group 2, respectively; image 3 A). exist image 3 A detailed study plan is schematically shown in A.

[0245] Immune memory cells, while present in a functionally quiescent state, are poised to rapidly expand and induce effector functions following regeneration. To test this hypothesis, immune memory in Compound 1-treated tumors was...

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Abstract

The present invention pertains to a method of treating cancer or its relapse in mammals by employing platinum based compounds. More particularly, the present invention provides to enhance immunity ina mammal, using a compound of formula I and / or formula II, preferably compound 1 or its derivative, salt, tautomeric form, isomer, polymorph, solvate, or intermediates thereof. The method of inducingan immune response in a mammal is mediated through immune memory. The present invention also provides for such platinum based compounds and their use in treating cancer, metastasis or cancer relapse.

Description

technical field [0001] The invention belongs to the fields of pharmaceutical science and medicinal chemistry. The present invention relates to a method for treating or controlling cancer and preventing cancer metastasis or recurrence by using a platinum-based compound capable of regulating host immune system and increasing tumor infiltration of immune cells, thereby changing the expression of immune markers. The compounds are useful in immunotherapy because they induce immunological memory in the host immune system. Background technique [0002] Cancer is a disease involving the uncontrolled growth of cells. It is a clinically complex disease in which multiple parameters, including the patient's tumor microenvironment and immune response, contribute to disease progression as well as therapy selection and outcome. Although tumors have a variety of antigens that are recognized by the immune system, the ability of tumors to evade or suppress the immune system often renders im...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/575A61K33/243C07F15/00C07H23/00C07J41/00A61P35/00A61P35/04
CPCA61K31/575C07J41/0055C07J51/00A61P35/04A61K31/282C07H23/00A61K33/243A61K31/555A61K47/543A61P35/00A61K9/0019C07F15/0006C07J41/00
Inventor 希拉迪蒂亚·森古普塔阿尼律陀·森古普塔桑哈米特拉·麦拉瓦拉普莫尼迪帕·罗伊
Owner 阿卡马拉医疗公司
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