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Application of PI3K gamma inhibitor in treatment of radiofrequency ablation residual tumor

A technology of radiofrequency ablation and inhibitors, which is applied in the direction of antineoplastic drugs, microbial measurement/inspection, and medical preparations containing active ingredients, etc. It can solve the problems of lack of treatment methods, improve survival rate, inhibit recurrence, and prolong survival period effect

Pending Publication Date: 2022-03-01
SUN YAT SEN MEMORIAL HOSPITAL SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Based on the performance of IRFA residual tumors, there is a lack of more effective treatment methods in the prior art

Method used

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  • Application of PI3K gamma inhibitor in treatment of radiofrequency ablation residual tumor
  • Application of PI3K gamma inhibitor in treatment of radiofrequency ablation residual tumor
  • Application of PI3K gamma inhibitor in treatment of radiofrequency ablation residual tumor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Increased number of macrophages in residual tumor after IRFA

[0058] (1) Liver cancer sample research

[0059] In order to study whether residual tumors recruit macrophages after IRFA, a retrospective study was conducted on some patients with liver cancer in Sun Yat-sen Memorial Hospital of Sun Yat-sen University. Among them, 21 patients who underwent tumor resection after RFA due to recurrence were assigned to the RFA group, and 19 patients who received primary tumor resection were assigned to the RFA group. Patients who underwent tumor resection but did not undergo RFA were assigned to the non-RFA group, and there were no differences in clinical, biological, and histological characteristics.

[0060] In specimens, a higher number of tumor-infiltrating CD68 was observed in the RFA group compared to the non-RFA group + macrophages, with more infiltration around the ablation zone (eg figure 1 shown in A). Moreover, according to existing research records, for simple r...

Embodiment 2

[0069] Immunosuppressive function of macrophages after IRFA identified by single-cell transcriptome

[0070] Using the IRFA animal model, tumor cells from the NC and IRFA groups were collected. Two groups of freshly isolated tumors were rapidly dissociated and subjected to fluorescence-activated cell sorting (FACS) to obtain viable single cells. Then, cDNA was prepared from individual cells, a single-cell RNA-seq library was constructed, and next-generation sequencing (NGS) was performed. A total of 10690 cells were analyzed in the NC group, and 9672 cells were analyzed in the IRFA group. Among them, 99.85% of the cells in the NC group and 99.7% of the cells in the IRFA group passed the quality control. The average number of mapped reads per cell was approximately 8000 for the NC group and 7000 for the IRFA group. The median number of genes per cell was 726 and 1038 for the NC and IRFA groups, respectively. For non-malignant cells, these clusters of non-malignant cells wer...

Embodiment 3

[0076] 1. Phagocytosis of heat-treated tumor cells by macrophages

[0077] As shown in Example 1, macrophages aggregated around the transition zone (TZ) after IRFA ( figure 1D). In order to obtain the relationship between heat-treated tumor cells and macrophages, the inventors first established a heat-treated tumor cell model based on previous studies. Hepa1-6 cells were exposed at 60°C for 10 minutes and then stained with PI / Annexin V. Compared with the tumor cells at 37 °C, the tumor cells after heat treatment showed a significantly higher proportion of Annexin V and PI positive cells ( Figure 10 A). Heat-treated cells were further assessed by membrane-impermeable nuclear fluorescent dyes, Ethidium Homodimer 1 (EthD-1) and Cleaved-Caspase-7 (e.g. Figure 10 B, C).

[0078] We then extracted bone marrow-derived macrophages (BMDMs) and induced their maturation, using flow cytometry to determine the purity of the macrophages ( Figure 10 D).

[0079] A Hepa1-6 cell line...

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Abstract

The invention discloses application of a PI3K gamma inhibitor in preparation of a medicine for treating radiofrequency ablation residual tumors. Through the PI3K gamma inhibitor targeting lymphocyte, macrophages infiltrated in residual tumors can be reprogrammed, besides the anti-tumor effect of the PI3K gamma inhibitor, anti-PD-1 mediated tumor regression can be promoted, the anti-PD-1 treatment sensitivity of radiofrequency ablation of the residual tumors is enhanced, and the drug resistance of radiofrequency ablation of the residual tumors in the prior art is overcome. A treatment strategy for treating residual tumors after IRFA through combination of the PI3K gamma inhibitor and the anti-PD-1 is provided, and compared with independent application, the combined use effect is more remarkable. Through the treatment strategy of the PI3K gamma inhibitor and the cooperation of the PI3K gamma inhibitor and the PD-1 blocking agent provided by the invention, more clinical treatment schemes and development directions of related drugs can be provided for residual tumors after clinical IRFA, so that the recurrence of the residual tumors after IRFA is inhibited, and the lifetime of a patient is prolonged.

Description

technical field [0001] The present invention relates to the field of immunotherapy, and more specifically, relates to the use of PI3Kγ inhibitors in the treatment of radiofrequency ablation of residual tumors. Background technique [0002] Radiofrequency ablation (RFA), a thermal ablation technique, is one of the main curative therapies for early-stage hepatocellular carcinoma (HCC). RFA causes heating of tumor tissue as well as surrounding liver tissue, leading to tumor necrosis. RFA treatment is effective and minimally invasive, with a low incidence of complications. However, in some cases, patients undergoing RFA experience a phenomenon known as "RFA insufficiency (IRFA)," in which the tumor cannot be ablated due to its size or location such that the local temperature for ablation does not reach the target temperature. Completely melted. The residual tumor cells after radiofrequency ablation may be the main source of recurrence and metastasis. Recently, some patients ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K45/06C12Q1/02A61P35/00A61K31/525A61K31/519
CPCA61K45/00A61K45/06A61P35/00G01N33/5011G01N33/5055A61K31/525A61K31/519
Inventor 罗葆明刘晓迪曹金成许燕妮
Owner SUN YAT SEN MEMORIAL HOSPITAL SUN YAT SEN UNIV
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