Compositions and methods for enhancing the efficacy of cancer therapy

A technology of radiotherapy and chemotherapy, applied in chemical instruments and methods, drug combinations, X-ray/γ-ray/particle irradiation therapy, etc., can solve the problem of less optimal treatment effect

Inactive Publication Date: 2018-01-02
PROVIDENCE HEALTH & SERVICESOREGON
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, although combination use is becoming more common, few studies have been designed to optimize treatment effects based on the timing of each agent's administration

Method used

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  • Compositions and methods for enhancing the efficacy of cancer therapy
  • Compositions and methods for enhancing the efficacy of cancer therapy
  • Compositions and methods for enhancing the efficacy of cancer therapy

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0174] Example 1: Immunotherapy improves response to chemotherapy.

[0175] To investigate whether immunotherapy improves response to chemotherapy, the Panc02 mouse model of pancreatic adenocarcinoma was used. This model, like pancreatic adenocarcinoma in patients, is sensitive to cytotoxic agents at similar levels to other cell lines in vitro, but is highly resistant to chemotherapy and radiation in vivo (Priebe et al., Cancer ChemotherPharmacol 1992;29:485-9; Young et al. Cancer Immunol Res 2014). Panc02 tumors have been highly infiltrated by macrophages in vivo, and macrophage differentiation in Panc02 tumors has been shown to be a significant factor limiting the in vivo efficacy of radiotherapy (Crittenden et al., PloS one 2012;7:e39295) .

[0176] To determine the effect of chemotherapy on macrophages in tumors, mice with established Panc02 tumors were treated with gemcitabine chemotherapy and tumors were harvested after one week of treatment. Immunofluorescent histolo...

example 2

[0177] Example 2: Pretreatment with a combination of anti-OX40 and anti-CTLA4 significantly improves tumor control with chemotherapy.

[0178] Based on this timing of macrophage differentiation, the effect of chemotherapy delivered starting on day 4 after immunotherapy was tested. In this model, immunotherapy alone is ineffective in tumor treatment, while chemotherapy with gemcitabine confers a transient tumor delay. ( figure 2 A, panel (i)) and significantly prolonged survival ( figure 2 B, panel (ii)). Pretreatment with anti-OX40 or anti-CTLA4 as single agents did not alter the response to chemotherapy. However, pretreatment with antibodies in combination with chemotherapy significantly improved tumor control with chemotherapy ( figure 2 A, panel (ii)), and improved survival compared to chemotherapy or antibody combinations alone ( figure 2 B). To determine how sensitive this effect was to timing, the effect of chemotherapy started on the same day as antibody immun...

example 3

[0179] Example 3: The effect of immunotherapy on the tumor environment at different time points.

[0180] To examine the effect of immunotherapy on the tumor environment at these time points, tumors were harvested and flow cytometry of the infiltrating cell population was performed. The treatment combination did not alter the myeloid proportion and, surprisingly, there was no statistically significant difference in the overall proportion of CD8 T cells in the tumor after treatment ( image 3 ). This poor infiltration of CD8 T cells in response to immunotherapy differs from the response to immunotherapy in more immunogenic tumor types (Gough et al., Cancer Res 2008;68:5206-15; Redmond et al., Cancer Immunology Research 2013;2:142-53), potentially explaining why Panc02 tumors respond poorly to immunotherapy alone. Like CD8 T cells, CD11b + The proportion of myeloid cells was unchanged, suggesting that the changes in each cell population induced by immunotherapy were not in pr...

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PUM

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Abstract

The present invention features compositions and methods for enhancing an anti-tumor response by administering an OX40 agonist (e.g., an anti-OX40 antibody) and / or an anti-CTLA4 antibody (e.g., a CTLA4-blocking antibody) in combination with a cancer therapy.

Description

Background technique [0001] The estimated 1-year survival rate for all stages of pancreatic cancer is about 20%, while the 5-year survival rate is only 6%. These low survival rates are due to the fact that, by the time of diagnosis, many patients have tumors that have spread beyond the pancreas and have metastasized to locations where surgical resection is not possible. [0002] Recent studies have reported that reduced T cell infiltration alone or in combination with increased macrophage infiltration is associated with reduced survival in various cancers, including patients with pancreatic cancer. In these retrospective studies, patients had been treated with conventional cancer therapies, including chemotherapy, radiation therapy, and surgical resection, suggesting that infiltration of T cells and macrophages in tumors influences the outcome in response to conventional therapies . [0003] Over the past few years, there has been a surge of interest in immunotherapy, a nove...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/715C07K16/28G01N33/569
CPCA61K39/39558C07K16/2818A61K2039/507A61K2039/545C07K2317/76G01N2800/125C07K14/70578C07K16/2878A61K31/7068C07K16/247C07K2317/75A61P1/00A61P1/18A61P35/00A61P43/00A61K2300/00A61N5/10A61N2005/1098C07K2317/24C07K2317/52C07K2317/54C07K2317/55C07K2317/56C07K2317/565C07K2317/567C07K2317/94C07K2319/30
Inventor M.高夫M.克里滕登
Owner PROVIDENCE HEALTH & SERVICESOREGON
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