Prognostic and treatment response predictive method

A treatment response and immunotherapy technology, applied in chemical instruments and methods, biochemical equipment and methods, pharmaceutical formulations, etc., can solve the problems that other models of cancer patients' treatment response do not meet

Pending Publication Date: 2021-03-26
CANCER RES TECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although previously described cancer prediction models show promise, there remains an unmet need for additional models that can predict treatment response and / or survival in cancer patients

Method used

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  • Prognostic and treatment response predictive method
  • Prognostic and treatment response predictive method
  • Prognostic and treatment response predictive method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0169] Example 1 - Neutropenia and increased NK cell accumulation in tumors formed by COX-deficient cells

[0170] As previously reported (Zelenay et al., 2015), COX-deficient Braf produced using CRISPR-Cas technology V600E Driving melanoma cells were invariably unable to form progressive tumors in immunocompetent mice, whereas their COX-active parental counterparts efficiently evaded immune elimination and grew uncontrollably ( figure 1 A). To demonstrate definitively that these categorically opposite tumor fates are caused by impaired COX activity and exclude the possibility that they are due to unforeseen off-target CRISPR effects, we restored COX-1 and COX-2 by retroviral transduction Double defect (Ptgs1 - / - Ptgs2 - / - COX-2 expression in ) cells ( figure 1 A). Like their parental lines, COX-2-recovered melanoma cells secrete large amounts of PGE in vitro 2 , and regained the ability to grow sexually in wild-type isogenic mice ( figure 1 A, B).

[0171] Having d...

Embodiment 2

[0172] Example 2 - Decreased neutrophils and elevated NK cell numbers in COX-deficient colorectal and breast cancer models

[0173] To assess whether COX-dependent changes in immune cell composition at tumor sites are Braf V600E Unique to the melanoma model, we extended our analysis to MC38 colon cancer cells. These cells express COX-2 and produce PGE 2 , although its level was significantly lower than that of melanoma cells ( figure 2 A). Nonetheless, CRISPR-mediated ablation of COX-2 completely abolished PGE 2 produces and diminishes its ability to form progressive tumors in immunocompetent hosts ( figure 2 A, B). with Braf V600ET and B cells deficient in Rag1, as in melanoma models - / - or cDCl-deficient Batf3 - / - COX-2 deficiency in mice (Ptgs2 - / - ) The growth spectrum of MC38 cells is similar to that of parental Ptgs2 + / + or COX-2 restored Ptgs2 - / - equivalent in cells. These observations reveal a dominant role of cancer cell-intrinsic COX-2 activity in evad...

Embodiment 3

[0177] Example 3: NK cells are essential for spontaneous or therapy-induced tumor control

[0178] We then discuss the role of NK cells, which are frequently involved in the control of hematologic malignancies and metastasis, but less so of solid tumors (Imai et al., 2000). Except for NK cells themselves, the overall immune cell composition of COX-deficient tumors was not significantly altered after NK cell depletion ( image 3 A and Figure S3 C). However, NK cell ablation resulted in Ptgs2 comparable to COX-active tumors - / - Significant increases in tumor size and weight were evident four days after cancer cell implantation ( image 3 C). Furthermore, strikingly, in NK cell-depleted mice, COX-deficient melanoma cells grew progressively like their parental cells, with no apparent signs of innate or adaptive immune-dependent control ( image 3 C). Similar results were obtained using the MC38 colorectal model ( image 3 D to F and Figure S3 D). We thus reasoned that N...

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Abstract

The present invention provides a method for predicting the treatment response to anti-cancer immunotherapy of a mammalian cancer patient, the method comprising: a) measuring the gene expression of atleast 2 the following cancer promoting genes: PTGS2, VEGFA, CCL2, IL8, CXCL2, CXCL1, CSF3, IL6, IL1B and IL1A in a sample obtained from the tumour of the patient; b)measuring the gene expression of atleast 2 of the following cancer inhibitory genes: CXCL11, CXCL10, CXCL9, CCL5, TBX21, EOMES, CD8B, CD8A, PRF1, GZMB, GZMA, STAT1, IFNG, IL12B and IL12A in a sample obtained fromthetumour of the patient; c) computing a ratio of the gene expression of said at least 2 cancer promoting genes and the gene expression of said at least 2 cancer inhibitory genes; and d) making a prediction of the treatment response and / or prognosis of the patient based on the gene expression ratio computed in step c). Also provided are related methods for stratifying patients and for treating patients, including withimmune checkpoint blockade therapy.

Description

[0001] This application claims priority from GB1810190.7, filed 21 June 2018, the contents and elements of which are incorporated herein by reference for all purposes. technical field [0002] The present invention relates to materials and methods for predicting response to cancer therapy and overall survival of cancer patients, particularly patients receiving immune checkpoint blockade therapy. Background technique [0003] The concept that cancer induces inflammation and that inflammatory cells at tumor sites can support cancer progression is well established (Coussens et al., 2013; Hanahan and Weinberg, 2011; Mantovani et al., 2008). Several cellular and molecular inflammatory mediators commonly found in clinically apparent tumors are known to have pro-tumorigenic effects and are associated with many features of aggressive and invasive tumors in both preclinical models and cancer patients. These include prevalent tumor-infiltrating leukocytes such as macrophages, neutroph...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/6886
CPCC12Q1/6886C12Q2600/106C12Q2600/158G16B25/10G16B40/00A61K39/39541A61K39/3955A61K2039/507C07K16/22C07K16/2818C07K2317/76
Inventor 克里斯蒂安·P·布罗姆利爱德华多·博纳维塔桑蒂亚戈·P·泽列纳伊
Owner CANCER RES TECH LTD
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