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Immunotherapy methods for patients whose tumors carry a high passenger gene mutation burden

A technology for immunotherapy and patients, applied in the field of immunotherapy, which can solve the problems of undeveloped immunogenicity and reduced sensitivity

Pending Publication Date: 2020-05-08
REGENERON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the overall mutational burden includes driver mutations that may actually suppress immunogenicity and reduce sensitivity to therapy
[0006] Existing methods have not been developed for the purpose of identifying passenger genes and their mutations for the purpose of evaluating immunogenicity

Method used

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  • Immunotherapy methods for patients whose tumors carry a high passenger gene mutation burden
  • Immunotherapy methods for patients whose tumors carry a high passenger gene mutation burden
  • Immunotherapy methods for patients whose tumors carry a high passenger gene mutation burden

Examples

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Effect test

example 1

[0140] Passenger Gene Index

[0141] The Passenger Gene Index (PGI) method involved all TCGA samples binned by cancer type, and for bins the median of mutated genes was determined. Mutations are restricted to non-silent somatic mutations by comparing solid tumors with blood-derived counterparts or normal solid counterparts, except for acute myeloid leukemia, in which blood-derived tumors are associated with Normal solid tissue for comparison. Mutation profiles were constructed as binary matrices such that a bin was set to 1 if any locus corresponding to a gene had a mutation in that patient. PGI for each gene X i Calculated as having gene X i Pearson correlation between the sample fraction of mutations and the median of mutated genes in each cancer type. Before computing the correlation, an infinitesimal amount of uniformly distributed noise is added to the fraction of samples with mutations to avoid the problem of having all zero entries.

example 2

[0143] Z-scores for driver and passenger gene tumor mutational burden

[0144] The Z-score method for driver / passenger TMB involves the following. To calculate z-scores with respect to TMB, the background distribution of TMB was first determined using a randomly selected gene set of 1000 equal sizes. The number of mutated driver / passenger genes is then compared to the background distribution to calculate a z-score indicating how many standard deviations the number is from the background mean. Driver genes were downloaded from the COSMIC Cancer Gene Census on January 22, 2015, and passenger genes were defined as the top n genes by PGI derived from TCGA data.

example 3

[0146] Passenger gene tumor mutation burden and immunotherapy responsiveness

[0147] To calculate the Passenger Gene Index (PGI), a list of non-silent somatic mutations from 6,685 samples spanning 20 TCGA tumor types was compiled. Somatic mutations are determined by comparing the tumor genome with that of a germline, eg, blood-derived normal sample from a systemic patient. The median number of altered genes / sample ranged from 9 in acute myeloid leukemia to 289 in cutaneous melanoma of the skin, representing a more than 32-fold difference between the lowest and highest mutation rate cancers ( Figure 5 ). This is consistent with previous observations that skin and lung cancer samples had the highest mutation rates due to exposure to environmental mutagens. Figure 5 The number of non-silent somatic mutations / sample in the 6,685 TCGA cancer exomes is shown.

[0148] The 20 cancer types included in this study were bladder urothelial carcinoma (BLCA), breast invasive carcinoma...

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Abstract

Methods for selecting a cancer patient for immunotherapy comprise establishing a total passenger gene mutation burden from a tumor of a cancer patient, generating a background distribution for the mutational burden of the tumor, normalizing the total passenger gene mutation burden against the background distribution, and categorizing the cancer patient as an immunotherapy responder when the totalpassenger gene mutation burden is greater than the mean of the background distribution. When the cancer patient is an immunotherapy responder, the patient may be administered an immunotherapy regimenthat comprises activation / inhibition of T cell receptors that promote T cell activation and / or prolong immune cytolytic activities.

Description

[0001] Cross References to Related Applications [0002] This patent application claims the benefit of U.S. Provisional Application No. 62 / 560,955, filed September 20, 2017, and is hereby incorporated by reference in its entirety. technical field [0003] The present disclosure relates generally to the field of immunotherapy. More specifically, the present disclosure relates to methods of administering immunotherapy to patients whose tumors have a high passenger gene mutation burden. Background technique [0004] Throughout the specification, various publications are cited, including patents, patent applications, published patent applications, accession numbers, technical papers, and scholarly treatises. Each of these cited publications is hereby incorporated by reference in its entirety and for all purposes. [0005] Recent studies suggest that patients with a higher overall tumor mutation burden (TMB) in their tumors are more likely to benefit from immunotherapy treatme...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/6886C12Q1/6809
CPCA61P35/00A61P35/02C12Q1/6886A61K2039/505C12Q2600/156C12Q2600/106C07K2317/56C07K16/2803C07K16/2818G16B20/50G16B30/00G16B40/00G16H20/10A61K2039/876A61K2039/86A61K2039/804C12Q1/6809C12Q2600/158Y02A90/10C12Q2535/122G16B30/10C12Q2565/519C12Q1/6806G16B5/00G16B15/00
Inventor 林伟杰
Owner REGENERON PHARM INC
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