Checkpoint Blockade and Microsatellite Instability

a checkpoint blockade and microsatellite technology, applied in the field of cancer, can solve the problem of accumulation of sequencing errors in microsatellites, microsatellite instability (msi) is the accumulation of sequencing errors, and achieve the effect of high mutational burden

Inactive Publication Date: 2017-09-21
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]According to one embodiment of the invention a method of treating a cancer patient is provided. The cancer patient has a high mutational

Problems solved by technology

Microsatellite instability (MSI) is the accumu

Method used

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  • Checkpoint Blockade and Microsatellite Instability
  • Checkpoint Blockade and Microsatellite Instability
  • Checkpoint Blockade and Microsatellite Instability

Examples

Experimental program
Comparison scheme
Effect test

example 1

MSI Testing

[0041]MSI testing is already standardized and performed in CLIA-certified laboratories without need for assay development. Archived tumor samples or newly obtained biopsies will be used for determining MSI. MSI status will be performed locally by CLIA certified immunohistochemistry (IHC) or PCR based tests for eligibility. Evaluable patients will be confirmed using the MSI Analysis System from Promega at Johns Hopkins. This test will determine MSI status through the insertion or deletion of repeating units in the five nearly monomorphic mononucleotide repeat markers (BAT-25, BAT-26, MONO-27, NR-21 and NR-24). At least 2 MSI loci are required to be evaluable in Cohorts A and C. Patients may be assigned to a new cohort and / or replaced based on the Promega test results.

example 2

Methods

[0042]Patients

[0043]Treatment-refractory progressive metastatic cancer patients for this phase 2 study were recruited from three participating centers (Table 1). Three cohorts were evaluated: Cohort A was composed of patients with MMR-deficient colorectal adenocarcinomas; Cohort B was composed of patients with MMR-proficient colorectal adenocarcinomas; and Cohort C was composed of patients with MMR-deficient cancers of types other than colorectal.

[0044]Study Oversight

[0045]The protocol, which can be found at NEJM.org, was approved by each site's institutional review boards, and the study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. All the patients provided written informed consent before study entry. The principal investigator (D.L.) and study sponsor (L.A.D.) were responsible for oversight of the study. Merck donated the study drug, reviewed the final drafts of the proto...

example 3

Supplementary Methods

[0055]Patients

[0056]To be eligible for participation in this study, patients had to be at least 18 years of age, have histologically confirmed evidence of previously-treated, progressive carcinoma. All patients underwent MMR status testing prior to enrollment. All patients had at least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1, and adequate hematologic, hepatic, and renal function. Eligible patients with CRC must have received at least 2 prior cancer therapies and patients with other cancer types must have received at least 1 prior cancer therapy. Patients with untreated brain metastases, history of HIV, hepatitis B, hepatitis C, clinically significant ascites / effusions, or autoimmune disease were excluded.

[0057]Study Oversight

[0058]Initial drafts of the manuscript were prepared by a subset of the authors and all autho...

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Abstract

Blockade of immune checkpoints such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) shows promise in patients with cancer. Inhibitory antibodies directed at these receptors have been shown to break immune tolerance and promote anti-tumor immunity. These agents work particularly well in patients with a certain category of tumor. Such tumors may be particularly susceptible to treatment because of the multitude of neoantigens which they produce.

Description

[0001]This invention was made with government support under CA43460 and CA62924 awarded by the National Institutes of Health. The government has certain rights in the invention.TECHNICAL FIELD OF THE INVENTION[0002]This invention is related to the area of cancer. In particular, it relates to cancer therapy.BACKGROUND OF THE INVENTION[0003]Microsatellite instability (MSI) is the accumulation of sequencing errors in microsatellites. This occurs in tumors with deficiency in DNA mismatch repair. MSI is present in Lynch Syndrome which is an inherited cancer syndrome that predisposes patients to colon, endometrial, gastric cancer, ovarian, small intestine, liver, hepatobiliary, upper urinary tract, brain, and prostate cancer. MSI is also present in 10-20% of sporadic colorectal, gastric, prostate, lung, ampullary, and endometrial cancers. Between 0.3% and 13% of pancreatic cancers are reported to be MSI as well.[0004]The importance of intact immune surveillance in controlling outgrowth of...

Claims

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Application Information

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IPC IPC(8): C07K16/28C12Q1/68A61K39/395G01N33/574
CPCC07K16/2803C07K2317/00A61K2039/55C12Q1/6886C07K16/2818A61K2039/505C07K2317/24C07K2317/76C12Q2600/106C12Q2600/156C12Y113/11052A61P1/04A61P1/16A61P13/08A61P15/00A61P35/00C07K16/2827C07K16/30C07K16/40
Inventor DIAZ, LUISVOGELSTEIN, BERTKINZLER, KENNETH W.PAPADOPOULOS, NICKOLASLE, DUNG
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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