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Mesothelin vaccines and model systems

A mesothelin and vaccine technology, applied in the direction of antibody medical components, carrier-bound antigen/hapten components, peptide/protein components, etc., can solve the problem of inability to generate T cell lines, cloning, and clinical response.

Inactive Publication Date: 2006-11-08
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A major limitation is the inability to generate patient-derived T cell lines and clones that can be used to identify immune-related tumor targets
Moreover, T cell responses to specific human tumor antigens have not been correlated with clinical response after immunotherapy

Method used

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  • Mesothelin vaccines and model systems
  • Mesothelin vaccines and model systems
  • Mesothelin vaccines and model systems

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] In order to identify genes that can be potential immune targets for most pancreatic cancer patients, we only focused on those unmutated genes that were overexpressed in most pancreatic cancer patients and overexpressed in vaccine cell lines. The first gene on this list is mesothelin (20, 21). For comparison and confirmation, we also studied prostate stem cell antigen (PSCA). SAGE data confirm that pancreatic cancer will express PSCA at levels similar to mesothelin (22).

[0097] We use a combination of two publicly available computer algorithms (23-25) to predict peptide nonamers that can bind to three common human leukocyte antigen (HLA) class I molecules. All 14 patients treated with the allogeneic GM-CSF vaccine expressed at least one of these HLA class I molecules (Table 2). The prediction algorithm "BIMAS" ranks possible HLA binding epitopes based on the predicted half-life dissociation of the peptide / HLA complex (23). The "SYFPEITHI" algorithm ranks peptides based on ...

Embodiment 2

[0110] To determine whether mesothelin and PSCA are affected by CD8 + T cell recognition, we use the patient’s CD8-rich + The PBL of T cells screens antigen-pulsed T2 cells, and these patients receive an allogeneic pancreatic cancer vaccine that secretes GM-CSF. We previously reported that in 3 of 8 patients who received up to two vaccines, delayed-type hypersensitivity (DTH) reactions in vivo after vaccination were associated with autologous tumors. These "DTH responders" (they all have poor prognostic indicators at the first surgical resection) (27) are only patients who have not had pancreatic cancer clinically for more than 4 years after diagnosis ((27), Table 2). The PBL obtained before vaccination and 28 days after the first vaccination was analyzed initially. T2-A3 cells pulsed with two A3 binding epitopes are enriched with peripheral blood isolated from patient 10 (non-DTH responder, relapsed 9 months after diagnosis) and patient 13 (DTH responder, still disease-free) CD8 ...

Embodiment 3

[0116] The above data clearly demonstrates the in vivo DTH response to autologous tumors and the long-term disease-free survival and mesothelin-specific CD8 + Correlation between post-vaccination induction of T cell responses. However, this correlation may be systemic immunosuppression (for patients who cannot prove DTH response to autologous tumors and disease progression after vaccination), rather than vaccine-specific induction of mesothelin in patients who remain disease-free DTH response T cell response. To prove CD8 specific for mesothelin + The induction of T cells after vaccination is tumor antigen-specific, and we evaluated the T cell response of each HLA-A2-positive patient to HLA-A2-binding influenza matrix peptide M1 (28). We chose the influenza M1 peptide because most of the patients in the vaccine study received an influenza vaccine some time before participating. Such as image 3 As shown, all HLA-A2-positive patients demonstrated similar pre-vaccination and post-va...

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Abstract

Mesothelin can be used as an immunotherapeutic target. It induces a cytolytic T cell response. Portions of mesothelin which induce such responses are identified. Vaccines can be either polynucleotide- or polypeptide-based. Carriers for raising a cytolytic T cell response include bacteria and viruses. A mouse model for testing vaccines and other anti-tumor therapeutics and prophylactics comprises a strongly mesothelin-expressing, transformed peritoneal cell line.

Description

[0001] The contents of all the following applications are quoted here: US provisional application serial number 60 / 395,556 filed on July 12, 2002, 60 / 398,217 filed on July 24, 2002, serial number 60 filed on September 30, 2002 / 414,931, serial number 60 / 475,783 filed on June 5, 2003. [0002] The invention was developed with funds from the US government. The terms of the funds NCI CA62924, NCI R01CA72631, NCI R01 CA71806, U19 CA72108-02 and NCDDG RFA CA-95-020 allow the US government to reserve certain rights in this invention. [0003] Part of the disclosure of this patent document includes material protected by copyright. The copyright owner does not object to anyone copying patent documents or patent disclosures in the form of patent documents or records in the Patent and Trademark Office, except that all copyrights are reserved. Invention field [0004] The invention relates to the field of cancer treatment, cancer prognosis and anticancer drug developme...

Claims

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Application Information

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IPC IPC(8): A01N63/00A01K67/00A01K67/027A01K67/033A61K38/00A61K39/00A61K39/38A61K39/385
CPCY02A50/30
Inventor E·雅菲T-C·伍C-F·翰格R·赫鲁班
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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