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T cell receptors recognizing mutated p53

A cell-receptor, specific technology for the treatment or prevention of cancer in mammals to address the limited options for cancer treatment, the unmet need for additional cancer treatments, and poor cancer prognosis

Pending Publication Date: 2020-07-07
UNITED STATES OF AMERICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Treatment options for some cancers may be very limited, especially when the cancer has metastasized and is unresectable
Many cancers (such as pancreatic, colorectal, lung, endometrial, ovarian, and prostate) can have a poor prognosis despite advances in treatments such as surgery, chemotherapy, and radiation therapy
Therefore, there is an unmet need for additional treatments for cancer

Method used

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  • T cell receptors recognizing mutated p53
  • T cell receptors recognizing mutated p53
  • T cell receptors recognizing mutated p53

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0167] This example demonstrates the isolation and specific reactivity of 4 TCRs against mutated p53 from patient 4127.

[0168] combine Figure 1-7 Experiments were performed on patient 4127 as described in , 36 and 37A-37C. Mutant p53-reactive T cells in this patient were identified by the methods described in US Patent Application No. 2017 / 0224800 ("Tran Method"). The method for isolating individual TCRs is described below.

[0169] use figure 1 One of the TCRs shown in transduced autologous PBLs and tested 2 weeks later. Autologous DC cells were plated at 3 x 10 4 Cells / well were plated and pulsed overnight with decreasing concentrations of WT p53-G245 peptide (wt) or mutant p53-G245S peptide (mut). Add 3x 10 per hole 4 Transduced T cells were co-cultured overnight at 37°C. The supernatant was harvested for IFN-γ ELISA. IFN-γELISA results see figure 1 . 4-1BB expression by FACS gating: lymphocytes\PI(neg)CD3 + \CD3 + MTCR + \CD8(neg)CD4 + . For FACS results ...

Embodiment 2

[0233]This example demonstrates the isolation and specific reactivity of 3 anti-mutant p53 TCRs from patient 4196.

[0234] Experiments were performed on Patient 4196 as described in Figures 8-11. The patient's p53-reactive T cells were identified by the Tran method as described in US Patent Application No. 2017 / 0224800. Individual TCRs were isolated using the Fluidigm method. The statistics of patient 4196 are shown in Table D.

[0235] Characterization of p53-responsive cells: the challenge of identifying the minimal epitope: The first predicted peptide with the mutated amino acid p53 R 175H is shown in Table C.

[0236] Form C

[0237] HLA HLA-A0201 Peptide HMTEVVRHC (SEQ ID NO: 530) core HMTEVVRHC (SEQ ID NO: 530) Affinity (nM) 7826.06 %grade 13.00

[0238] MG1 vs 4196-Rx1 TIL:COS7 cells were transfected with plasmids for TMG1 and HLA alleles. Cells were co-cultured with 4196Rx1 TIL infusion bags for 20 hours (h). see the res...

Embodiment 3

[0270] This example demonstrates the isolation of 11 anti-mutant p53 TCRs from patient 4238.

[0271] as for Figure 12-15 The experiment was performed on patient 4238 as described.

[0272] TIL fragments from patient 4238 (F1-F24, n=24) were co-cultured with TMG electroporated autologous APCs consisting of unrelated or mutated p53 sequences. Co-cultures were grown overnight at 37°C. IFN-γ secretion was assessed using the ELISPOT assay. see the results Figure 12 . Expression of 4-1BB was assessed by flow cytometry after gating on lymphocytes→live cells (PI negative)→CD3+ (T cells). see the results Figure 14 .

[0273]TIL fragments of patient 4238 (F1-F24, n=24) were co-cultured with autologous APCs pulsed with peptide vehicle (DMSO) or with a purified 25 amino acid peptide consisting of the mutant p53-R248Q sequence (HPLC method >95%) pulsed. Co-cultures were grown overnight at 37°C. IFN-γ secretion was assessed using the ELISPOT assay. see the results Figure 13...

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Abstract

Disclosed is an isolated or purified T cell receptor (TCR) having antigenic specificity for mutated human p53. Related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions are also provided. Also disclosed are methods of detecting the presence of cancer in a mammal and methods of treating or preventing cancer in a mammal.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This patent application claims the benefit of US Provisional Patent Application No. 62 / 565,383, filed September 29, 2017, which is incorporated herein by reference in its entirety. [0003] Statement Regarding Federally Funded Research and Development [0004] The present invention was made by the National Cancer Institute of the National Institutes of Health (National Institutes of Health, National Cancer Institute) with government support, and the project number is BC010985. The government has certain rights in this invention. [0005] Incorporate by reference electronically submitted material [0006] Incorporated herein by reference in its entirety is the computer-readable nucleotide / amino acid sequence listing concurrently filed and identified as: a 687,555-byte ASCII ( text) file. [0007] Background of the Invention [0008] Treatment options for some cancers can be very limited, especially when the cancer has m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/725
CPCA61K39/464451A61K39/4632A61K39/4611C07K14/7051C12N5/0636G01N33/574A61K38/00A61P35/00G01N2800/7028
Inventor 德鲁·C·丹尼格尔史蒂文·A·罗森伯格安娜·帕塞托拉米·约瑟夫威尼弗雷德·M·卢卢勇成玛丽亚·R·帕克赫斯特保罗·F·罗宾斯帕里萨·马勒克扎德
Owner UNITED STATES OF AMERICA
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