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US-12617834-B2 - Composition of NY-ESO-1-specific t cell receptors restricted on multiple major histocompatibility complex molecules

US12617834B2US 12617834 B2US12617834 B2US 12617834B2US-12617834-B2

Abstract

Tumor-specific T cell receptor (TCR) gene transfer enables specific and potent immune targeting of tumor antigens. The canonical cancer-testis antigen, NY-ESO-1, is not expressed in normal tissues but is aberrantly expressed across a broad array of cancer types. It has also been targeted with A2-restricted TCR gene therapy without adverse events or notable side effects. To enable the targeting of NY-ESO-1 in a broader array of HLA haplotypes, we isolated TCRs specific for NY-ESO-1 epitopes presented by four MHC molecules: HLA-A2, -B07, -B18, and -C03. Using these TCRs, we have developed an approach to extend TCR gene therapies targeting NY-ESO-1 to patient populations beyond those expressing HLA-A2.

Inventors

  • Owen N. Witte
  • Jami McLaughlin Witte
  • Antoni Ribas
  • Lili Yang
  • MICHAEL T. BETHUNE
  • Jonathan Cebon
  • Katherine Woods
  • Ashley J. Knights
  • David Baltimore

Assignees

  • THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
  • CALIFORNIA INSTITUTE OF TECHNOLOGY
  • LUDWIG INSTITUTE FOR CANCER RESEARCH LTD

Dates

Publication Date
20260505
Application Date
20190904

Claims (7)

  1. 1 . A polynucleotide disposed in a vector, wherein: the polynucleotide encodes a Vα T cell receptor polypeptide and a Vβ T cell receptor polypeptide; and when a Vα/Vβ T cell receptor comprising the Vα T cell receptor polypeptide and/or the Vβ T cell receptor polypeptide is expressed in a CD 8 + T cell, the Vα/Vβ T cell receptor recognizes a NY-ESO-1 peptide associated with: human leukocyte antigen A2; and the vector comprises: (a) a polynucleotide encoding a 3A1 Vα polypeptide (SEQ ID NO: 3); and (b) a polynucleotide encoding a 3A1 Vβ polypeptide (SEQ ID NO: 4); wherein the vector comprises a polynucleotide sequence that modulates expression of the polypeptide within CD 8 + T cells.
  2. 2 . The polynucleotide of claim 1 , wherein the vector is a Sendai viral vector, an adenoviral vector, an adeno-associated virus vector, a retroviral vector, or a lentiviral vector.
  3. 3 . A composition of matter comprising a host cell transduced with a vector comprising a polynucleotide, wherein: the polynucleotide encodes a Vα T cell receptor polypeptide and a Vβ T cell receptor polypeptide; and when a Vα/Vβ T cell receptor comprising the Vα T cell receptor polypeptide and/or the Vβ T cell receptor polypeptide is expressed in a CD 8 + T cell, the Vα/Vβ T cell receptor recognizes a NY-ESO-1 peptide associated with: human leukocyte antigen A2; and the vector comprises: (a) a polynucleotide encoding a 3A1 Vα polypeptide (SEQ ID NO: 3); and (b) a polynucleotide encoding a 3A1 Vβ polypeptide (SEQ ID NO: 4).
  4. 4 . The composition of claim 3 , wherein the host cell is a human CD 8 + T cell.
  5. 5 . The composition of claim 4 , wherein the composition is a pharmaceutical composition comprising one more pharmaceutically acceptable excipients selected from the group consisting of buffering agents, antimicrobial agents, tonicity adjusting agents, wetting agents, detergents and pH adjusting agents.
  6. 6 . The composition of claim 5 , wherein: the CD8 + T cell is obtained from an individual diagnosed with a cancer that expresses a NY-ESO-1 antigen; and the CD8 + T cell is transduced with a vector comprising a polynucleotide encoding a TCR Vα polypeptide in combination with a polynucleotide encoding a TCR Vβ polypeptide such that a heterologous TCR is expressed on a surface of the CD8 + T cell, wherein the heterologous TCR recognizes a NY-ESO-1 peptide associated with a human leukocyte antigen expressed on the surface of cells of the cancer.
  7. 7 . The composition of claim 6 , wherein the vector is a retroviral vector.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. Section 119(e) of commonly-assigned U.S. Provisional Patent Application Ser. No. 62/727,485, filed on Sep. 5, 2018, and entitled “COMPOSITION OF NY-ESO-1-SPECIFIC T CELL RECEPTORS RESTRICTED ON MULTIPLE MAJOR HISTOCOMPATIBILITY COMPLEX MOLECULES” which application is incorporated by reference herein. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT This invention was made with government support under Grant Numbers CA132681 and CA197633, awarded by the National Institutes of Health. The government has certain rights in the invention. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Aug. 28, 2019, is named 30435_364-WO-U1_SL.txt and is 101,375 bytes in size. TECHNICAL FIELD The present invention relates to methods and materials useful in αβ T cell receptor gene therapy. BACKGROUND OF THE INVENTION The αβ T cell receptor (TCR) determines the unique specificity of each naïve T cell. Upon assembly with CD3 signaling proteins on the T cell surface, the TCR surveils peptide ligands presented by major histocompatibility complex (MHC) molecules on the surface of nucleated cells. The specificity of the TCR for a peptide-MHC complex is determined by both the presenting MHC molecule and the presented peptide. The MHC locus (also known as the human leukocyte antigen (HLA) locus in humans) is the most multi-allelic locus in the human genome, comprising >18,000 MHC class I and II alleles that vary widely in frequency across ethnic subgroups (1, 2). Ligands presented by MHC class I molecules are derived primarily from proteasomal cleavage of endogenously expressed antigens. Infected and cancerous cells present peptides that are recognized by CD8+ T cells as foreign or aberrant, resulting in T cell-mediated killing of the presenting cell. T cells can be engineered to kill tumor cells through the transfer of tumor-reactive as TCR genes (3). Key to this approach is that the patient expresses the MHC allele on which the therapeutic TCR is restricted and that the targeted peptide is derived from a tumor-associated or tumor-specific antigen. Private (patient-specific) neoantigens resulting from tumor-specific mutations are a potential source of such targets (4). However, implementation of personalized TCR gene therapy is complicated by the need to identify mutations through sequencing, to isolate mutation-reactive, patient-specific TCRs, and to genetically modify patient T cells on-demand. This is still more challenging for tumors that cannot be accessed for sequencing and for low mutational burden tumors with few or no neoantigens (5). Particularly for these last tumor types, targeting public (non-patient specific), tumor-restricted antigens with off-the-shelf TCRs remains an attractive option. The first public antigen targeted with TCR gene therapy in the clinic was melanocyte antigen MART1/Melan-A, yielding objective responses in 2/15 patients with metastatic melanoma (6). Use of a higher affinity MART1-reactive TCR (F5) increased the response rate to 30% but also produced a variety of side effects including vitiligo, uveitis, and transient hearing loss due to MART1 expression on healthy melanocytes in the skin, eye, and middle ear (7). T cell therapies targeting other public antigens have similarly resulted in morbidity or other serious adverse events due to on-target/off-tumor reactivity. For example, targeting carcinoembryonic antigen produces severe colitis in patients with metastatic colorectal cancer due to reactivity with normal colorectal tissue (8). More seriously, T cell therapies targeted at ERBB2 or MAGE-A3 each resulted in deaths due to unappreciated expression of the target antigen (or similar variant) on vital organs (9, 10). Thus, these studies underscore the importance of identifying stringently tumor-specific public antigens (11), particularly when well-expressed, high-affinity targeting receptors necessary for therapeutic success are employed (7, 12). NY-ESO-1—the product of the CTAG1B gene—is an attractive target for off-the-shelf TCR gene therapy. As the prototypical cancer-testis antigen, NY-ESO-1 is not expressed in normal, non-germline tissue, but it is aberrantly expressed in many tumors (13). The frequency of aberrant expression ranges from 10-50% among solid tumors, 25-50% of melanomas, and up to 80% of synovial sarcomas (13-18), with increased expression observed in higher-grade metastatic tumor tissue (14, 15, 19). Moreover, NY-ESO-1 is highly immunogenic, precipitating spontaneous and vaccine-induced T cell immune responses against multiple epitopes presented by various MHC alleles (20-23). As a result, the epitope NY-ESO-1157-165 (SLLMWITQC, (SEQ ID NO. 36)) presented by HLA-A*02:01 has been targeted with cognate 1G4 TCR in gene t