US-12622926-B2 - Immunotherapy targeting tumor neoantigenic peptides

US12622926B2US 12622926 B2US12622926 B2US 12622926B2US-12622926-B2

Abstract

The present disclosure relates to a method for selecting a tumor neoantigenic peptide wherein said method comprises: —a step of identifying, among mRNA sequences from cancer cells of a subject, a fusion transcript sequence comprising a transposable element (TE) sequence and an exonic sequence, and including an open reading frame (ORF), and—a step of selecting a tumor neoantigenic peptide of at least 8 amino acids, encoded by a part of said ORF of the fusion transcript sequence, wherein said ORF overlaps the junction between the TE and the exonic sequence, is pure TE and/or is non-canonical, and wherein said tumor neoantigenic peptide binds to at least one Major Histocompatibility Complex (MHC) molecule of said subject. The present disclosure also relates to tumor neoantigenic peptide obtained according to the present method, vaccine or immunogenic composition, antibodies and immune cells derived thereof and their use in therapy of cancer.

Inventors

Sebastian Amigorena
Marianne BURBAGE
Alexandre HOUY
Marc-Henri Stern
Joshua Waterfall
Benjamin SADACCA
Antonela MERLOTTI IPPOLITO
Yago ARRIBAS DE SANDOVAL

Assignees

INSTITUT CURIE
MNEMO THERAPEUTICS
INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

Dates

Publication Date: 20260512
Application Date: 20200902
Priority Date: 20191220

Claims (6)

1 . A method of treating cancer, inhibiting cancer cell proliferation or providing cancer vaccination therapy in a subject, the method comprising administering to the subject in need thereof a composition comprising a tumor neoantigenic peptide comprising at least 8 amino acids, or a nucleic acid encoding the tumor neoantigenic peptide, wherein the neoantigenic peptide is encoded by a part of an open reading frame (ORF) from a fusion transcript comprising a transposable element (TE) sequence and an exonic sequence, and wherein the ORF overlaps the junction between the TE and the exonic sequence, is pure TE or is non-canonical.
2 . The method of claim 1 comprising administering at least one further therapeutic agent.
3 . The method of claim 2 wherein said at least one further therapeutic agent is a chemotherapeutic agent, or an immunotherapeutic agent, optionally a checkpoint inhibitor.
4 . The method of claim 1 wherein the subject is suffering from NSCLC or is at risk of suffering from NSCLC.
5 . A method according to claim 1 , wherein said tumor neoantigenic peptide is 8 to 11 amino acids long, and binds to at least one MHC class 1 molecule of said subject, or wherein said tumor neoantigenic peptide is from 13 to 25 amino acids long, and binds to at least one MHC class II molecule of said subject.
6 . A method according to claim 1 , wherein said neoantigenic peptide is expressed at higher levels in tumor cells compared to normal healthy cells; is expressed in at least 1% of subjects from a population of subjects suffering from cancer; and/or binds MHC class I or class II with a Kd binding affinity of less than about 10 −5 M.

Description

FIELD OF THE DISCLOSURE The present disclosure provides neoantigenic peptides encoded by transposable element (TE)-exon fusion transcripts, nucleic acids, vaccines, antibodies and immune cells that can be used in cancer therapy. INCORPORATION BY REFERENCE This application includes, as a separate part of disclose, a Sequence Listing in computer-readable form (Filename: SubSeqListing.txt, Size: 26.2 MB; Created: Apr. 20, 2023). The contents of the Sequence Listing text file incorporated herein by reference in their entirety. BACKGROUND Harnessing the immune system to generate effective responses against tumors is a central goal of cancer immunotherapy. Part of the effective immune response involves T lymphocytes specific for tumor antigens. T cell activation requires their interaction with antigen-presenting cells (APCs), commonly dendritic cells (DCs), expressing TCR-cognate peptides presented in the context of a major histocompatibility molecule (MHC) and co-stimulation signals. Subsequently, activated T cells can recognize peptide-MHC complexes presented by all cell types, even malignant cells. Neoplasms often contain infiltrating T lymphocytes reactive with tumor cells. However, the efficiency of immune responses against tumors is severely dampened by various immunosuppressive strategies developed by tumors; e.g, tumor cells express receptors that provide inhibitory signals to infiltrating T cells, or they secrete inhibitory cytokines. The development of checkpoint blockade therapy has provided means to bypass some of these mechanisms, leading to more efficient killing of cancer cells. The promising results yielded by this approach have opened up new avenues for the development of T cell-based immunotherapy. Checkpoint inhibitors are, however, effective in a minority of patients and only in limited types of cancer. A major goal in immunotherapy is to increase the proportion of responding patients and extend the cancer indications. Vaccination, administration of anti-tumor antibodies, or administration of immune cells specific for tumor antigens have all been proposed to increase the anti-tumor immune response, and can be administered alone, with other therapies such as chemotherapy or radiation, or as a combination therapy with checkpoint blockers. The selection of antigens able to trigger anti-tumor immunity without targeting healthy tissues has been a long-standing challenge. The search for tumor neoantigens has mostly been focused on mutated sequences appearing as in cancer cells. These antigens are unique to each patient. Tumor antigens (the ones preferentially expressed in tumor cells) are, however, self-antigens that represent poor targets for vaccination (probably due to central tolerance). Identifying shared true neoantigens (absent from tissues) is a major challenge for the field. A few prior reports regarding transposable elements (TE) in tumors include (Helman, E. et al. (2014). Genome Res.)(Schiavetti, F. et al. (2002). Cancer Res., Takahashi, Y. et al. (2008). J Clin. Invest.). (Chiappinelli, K. B. et al. (2015). Cell, Roulois, D. et al. (2015). Cell). However, the relationship of TE to the antigenic landscape presented by tumor cells has not been investigated in depth. New tumor neoantigens would be of interest and might improve or reduce the cost of cancer therapy in particular in the case of vaccination and adoptive cell therapy. SUMMARY The present disclosure provides a tumor neoantigenic peptide comprising at least 8 amino acids, wherein said neoantigenic peptide is encoded by a part of an open reading frame (ORF) from a fusion transcript sequence comprising a transposable element (TE) sequence and an exonic sequence. Typically said ORF may overlaps the junction between the TE and the exonic sequence,be pure TE, and/orbe non-canonical. The present disclosure also provides a method for selecting a tumor neoantigenic peptide which comprises: a step of identifying, among mRNA sequences from cancer cells of a subject, a fusion transcript sequence comprising a transposable element (TE) sequence and exonic sequence, including an open reading frame (ORF), anda step of selecting a tumor neoantigenic peptide of at least 8 amino acids, encoded by a part of said ORF of the fusion transcript sequence, wherein said ORF overlaps the junction between the TE and the exonic sequence, is pure TE and/or is non-canonical, and wherein said tumor neoantigenic peptide binds to at least one Major Histocompatibility Complex (MHC) molecule of said subject. In one embodiment, the tumor neoantigenic peptide is 8 or 9 amino acids long, notably 8 to 11, and binds to at least one MHC class I molecule. In another embodiment, the tumor neoantigenic peptide is from 13 to 25 amino acids long, and binds to at least one MHC class II molecule of said subject. According to the present disclosure, “neoantigen peptide characteristics” include: the TE sequence can be located in 5′ end of the fusion transcript sequence and the