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EP-4735024-A1 - MODIFIED HUMAN LYMPHOCYTES CONTAINING AND EXPRESSING POSITIVE REGULATORS OF AUTOPHAGY

EP4735024A1EP 4735024 A1EP4735024 A1EP 4735024A1EP-4735024-A1

Abstract

The present invention relates to a modified human lymphocyte containing and expressing a recombinant nucleic acid or a set of recombinant nucleic acids encoding at least one positive regulator of autophagy. The modified human lymphocyte according to the invention may further contain and express a recombinant nucleic acid or a set of recombinant nucleic acids encoding a T-cell receptor or a chimeric antigen receptor. The invention also relates to methods of producing such modified human lymphocytes, pharmaceutical compositions comprising the same, as well as their uses in medicine and for methods for the treatment of cancer including the immunotherapeutic treatment of cancer.

Inventors

  • CARUANA, Ignazio
  • MACKWIRTH, Markus
  • SCHLEGEL, Paul-Gerhardt
  • THEINERT, Tobias

Assignees

  • Julius-Maximilians-Universität Würzburg

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1. A modified human lymphocyte containing a recombinant nucleic acid or set of recombinant nucleic acids encoding at least one positive regulator of autophagy.
  2. 2. The modified human lymphocyte according to claim 1, wherein the at least one positive regulator of autophagy is one or more human protein(s).
  3. 3. The modified human lymphocyte according to claim 1 or 2, wherein the one or more human protein(s) are selected from the group consisting of: human TFEB, human Beclin-1, human ATG5, human AMBRA1, human ULK1, human ATG14, human WIPI1, human WIPI2, human p62, human VP34, human ATG4A, human Annexin A2, human Polycystin 2, human NFT2, and human ATG7.
  4. 4. The modified human lymphocyte according to any one of the preceding claims, wherein the at least one positive regulator of autophagy is human TFEB, human Beclin-1, and/or human ATG5.
  5. 5. The modified human lymphocyte according to any one of claims 1-4, wherein the at least one positive regulator of autophagy is human TFEB.
  6. 6. The modified human lymphocyte according to any one of claims 1-4, wherein the at least one positive regulator of autophagy is human Beclin-1 .
  7. 7. The modified human lymphocyte according to any one of claims 1-4, wherein the at least one positive regulator of autophagy is human ATG5.
  8. 8. The modified human lymphocyte according to claim 1, wherein the at least one positive regulator of autophagy is one or two peptides selected from the following group: TNVFNATFHIWHSGQFGT (SEQ ID NO: 1) and TNVFNATFEIWHDGEFGT (SEQ ID NO: 2).
  9. 9. The modified human lymphocyte according to any one of the preceding claims, wherein the lymphocyte expresses said at least one positive regulator of autophagy from said recombinant nucleic acid or set of recombinant nucleic acids.
  10. 10. The modified human lymphocyte according to claim 9, wherein the expression of said at least one positive regulator of autophagy from said recombinant nucleic acid or set of recombinant nucleic acids is constitutive.
  11. 11 . The modified human lymphocyte according to claim 9, wherein the expression of said at least one positive regulator of autophagy from said recombinant nucleic acid or set of recombinant nucleic acids is inducible.
  12. 12. The modified human lymphocyte according to any one of the preceding claims, wherein the lymphocyte is a T-cell, an NK cell, or an NKT cell.
  13. 13. The modified human lymphocyte according to any one of the preceding claims, wherein the lymphocyte is a T-cell.
  14. 14. The modified human lymphocyte according to any one of the preceding claims, wherein the lymphocyte is an op T-cell.
  15. 15. The modified human lymphocyte according to any one of claims 1-13, wherein the lymphocyte is an y5 T- cell.
  16. 16. The modified human lymphocyte according to any one of the preceding claims, wherein the lymphocyte is a CD8 + T-cell.
  17. 17. The modified human lymphocyte according to any one of claims 1-15, wherein the lymphocyte is a CD4 + T-cell.
  18. 18. The modified human lymphocyte according to any one of claims 1-12, wherein the lymphocyte is an NK cell.
  19. 19. The modified human lymphocyte according to any one of claims 1-12, wherein the lymphocyte is a NKT cell.
  20. 20. The modified human lymphocyte according to any one of the preceding claims, wherein the lymphocyte further contains and expresses a recombinant nucleic acid or a set of recombinant nucleic acids encoding a T-cell receptor or a chimeric antigen receptor.

Description

Modified human lymphocytes containing and expressing positive regulators of autophagy. FIELD OF THE I NVENTION The present invention relates to a modified human lymphocyte containing and expressing a recombinant nucleic acid or a set of recombinant nucleic acids encoding at least one positive regulator of autophagy. The modified human lymphocyte according to the invention may further contain and express a recombinant nucleic acid or a set of recombinant nucleic acids encoding a T-cell receptor or a chimeric antigen receptor. The invention also relates to methods of producing such modified human lymphocytes, pharmaceutical compositions comprising the same, as well as their uses in medicine and for methods for the treatment of cancer including the immunotherapeutic treatment of cancer. BACKGROUND Over the past decades great improvements have been made in the field of haematology and oncology with the development of intense multimodal treatments, supportive care and a better characterization of tumour biology. Nevertheless, patients suffering from recurrent or resistant tumours still maintain an unfavourable outcome1’2. For these patients there is the urgent clinical need to identify new and more efficient intervention strategies. It has been clearly shown that tumours are susceptible to targeted and immune-based therapies including adoptive cell therapy which involves harvesting immune cells (T, NK and NK-T cells), expanding them ex vivo and re-directing them to target cancer cells. Although these kinds of therapies have been studied for decades, only recently they were able to elicit clinical benefit in a wider range of patients. Observations that Epstein Barr Virus (EBV)-specific cytotoxic T cells (CTLs) from seropositive donors were able to control EBV- transformed B cells in vitro led to the first antigen specific T cell therapies that were used to treat post-transplant lymphoproliferative disorder (PTLD)3 4. Several efforts have also focused on the genetical modification of T cells to recognize tumour cells either via an exogenous T cell receptor (TCR) or with the addition of a Chimeric Antigen Receptor (CAR). The first is able to recognize peptide antigens (mainly derived from intracellular proteins) but is limited by the major histocompatibility complex (MHC) restriction and the lack of the appropriate continuation necessary for the optimal T cell activation. CARs instead contain an antibody-derived single chain variable fragment (scFv), conferring target specificity, fused to a transduction signal domain like the CD3 chain capable to activate the T cells. This structure allows the T cell to recognize antigens including non-peptide targets like glycolipids and carbohydrates, and become activated without MHC presentation5. In addition to the a/p-T cells, also the y5-T cells and NK cells are an emerging research area. While y5-T cells are able to recognize unprocessed antigens in an MHC independent manner6 7, NK cells kill through "missing-self mechanisms” by attacking cells that have a decrease or lack in the expression of MHC-I8. Both these cell platforms do not cause graft versus host disease (GvHD) making them a prime candidate for "off the shelf' therapy6 9. Recently, several of these advanced forms of approaches have been classified as Advanced Therapy Medicinal Products (ATMP) and are revolutionizing biomedicine with the establishment of new treatments for diseases for which there is currently no cure10 11. In particular, CAR immunotherapies have been an especially active area of research, but despite the health impact which some of the proposed treatments have shown on patients refractory to more traditional treatments, only 5 adoptive cell therapies targeting CD19 and the B-cell maturation antigens have been so far approved by the American and European regulatory agencies (FDA and EMA)12 13. Challenges to achieve similar responses in patients harbouring other malignancies including solid tumours and CD19nes leukaemia/lymphoma are still considerable14’16. It has been proven that this limited efficacy is mainly due to the nature of these tumours, the presence of an immunosuppressive tumour microenvironment (TME) as well as the low persistence and functionality of CAR T cells17’20. A recent clinical study in refractory high-risk neuroblastoma patients (NCT03373097) treated with 3° generation GD2.CAR T cells, demonstrated that CAR optimization is crucial to improve safety and efficacy of this technology observing a 3-year overall survival and event free survival of 60% and 36%, respectively, with the recommended dose21, but also how the TME and its elements are responsible for the loss of function and persistence of GD2.CAR T cells affecting their metabolism and activation status20. To address this limitation, several groups including ours, investigated new strategies to metabolically reprogram CAR T cells22’27. These studies underlined that this reprogramming could be performed using different st