Engineering chimeric antigen receptor T Cells against human LILRB3 for treatment of acute myeloid leukaemia (AML)
Lead Research Organisation:
University of Southampton
Department Name: Cancer Sciences
Abstract
Skills Priority Alignment: Whole Organism, Advanced Therapeutics
Acute Myeloid Leukemia (AML) remains an unmet medical need with ~20,000 new cases and ~10,000 deaths in the US alone each year. Current treatments for AML fail to induce long-term tumour regression, demonstrating the need for new therapies. Recent studies demonstrate a role for leukocyte immunoglobulin-like receptors (LILRs) in regulating leukocyte function, and that inhibitory LILRs (LILRBs) are dysregulated in haematological malignancies, including AML.
BioInvent and Southampton have produced and extensively characterised a unique panel of monoclonal antibodies (mAb) specific for human LILRB3. Moreover, alongside Prof Chen at MIT, by genetically modifying human CD34+ hematopoietic stem cells and engrafting them into NOD-SCID Il2rg-/- recipient mice, a humanized mouse model of AML with an autologous human immune system has been successfully developed. Using the previously generated reagents and established pre-clinical platforms and existing expertise in mAb and CAR T cell therapy, it is proposed to develop autologous LILRB3-specific CAR-T cells and evaluate their capacity against AML in vivo.
This proposal aims to 1) generate and optimise autologous T cells expressing chimeric antigen receptors based on BioInvent n-CoDeR generated/derived anti-LILRB3 antibodies (LILRB3-CAR T cells), and 2) evaluate the efficacy and safety of LILRB3-CAR T cells in humanized
AML and patient-derived xenograft mouse models.
Acute Myeloid Leukemia (AML) remains an unmet medical need with ~20,000 new cases and ~10,000 deaths in the US alone each year. Current treatments for AML fail to induce long-term tumour regression, demonstrating the need for new therapies. Recent studies demonstrate a role for leukocyte immunoglobulin-like receptors (LILRs) in regulating leukocyte function, and that inhibitory LILRs (LILRBs) are dysregulated in haematological malignancies, including AML.
BioInvent and Southampton have produced and extensively characterised a unique panel of monoclonal antibodies (mAb) specific for human LILRB3. Moreover, alongside Prof Chen at MIT, by genetically modifying human CD34+ hematopoietic stem cells and engrafting them into NOD-SCID Il2rg-/- recipient mice, a humanized mouse model of AML with an autologous human immune system has been successfully developed. Using the previously generated reagents and established pre-clinical platforms and existing expertise in mAb and CAR T cell therapy, it is proposed to develop autologous LILRB3-specific CAR-T cells and evaluate their capacity against AML in vivo.
This proposal aims to 1) generate and optimise autologous T cells expressing chimeric antigen receptors based on BioInvent n-CoDeR generated/derived anti-LILRB3 antibodies (LILRB3-CAR T cells), and 2) evaluate the efficacy and safety of LILRB3-CAR T cells in humanized
AML and patient-derived xenograft mouse models.
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/R502261/1 | 01/10/2017 | 30/09/2022 | |||
| 1949567 | Studentship | MR/R502261/1 | 01/10/2017 | 30/09/2021 | Charys Papagregoriou |
| Title | Characterisation of a human transgenic mouse model |
| Description | The newly characterised LILRB3 Tg mouse model enables us to investigate further the inhibitory nature of the receptor and support its suitability as a target for CAR T cell therapy for AML. |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Year Produced | 2017 |
| Provided To Others? | No |
| Impact | The Tg mouse model is helping us understand the function of a novel human immune checkpoint receptor in vivo and to evaluate its potential as a therapeutic target for immunotherapy. |
| Description | BioInvent International, Lund, Sweden |
| Organisation | BioInvent International AB |
| Country | Sweden |
| Sector | Private |
| PI Contribution | Generation, charaterisation and identification of monoclonal antibodies (mAb) with therapeutic potentials, one of which (anti-human CD32B) is currently in three Phase I trials: BI-1206 and an Anti-CD20 Antibody in Patients With CD32b Positive B-cell Lymphoma or Leukaemia (ClinicalTrials.gov Identifier: NCT02933320) A Study of BI-1206 in Combination With Rituximab in Subjects With Indolent B-Cell Non-Hodgkin Lymphoma (ClinicalTrials.gov Identifier: NCT03571568) A Study of BI-1206 in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors (ClinicalTrials.gov Identifier: NCT04219254) |
| Collaborator Contribution | Provided a phage display library platform for producing the mAb or allowed access to mAbs generated at the company. Also provided funding and internship positions for staff and students involved with projects. |
| Impact | Scientific publications (eg, Roghanian A. et al., Cancer Cell, 2015) and patents. |
| Start Year | 2010 |
| Description | My project uses monoclonal antibody reagents that were previously produced in collaboration between our group at the University of Southampton and a biotech focused on immune-oncology, BioInvent International, Lund, Sweden. |
| Organisation | BioInvent International AB |
| Country | Sweden |
| Sector | Private |
| PI Contribution | My project is an Industrial Cooperative Awards in Science & Technology (iCASE) funded also from the BioInvent International, a Swedish research, biotech focus on clinical development of antibody drugs for immunotherapy against cancer. As part of my project, I have generated a number of CAR constructs and will shortly be testing the efficacy of the therapy in vitro and in vivo. I have also contributed to characterisation of some novel antibodies produced by the company. |
| Collaborator Contribution | The antibodies used for the production of the CAR T-cell therapy were generated by BioInvent International through a previous collaboration and continue to contribute to this project. I was also appointed with an industrial supervisor, Dr Björn Frendéus, the chief scientific officer of the company, with whom I have annually shared the updates of the findings of the project either through face to face meetings in Southampton or via email. I have also the opportunity of a short placement at the company in Sweden during the PhD. |
| Impact | No impact yet but if the therapy is efficacious, it would potentially be translated into the clinic for the treatment of AML and other malignancies. |
| Start Year | 2017 |
| Description | Pint of Science 2018 Southampton |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | I was an organiser of the Pint of Science 2018 under the theme "the human body". As part of the Pint of Science, I and the rest of the group members were able to engage the general public about how powerful and revolutionary immunotherapies are in the treatment of Cancer and how far we have progressed to date. As part of the group, we had to organise a three day event which involved inviting speakers, mainly scientists or clinicians who delivered a 30-minute presentation about their research. Having both scientists and clinicians enabled us to engage a broader spectrum of participants, successfully demonstrating how a therapy is generated, tested pre-clinically and then translated into human clinical trials. Each day around 40 people attended the event which involved questions and discussions with the general public after each presentation of the guest speakers. The sessions ended up with an increased interest in the use of immunotherapies against other diseases apart from cancer such as autoimmune diseases. |
| Year(s) Of Engagement Activity | 2018 |