Dendritic Cells in Immune Oncology
Research type
Research Study
Full title
Optimisation of the Manufacture, Storage and Transport of a Novel Source of CD141+ Dendritic Cells for Downstream Use in Cancer Immunotherapy
IRAS ID
266907
Contact name
Paul Fairchild
Contact email
Sponsor organisation
University of Oxford
Duration of Study in the UK
0 years, 11 months, 30 days
Research summary
Research Summary
Dendritic cells (DC) play an essential role in all immune responses, whether protecting against infectious diseases or preventing the development of tumours. Their function is to present protein antigens to naïve T cells, thereby inducing their activation and instructing them to destroy appropriate targets. Given the significance of their role, DC have been widely exploited for cancer immunotherapy but clinical trials have proven disappointing since conventional DC differentiated from a patient’s own peripheral blood monocytes (moDC), fail to present tumour antigens to cytotoxic T cells, essential for the eradication of an established tumour. Instead, a rare population of DC, defined by its surface expression of the molecule CD141, is uniquely capable of presenting antigen to cytotoxic T cells but cannot be obtained from patients in sufficient numbers for clinical use. By producing so-called induced pluripotent stem cells (iPSC) from individual patients, we have recently demonstrated the feasibility of differentiating them into unlimited numbers of CD141+ DC thereby making this subset of DC available for clinical applications for the first time.
Separate research, to be performed under existing Home Office licenses, will allow us to assess the utility of these cells for cancer immunotherapy by embarking on a proof-of-concept study in which we propose to use mice lacking an immune system of their own which will be reconstituted with T cells from a healthy human donor. We shall compare the ability of moDC from the same donor and our proprietary CD141+ DC to elicit cytotoxic T cell responses to a defined tumour antigen. Success will be assessed as a function of the activation of antigen-specific T cells in immunized mice and their capacity to kill tumour cells. If successful, our findings will provide essential proof-of-concept data which will galvanise the use of this novel cell therapy product in first-in-man clinical trials.Summary of Results
Dendritic cells are responsible for initiating all immune responses and have, therefore, been used therapeutically in an attempt to induce potent responses to tumour antigens that might target an established tumour for destruction. A novel subset of dendritic cells has recently been identified, defined by expression of CD141, which is able to elicit responses among cytotoxic T cells and which are, therefore, attractive candidates for use in cancer immunotherapy. CD141+ dendritic cells are, however, very rare and cannot normally be obtained in sufficient numbers from a patient to be used clinically. Having recently succeeded in differentiating this population of cells in bulk from so-called induced pluripotent stem cells, we now have access to an almost inexhaustible supply of cells. In this project, we have successfully characterised the CD141+ subset and optimised their manufacture and transport by embedding them in an appropriate hyrdogel. We have also used immunocompromised mice reconstituted with a human immune system (so-called humanised mice) to compare the ability of this novel source of cells with conventional dendritic cells to induce immune responses to CEA, a tumour antigen associated with colorectal cancer. Our results have demonstrated a trend towards the increased activation of CEA-specific cytotoxic T cells in mice receiving CD141+ dendritic cells compared to those treated with conventional dendritic cells, suggesting that this novel source may improve outcomes among patients if used for cancer immunotherapy in the future.REC name
London - Brent Research Ethics Committee
REC reference
19/LO/1498
Date of REC Opinion
10 Oct 2019
REC opinion
Further Information Favourable Opinion