The human immune system defends against pathogens. However, sometimes the immune response is misdirected towards the body's own tissue, causing autoimmune disease. In organ transplantation, on the other hand, the immune system performs its defensive function but this leads to rejection of the transplant. The opposite may occur, in which intact donor immune cells may attack the recipient being treated for certain blood cancers (Graft Versus Host Disease, GVHD). Undesired immune response may also occur in response to infections. Thus, the control of inappropriate immune responses represents a fundamental medical challenge. This can be accomplished by leveraging the actions of cellular components of the immune system.
This project is designed to produce targeted T-regulatory cells to control overreactive immune responses in various disease settings. The ability to select and amplify desired regulatory T cells, under reproducible conditions, is the prerequisite for the future of cell therapy. Fraunhofer IZI will develop and validate GMP-compliant manufacturing and quality control processes in collaboration with ImReg Pharmaceuticals. Cell selection and automated manufacturing procedures will be tested to ensure a clinical grade cell product that meets regulatory standards for human trials.
With the so-called CAR-T cell therapy, the US Food and Drug Administration (FDA) approved a gene therapy for the first time in 2017 which has already resulted in impressive treatment outcomes in clinical trials involving cancer patients. This revolutionary form of therapy is also the basis of the ROR1 CAR-T research project.
The chimeric antigen receptor (CAR) developed at the University Hospital of Würzburg recognizes the ROR1 molecule, which is expressed in cancer cells in leukemia, for example, as well as in breast and lung cancer. In order to manufacture the cell product, immune cells are first taken from the patient’s body by leukapheresis. T helper cells and cytotoxic T cells are then selected by magnetic cell separation. The genetic material for the CAR is introduced into the genome of the T cells via a non-viral gene transfer using the so-called “Sleeping Beauty” transposon system (jumping gene). This reprograms the T cells in such a way that they recognize ROR1-positive cancer cells as “foreign” and eliminate them by releasing cytotoxic messengers. The reprogrammed cells are expanded and administered to the patients intravenously.
The project is being funded as a pilot project under the proof-of-concept initiative launched by the Fraunhofer-Gesellschaft, the Helmholtz Association and Deutsche Hochschulmedizin in order to promote the translation of innovative research projects. The funding will support the conduct of preclinical trials into the safety and efficacy of the ROR1 CAR-T cells and drive clinical translation into a phase I / II study (first in human).
Based on the successful process development on a small scale, an initial test batch adjusted to reflect the actual production scale was manufactured as part of the project, which will be used to further optimize the process with an eye to the stringent production requirements under GMP conditions. At the same time, the required equipment was qualified, the suitability of newly introduced GMP-compliant materials checked and the respective specifications compiled in order to guarantee the consistent quality of these materials. After additional test batches have been completed, the manufacturing process is expected to be validated in the third quarter of 2020. The analytical methods that form part of the so-called safety parameters (mycoplasma, sterility, bacterial endotoxins, vector copy number) are planned to be validated at the same time. An application will be sent to the responsible authority, i.e. Landesdirektion Sachsen (Saxony Land authorities), simultaneously for the manufacturing permit pursuant to Section 13 of the German Drug Act.
The CAR-T cell therapy is a new type of cancer immunotherapy that uses the patient’s own T cells to fight certain types of cancer. In order to do this, the cells are collected in the clinic by leukapheresis and then genetically reprogrammed in vitro in such a way that they can use a chimeric antigen receptor (CAR) to recognize cancer cells and other cells that have a special antigen on their surface. Following lymphodepleting chemotherapy, the reprogrammed cells are administered to the patient though an infusion. They then proliferate and can trigger the immune response.
In August 2017, the first CAR-T cell therapy became available in the USA in the form of Kymriah® (CTL019 / tisagenlecleucel). Kymriah® was granted FDA approval for children and young adults aged up to 25 years old diagnosed with acute lymphocytic B-cell leukemia (ALL) who are not responding to the usual therapies or have already suffered relapses. In May 2018, approval was also granted for adult patients with diffuse large B-cell lymphoma (DLBCL) who had suffered relapses after two or more lines of systemic therapy or who have not responded to therapy at all. On August 27, 2018, Novartis announced that it had received approval from the European Commission for both of these indications based on the recommendation given by the European Medicines Agency (EMA).
Fraunhofer IZI has long been an important manufacturing and development site for this innovative CAR-T cell therapy for clinical trials throughout Europe. Currently, prescription-only, approved T-cell therapies will also be manufactured on an interim basis in the Main Department of GMP Cell and Gene Therapy at Fraunhofer IZI, alongside investigational medicinal products. Following a one-year technology transfer period from Novartis’ Morris Plains site in New Jersey, USA, and after obtaining manufacturing authorization in accordance with Section 13 of the German Drug Act (AMG), the first clinical batch was manufactured at Fraunhofer IZI in Leipzig in August 2016. Since then, the Main Department of GMP Cell and Gene Therapy has continuously produced CAR-T cell therapies for Novartis.
Until the end of 2019, several 100 batches were delivered to patients, including many children, all across Europe. The extremely complex process involved in manufacturing a Kymriah®-Batch takes several days and involves not only state-of-the-art instrument engineering, but also manual tasks. Before being released for human use, extensive analytical release tests are first conducted on the finished product (e.g. concerning identity, purity, in vitro potency, microbiological safety) and the batch documentation is reviewed in detail.
The US American Food and Drug Administration FDA approved for the first time in 2017 a gene therapy with so-called CAR-T cell therapy. Clinical studies of cancer diseases show that impressive success has already been achieved in the treatment of cancer using this form of therapy. This revolutionary therapy is also the focus of a research project that the PoC initiative will be supporting with about 2.8 million euros. The chimeric antigen receptors (CAR) developed at the University Hospital of Würzburg detect a certain molecule (ROR1), which is barely present in healthy cells, but which occurs all the more on cancerous cells from leukemia, breast or lung cancer. In the case of the research project now being funded by the PoC initiative, the non-viral gene transfer takes place by means of the so-called "Sleeping Beauty" transposon system (SB100X). The funding is to be used to complete pre-clinical studies on the safety and efficacy of the ROR1 CAR-T cells and to achieve the clinical translation into a Phase I study (First-in-Man).
Thy project is funded by the Proof-of-Concept initiative. The initiative was instituted by the Helmholtz Association, the Fraunhofer-Gesellschaft and the German university medical departments, to promote translation of innovative, promising research projects into clinic.
The Main Department GMP Cell and Gene Therapy of Fraunhofer is collaborating with Iovance Biotherapeutics Inc. (San Carlos, CA, USA) on the technology transfer and subsequent continuous manufacturing of allogeneic feeder cells used in Iovances’ Tumor Infiltrating Lymphocyte manufacturing process. This collaboration supports Iovance’s upcoming European clinical trials for the treatment of solid tumors in metastatic melanoma and cervical carcinoma.
Iovance Biotherapeutics, Inc. is a clinical-stage biotechnology company focused on the development of cancer immunotherapy products for the treatment of various cancers. The Company's lead product candidate is an adoptive cell therapy using tumor-infiltrating lymphocyte (TIL) technology being investigated for the treatment of patients with metastatic melanoma, recurrent and/or metastatic squamous cell carcinoma of the head and neck and recurrent and metastatic or persistent cervical cancer. For more information, please visit www.iovance.com.