Paul-Ehrlich-Institut: Core activities within CARAT
The Paul-Ehrlich-Institut (PEI) is an internationally recognised medicines agency, responsible for the regulation of biomedicinal products and for conducting research in related areas. Research in the Section Molecular Biotechnology and Gene Therapy focusses on the delivery of therapeutic genes by viral vectors and in particular the surface engineering of viral vectors in order to achieve cell type specific gene delivery.
An important tool in the manufacturing process of CAR T cells are the vectors used for gene transfer and the conditions allowing high gene transfer rates. Usually, lentiviral (LV) or γ–retroviral vectors are applied. Both require that the T cells have been activated with cytokines to allow stable integration of the CAR gene into the genome. Maximized gene delivery rates can be achieved with transduction enhancers, such as retronectin or vectofusin, which enhance the colocalization between vector particles and cells. By surface engineering, this CARAT partner has generated LV vectors that use particular cell surface markers, such as CD4 or CD8, as entry receptors into T cells. Specificity for the targeted cell surface receptor is mediated by a high-affinity ligand, which can be a single-chain antibody displayed on the particle surface. These receptor-targeted vectors do not only deliver CAR genes selectively into specific subpopulations of T cells, but, in contrast to conventional LV vectors, also have the potential to reach non-activated resting T cells.
Within CARAT, lentiviral vectors targeted to subtypes of T cells will be evaluated for their potential to improve and facilitate the CAR T cell manufacturing process. Combination with transduction enhancers will be tested. Especially, vectors that deliver CAR genes directly into primary T lymphocytes that have not been activated before are highly promising in this respect. CAR T cells generated by this approach may be more potent and less exhausted.
Question & Answers from the Paul-Ehrlich-Institut Team
With the first CAR T cell products having achieved marketing authorization in the US, expectations are enormous that this novel concept in cancer therapy will become a breakthrough technology.
Where do you see the role of the PEI’s team within the international CARAT consortium?
Gene delivery into the patient’s lymphocytes is the key step during CAR T cell manufacturing. Improving the gene transfer vector for CAR delivery is therefore of fundamental relevance for CAR-based immunotherapy. PEI provides and tests these novel vector tools of which the most promising are then further investigated and used by the consortium.
What makes working in the CARAT consortium special for you?
The CARAT consortium has a unique composition of key players covering basic research, clinical research, manufacturing and regulation of CAR T cells. Being part of CARAT, therefore allows us to follow the latest developments at the forefront of this important field and to influence its future by contributing to the gene delivery technology and the regulation of this novel class of medicinal products.
In your opinion, what impact does CARAT have?
With the first CAR T cell products having achieved marketing authorization in the US, expectations are enormous that this novel concept in cancer therapy will become a breakthrough technology. CARAT focusses on very important hurdles that currently prevent a straight-forward and broad application of CAR T cells in the routine clinical practice in the EU. CARAT will contribute to overcoming these hurdles and thus have a major impact towards making these products better accessible for European cancer patients.
I am assessing all available information about clinical applications of CAR T cells in order to create status reports covering worldwide ongoing or completed trials.
What are your specific tasks in the CARAT team?
I am involved in two CARAT work packages. In work package 3, the main aim is to generate novel lentiviral vector systems for CAR gene delivery including vectors that deliver CARs into minimally activated lymphocytes. Work package 6 focusses on the identification of regulatory hurdles currently impairing CAR T cell therapy in the EU and possible solutions. Towards this goal, I am assessing all available information about clinical applications of CAR T cells in order to create status reports covering worldwide ongoing or completed trials.
What are “your” major achievements?
Our status report on the clinical development of CAR T cells was recently published in EMBO Molecular Medicine (Hartmann et al. EMBO Mol Med 2017) and achieved a lot of attention being the most read article in this journal since it has been published. It will hopefully further stimulate the discussion about the regulatory requirements for CAR T cells and foster the identification of powerful solutions. There is also continuous improvement in our vector project which will hopefully soon be ready for a first publication.
Where do you see future challenges in the field of CAR gene transfer therapy?
Despite the recent progress and success many challenges remain. Among these, translation of the substantial benefit observed in clinical trials with patients suffering from relapsed or refractory B-cell malignancies to other indications and tumor entities, especially solid tumors is probably the most relevant and exciting example.
Together with leading researchers and companies, we will bring this curative CAR therapy to patients suffering from cancer all over Europe.
What is your role in the CARAT team at the PEI?
At PEI, I work on the development of novel lentiviral vectors for CAR delivery specifically into T cell subpopulations. Importantly, I will expand our targeted vector portfolio towards mouse T cells to allow performance testing of CAR T cells generated by these vectors in immunocompetent mouse models. Thereby, I contribute to preclinical testing of our technology.
What is most exciting about being part of a collaborative international research program as CARAT?
The field of CAR therapy is rapidly evolving, with many internationally well-recognized researchers making great progress in translating the CAR technology towards standard treatment. It is very exciting to contribute to this process as part of CARAT. Together with leading researchers and companies, we will bring this curative therapy to patients suffering from cancer all over Europe.
Where do you see your tasks in the CAR therapy for the future?
Since CAR therapy is a very young discipline, lots of challenges will be ahead in the future, for instance regarding long-term safety of this living drug in treated patients. Also, solid tumor treatment with CAR T cells is still in its infancy. I hope to contribute with the knowledge and knowhow I acquire as part of CARAT to address these and other problems coming up in the CAR field.
Working in a research project like CARAT gives the opportunity to not only share professional expertise but also get to know involved researchers on a personal level.
What is the topic of your thesis? And why is this field of research so exciting?
The focus of my PhD thesis lies on the generation of better functional CAR T cells by transduction with T cell receptor-targeted LVs outperforming VSV-G-LV mediated CAR gene transfer. Thus, by transducing resting naïve or memory T cells we suggest producing CAR T cells that are more cytotoxic upon antigen encounter and provide longer survival.
This research field is so exciting due to the thousands of challenges that researchers are faced with, although outstanding successes have already been achieved.
How do you see the future of CAR gene transfer research evolving?
In my opinion, CAR immunotherapy has a bright future. All the different strategies of optimizing CAR T cell therapy by using different antigen, increasing safety of the products, precisely defining the product, finding a universal CAR-product or combining CAR T cell therapy with other therapy approaches such as checkpoint blockade currently examined in laboratories or clinical trials will hopefully cause substantial successes for various cancer types.
What is most exciting about being part of a collaborative research project as CARAT?
Working in a research project like CARAT gives the opportunity to not only share professional expertise but also get to know involved researchers on a personal level.
I am proud to be part of such an innovative project with the ultimate goal of serving patients with so far incurable hematologic malignancies and solid tumors.
Why is it special for you to work in the international CARAT project?
The most exciting thing about working in a collaborative international research program like CARAT is the opportunity to interconnect with so many cooperation partners from both research and companies. Sharing insights of each other’s research will help achieving milestones in CAR T cell therapy much faster.
What is your personal motivation?
I am proud to be part of such an innovative project with the ultimate goal of serving patients with so far incurable hematologic malignancies and solid tumors. Furthermore, it is an amazing experience to be part of a team of researchers from different European countries all aiming to give patients a better quality of life.
In your opinion, what are the long term benefits of the CARAT program?
The CARAT project paves the way for a new level of research by providing a platform to communicate with people working in the field of CAR T cell therapy to such a great extent. Not only meetings with all collaborators, but also sharing of material and knowledge result in transparency and support our research. I am optimistic that this combination will finally lead to a better treatment of cancer patients, hopefully also of those suffering from solid tumors.