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Cells fit for the fight against cancer
CAR T-cell therapy can be a powerful means of treating cancer, where a patients’ own T cells are extracted and modified, before being then re-introduced back into the patient to attack the cancer. Researchers in the CellFit project are working to develop new, more effective methods of producing T cells and assessing their efficacy, as Dr Else Marit Inderberg Ph.D explains.
The emergence of Chimeric Antigen Receptor T-cell (CAR T-cell) therapy gives clinicians a powerful option to treat certain types of cancer. In CAR T-cell therapy, a patients’ own T cells are extracted and modified to enhance their effectiveness as part of the immune response, then more of these cells are grown in the laboratory before being re-introduced back into the patient to attack the cancer. “CAR T-cell therapy is approved for certain haematological malignancies, and clinical trials are ongoing for some solid cancers as well,” outlines Dr Else Marit Inderberg, Head of the Translational Research Unit at Oslo University Hospital. The tumour microenvironment around a solid cancer forms a kind of protective layer however, limiting the effectiveness of CAR T-cell therapy against solid cancers. “There may be physical barriers like proteins that make it hard for T cells to penetrate a tumour. Or some cells may produce immuno-suppressive agents that will prevent the immune cells from doing their job,” says Dr Inderberg.
CellFit project
As the Principal Investigator of the CellFit project, Dr Inderberg is part of a team developing new methods of producing engineered T cells and evaluating their efficacy. The project brings together partners from both the academic and commercial sectors, with the ultimate aim of improving cancer treatment. “We’re trying to develop
extracted and modified, the next step is then to produce them in large quantities, which is the focus of a lot of attention in the project. “Our partners SINTEF have sophisticated drugscreening platforms that are used to assess drugs and see which are more effective against cancer cells,” continues Dr Inderberg. Researchers are now working to convert these platforms for the purpose of screening large numbers of the culture conditions which may affect T-cell production. The biotechnology company Thermo Fisher - another partner in CellFit - have deep expertise in the production of innovative reagents, which is being applied in the project. “We can produce different kinds of stimuli. The stimuli that is used in culture is of course not exactly the same as what would happen in the body however. If the kinetics are different, and we remove it faster, that may affect the number - and type - of T cells that are produced,” says Dr Inderberg. The nature
new methods so that we won’t need as many T cells in future when treating patients. The hope is that these T cells will stay in the body for much longer, and they will be able to then function more effectively,” she explains. The T cells initially taken from patients’ blood are typically quite heterogenous; one important sub-type are the memory T cells, which can persist in the body and attack a cancer should it recur. “When we vaccinate people, or we see that they’ve had an infection previously, they have a pool of memory T cells that are ready to attack the infection if it comes back,” says Dr Inderberg. “We think that these more stem-cell like memory T cells would be able to persist in the body for much longer.”
The cells infused in CAR T-cell therapy are typically ready to attack cancer cells straight away, with receptors which enable them to identify and attack a tumour, yet there are also other factors to consider in terms of therapeutic effectiveness. The surrounding microenvironment is quite harsh for T cells, and they are in competition with tumour cells for nutrients, so Dr Inderberg says that cells with a less active metabolism are likely to be more effective in the long term. “We expect that we’re looking for cells which use less sugar, less glycolysis. If they need less nutrients they might be more likely to survive in the tumour microenvironment and function effectively,” she outlines. Once the cells have been
understanding the ideal conditions for producing therapeutically effective T cells. “We may want to then scale up production further in future, if we are able to show that these T cells will have a positive impact on the health of patients,” says Dr Inderberg. The platforms could also be used to screen other types of cells beyond T cells, underlining the wider relevance of the project’s work. “It could be Natural Killer (NK) cells for example, or other types of immune cells,” explains Dr Inderberg. “It will probably be necessary to conduct some clinical trials before we supply information to drug manufacturers, and we will look to publish more of our findings as the project progresses.”
This reflects the project’s commitment to opening up its findings to other researchers, with data being shared through Digital Life Norway, which is part of the European Elixir platform. Effective collaboration and knowledge-sharing could also help reduce the
“We’re trying to develop new production methods so that we won’t need as many T cells in future when treating patients. The hope is that these T cells will stay in the body for much longer, and they will be able to then function more effectively.”
of the culture medium, and the availability of different types of nutrients, may also be an important factor. “We could have antioxidants, and different growth factors that are required to skew the T cells towards different phenotypes, different types of memory cell,” continues Dr Inderberg.
High-throughput screening
The platforms are now up and running, the high-throughput screening of conditions is in progress, and the project team are screening cells with novel reagents. The hope is to identify some strong candidates during the course of the project, and also make progress in terms of
cost of CAR T-cell therapy, which is currently quite expensive, costing up to $475,000. “If we need less T cells from a patient it will be logistically much easier to handle and less expensive to produce. If we manage to reduce production time – even just by 2-3 days –this will also help reduce costs,” outlines Dr Inderberg. This research is still at a relatively early stage, but there are indications from both animal models and recovering patients that these stem-like memory T cells are more effective in combatting cancer. “We have seen that patients who recovered well after immunotherapy treatment have more of these types of T cells,” continues Dr Inderberg.
CellFit
T cells fit to fight cancer
Project Objectives
To more efficient T cell therapy for solid cancers these T cells need to persist in the body for years and be able to tackle harsh tumour microenvironments. In the CellFit project we will produce T cells with stem-cell like properties could be far more resilient under such conditions.
Project Funding
Established in 2021, and funded by The Research Council of Norway.
Project Partners
The CellFit Project is a collaboration led by Oslo University Hospital, Department of Cellular Therapy. The project includes project partners Oslo Cancer Cluster, SINTEF, and Thermo Fisher Scientific.
https://cellfitproject.com/index.php/stakeholders/
Contact Details
Project Coordinator,
Dr Else Marit Inderberg, Ph.D
Department of Cellular Therapy
Oslo University Hospital Ullernchausseen 64, 0379 Oslo, Norway
T: +47 22782317
E: elsin@rr-research.no
W: https://cellfitproject.com
References from the lab:
Joaquina, S. et al. Front Bioeng Biotechnol 11, 1207576 (2023).
Mensali, N. et al. Nat Commun 14, 3375 (2023).
References on stem-like memory T cells: Meyran, D. et al. Sci Transl Med 15, eabk1900 (2023). Siddiqui, I. et al. Immunity 50, 195 211.e10 (2019).
Dr Else Marit Inderberg, Ph.D
Dr Else Marit Inderberg, Ph.D leads a research unit performing immunomonitoring in clinical trials and development of cellular therapy at the Dept. of Cellular therapy, Oslo University Hospital. Her main research focus is on T-cell function and therapy development, including identification of predictive biomarkers of therapy response. She has broad oncologyrelated clinical trial experience and holds an MSc equivalent degree in Immunology from France and a Ph.D in tumour immunology from the University of Oslo, Norway.
