CAR T-cell cancer treatment under development in CEITEC MU


In April 2012, Emily Whitehead, a then 7-year-old relapsed and refractory acute lymphocytic leukemia patient, was the first girl to be miraculously cured of her disease by an innovative immunotherapy featuring the Chimeric Antigen Receptor (CAR) T cells [1].


After more than 7 years, she remains disease-free.


Since this initial success, hundreds of previously incurable leukemia [2] and lymphoma [3] patients have been treated with CAR T cells, and an impressive proportion of them responded favorably to this “living” drug.


In 2017 the U.S. Food and Drug Administration approved it [4]; the media were filled with news about this ground-breaking therapy, starting a new era of cancer treatment


Nowadays, CAR T cells are already commercially available in the USA and Europe, and given their remarkable success rate in treating hemato-oncological patients, it is safe to say they are here to stay.


Unlike the traditional cancer treatment options (including chemo- and radiotherapy), which generally target rather unspecifically all rapidly dividing cells, CAR T cells represent the most advanced cell-based immunotherapeutic tool, which aims to harness the patient’s immune system to fight the disease.


T cells are the effector immune cells with the “license to kill” when they come across an unhealthy cell in the body. They recognise the harmed cells because the latter bear a signal on their surface called an antigen, which informs T cells about their fitness state. 


However, cancer cells often become invisible to T-cell surveillance by downregulating the molecule on their surface (termed Major Histocompatibility Complex; MHC) that presents the antigen to T-cell inspection. On top of that, tumour cells can even promote the establishment of an immunosuppressive microenvironment.


Scientists have found a way to overcome this challenge and to unleash T-cell killing potential toward malignant cells through their genetic engineering. 

By these means, CAR T cells express a tumor antigen-specific receptor on their cell surface termed Chimeric Antigen Receptor. When the CAR T cells are infused back into the patient, these receptors help them find and kill cancer cells.


As the name hints, this receptor is a molecular chimera – it combines the antigen recognition part from a B-cell receptor antibody with the T-cell signaling parts.

This is truly an ingenious way to make T cells able to recognise their target in an MHC-independent manner since B-cell antibodies bind targets in their native state-unbound to any presentation molecule.


This advanced genetic engineering thus extends the CAR T-cell specificity to any target of choice, as long as there is an antibody available for it and can even be fine-tuned by incorporating different T-cell activation domains in the CAR design.


CAR T cells represent the perfect example of truly personalized medicine, as the drug production starts with harvesting one’s T cells, and the final product is thus patient-specific.





However, the whole manufacturing process is highly technically challenging, time-consuming (which can be an issue in case of patients who are in urgent need of the therapy), and very costly (one drug costs up to $500,000 [5]).


On top of that, the CAR T-cell therapy is not without its risks. One of the most significant issues physicians face in the clinics is to tackle the immune response that comes with the treatment. It is often so powerful that it causes high fevers and induces the production of proteins involved in inflammation.


On the one hand, these symptoms are indicative of positive treatment responses, but on the other hand, they can be fatal to the patient. Therefore, much effort is being put into figuring out a way to deal with and control these side effects without compromising the effectiveness of the CAR T cells.


Finally, it became apparent from clinical trials that patients with some hemato-oncological diagnosis (e.g., chronic lymphocytic leukemia [CLL]), and even more markedly cancer patients with solid tumors, are currently less likely to benefit from this innovative “living” drug.


Until recently, this technology was available only within clinical trials mostly run in the USA and China. Even though two pharmaceutical companies (Novartis and Gilead) hold approval to treat European patients with CAR T cells in a commercial setting, the manufacturing is still mostly done overseas. Thus, many academic institutions have taken it upon themselves to establish and further develop this methodology in European laboratories, and offer it to the potential patients within clinical trials.


In CEITEC, we have also obtained a grant co-financed by the South Moravian Region and European Commission to set up and optimize CAR T-cell production.


In the past 3 years, we have focused on the anti-CD19 CAR methodology.



Anti-CD19 CARs are those that are achieving the most remarkable results in the clinics and are also becoming available commercially in the Czech Republic. Of note, we have already optimised several assays to monitor the treatment course for these drugs. 



Above that, we also aimed at developing exogenously regulated CAR T cells.


In this advanced CAR design, the CAR construct is split into two separate molecules. Successful CAR activation thus requires a small priming molecule in addition to the tumor antigen to trigger the therapeutic functions. The small molecule prompts the dimerization of the two parts of the split CAR, thereby initiating full receptor activation.


By adjusting the timing and dosage of the dimerizing molecule one could potentially regulate the duration and intensity of the therapeutic response and increase safety.


If these designs prove functional, their application in the clinics could allow physicians to shut down the CAR T cells’ immune response as a life-threatening side effect. Once the symptoms would resolve, the administration of the dimerizing molecule would switch CAR T cells back on.


Finally, in the group of Functional Genomics at CEITEC MU (group leader: Dr. Michal Šmída), we generally focus on uncovering diverse strategies for personalized therapy tailored to stratified groups of CLL patients. Therefore, we have also studied the effect of CAR T-cell therapy in different in vitro and in vivo CLL disease models.


CLL is genetically and clinically a very heterogeneous incurable disease, and so far, only minimal achievements were reached in clinical trials with CAR T cells.


The genetic mutations occurring in CLL are known to be essential factors of prognosis as well as response to standard treatments in clinics. We, therefore, wondered what is the impact of individual mutations on the response to CAR T-cell treatment?


Feasibly, some mutations could be associated with a better outcome.


By these means, we aimed to uncover novel predictive biomarkers of therapy response.

Overall, our goal is to prepare safer and more personalized CAR T cells as well as means for their clinical monitoring.

Thanks to the direct collaboration with the University Hospital Brno, our results might have an immediate impact on medical care provided to patients.


The experimental work is coming to completion, and we hope to publish our findings really soon.


So…. Stay tuned!



This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie, and it is co-financed by the South Moravian Region under grant agreement No. 665860. This report reflects only the author’s view, and the EU is not responsible for any use that may be made of the information it contains.



References


  1. Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. (2013) doi:10.1056/NEJMoa1215134
  2. Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. (2018) doi:10.1056/NEJMoa1709866.
  3. Locke, F. L. et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol. (2019) doi:10.1016/S1470-2045
  4. https://www.fda.gov/news-events/press-announcements/fda-approves-car-t-cell-therapy-treat-adults-certain-types-large-b-cell-lymphoma
  5. https://www.fiercepharma.com/pharma/at-475-000-per-treatment-novartis-kymriah-a-bargain-or-just-another-example-skyrocketing



Written by Veronika Mančíková

Infographics and visual ideation by Agnieszka Szmitkowska

Edited by Somsuvro Basu


Publication date: 23.01.2020