For many years, surgery, radiation therapy chemotherapy and immunotherapy have been the centerpiece in the treatment of cancer. The engineering of T-cells to a modified T-cell called the CAR T-cell brought in a major breakthrough in the treatment of cancers such as lymphomas. There are currently 6 approved CAR T-cells therapies for the treatment of blood cancers including some forms of leukemia and lymphomas [1]. These engineered CAR T-cells are very effective against some cancers (eg. lymphomas), even when we struggle for effective treatment in those cancer types. With the huge advantages also come disadvantages, such as higher treatment costs and the off-target effects (host related factors) [2].

One of the biggest challenges in engineering CAR T-cells to target solid tumors is that the recognition antigen in the cancer cell is usually also expressed in the normal healthy cells.

This, in the past few years, has resulted in off-target effects in patients such as tremors, impaired speech and other neurological effects which make the condition even worse, some decided to work on CAR T cells and solid tumors. In order to increase the recognition and to reduce the off-target effects/ toxicity, the iGEM team Munich has been working on the proximity based CAR T-cell activation system which uses the MESA receptor loop for the activation of quorum sensing [3].

The development stages of SpecifiCAR had multiple stages of review with the PI’s and researchers about the safety, biosecurity and efficacy before it was adapted into the final design. One of the main concerns we wanted to address was the specificity of the CAR T-cells. Even the successfully administered CAR T-cells have reportedly had adverse effects on the healthy cells [3]. To increase the specificity we added an additional condition to the existing CAR T-cell design which releases ligands/molecules enabling the activation of other CAR T-cells [4]. By doing this, the activation of CAR T-cells are specific only to the tumor microenvironment and the healthy cells remain healthy.

As soon as we decided to work on the CAR T-cells, we started collecting published literature on CAR T-cells and current treatment approaches. Initially, the literature survey helped us understand the limitations of the CAR T-cells treatment and later to envisage the project on a larger scale. We noticed that the off-target effects are still one of the major problems in effective treatment of cancer using the CAR T-cells. This is when we decided to work on it, as it had a larger chance of entering clinical trials which could bring a drastic change in the CAR T-cell treatment options.

During our brainstorming sessions, we came across articles, blogs and interviews of patients treated with CAR T-cells. This is where we came to learn about the struggles of patients to find a potential CAR T-cell trial that fits their requirements (the treatment costs are skyrocketing) and the aftermath of the treatment has detrimental effects on the patients and their loved ones. We wanted to know more about their opinion on CAR T-cell treatment, so we designed a patient interview series, where we collected opinions of patients that received CAR T-cell treatment and their suggestions in order to possibly incorporate them in our design and project. One of their major concerns were the side effects after the treatment procedure that lasted for a few or more days depending on the patient’s medical condition. This interview series largely helped us design experiments that could benefit the patients receiving the CAR T-cell therapy.

One of the biggest hurdles in the therapeutics project is the implementation. In order to get closer to the implementation, we decided to take insights from scientists and clinicians, who actually used the CAR T-cells to treat cancer patients. After our interview with our interview with Priv.-Doz. Dr. med. Ayuk we learned that the long duration of development is a huge hurdle for every party involved. After multiple discussions on how we could contribute, we decided to build a scientific database called “OSCAR”.

During the experimental design we noticed that there is no established database for the Chimeric Antigen Receptors (CAR’s) in general that scientists could use to design CAR T-cells for different cancer types. Therefore we thought of designing a database that picks up possible receptors, regulatory units such as kill switches and the recognition sites, sorted by the cancer type or the antigen of interest. This database could possibly solve the laborious literature survey and help the scientists, clinicians and other iGEM teams to accelerate their design strategy and focus more on implementing the project in the real world. The experimental design and the databases received positive feedback from the clinicians; these suggested that it would drastically reduce the time invested in the preliminary stages of research.

Read more details about our Database project on the Software page.

CAR T-cell therapy has produced remarkable results in the treatment of B-cell leukemia and lymphoma, yet there are many challenges and obstacles in implementing them to treat solid tumors – which accounts for approximately 90% of all adult cancers [5].

Even though our team is ambitious in implementing the proposed strategy, the biggest challenge is to validate the ideas with multiple clinical trials in cancer patients across different ethnicities. Technically these medical trials are time consuming, expensive and most importantly, require volunteers. Moreover, therapeutic projects such as SpecifiCAR have to pass through multiple rules, regulations and legal requirements in different countries across the globe, making it difficult to implement in the wider community [6].

There are multiple guidelines and phases for the approval of therapeutic innovations: The implementation strategy involves taking up evidence-based practices to improve the health-related process, especially when treating patients with cancer. The other goal is to provide generalized knowledge about the treatment procedures, barriers, and outcomes that can impact the clinical trials, which further determines the success or failure of the procedure. SpecifiCAR is currently being tested in cell culture systems and is in the proof-of-concept stage. The biggest challenge ahead is to translate the proof-of-concept to clinical CAR T-cell application. To do this we need to scale up the process with simultaneous testing in the xenograft mouse models supporting the development of hemato-lymphoid system and tumor tissues [7]. This helps us validate the novel CAR T cell strategy for safety and efficacy.

The final challenge we might face is the need for approved clinical trials, which employ patients based on the treatment approach and cancer type.

Cancer patients face difficulties in finding a potential CAR T-cell human trial with matching eligibility criteria. Since the CAR T-cell treatment is out of reach to many patients (cost for treatments are high) and the human trials are few in number, there is a need to conduct multiple clinical trials to help test approved preclinical therapies [8].

The clinical implementation process is the one thing, but the social acceptance of treatments that were genetically modified is another challenge. Especially in Europe, GMO is a controversial topic. Providing information about CAR T-cell therapy ensures that this treatment option comes into mind if needed and therefore can be discussed further with the respective physician.

We also conducted survey to address this challenge.

Conclusions

References