Peculiarities of Clinical Trials in CAR-T Cell Therapy

Chimeric antigen receptor T-cells (CAR-T cells) – are receptor proteins that have been engineered to give T-cells the new ability to target a specific antigen. The receptors are chimeric as they combine both antigen-binding and T-cell activating functions into a single receptor, thus making CAR-T cell therapy a groundbreaking method of using the body's immune system to target and kill cancerous cells. This type of personalized therapeutic approach involves the genetic modification of a patient's T cells so that they have specific receptors to recognize antigen on cancer cell in order to optimize the attack of the immune system against cancer.

CAR-T cells development started almost 40 years ago, when in 1987 chimeric immune receptors were first developed by Y. Kawama et al. It initially consisted of the variable (antigen binding) regions of a monoclonal antibody and the constant regions of the T-cell receptor (TCR) α and β chains.

Different generations of CAR-T cells have been developed since then, depending on the composition of the intra-cellular domain: (i) first generation, CD3z chain; (ii) second generation, CD3z chain and a co-stimulation domain such as CD28, 4-1BB or OX40; and (iii) third generation, CD3z chain and two co-stimulation domains. (iv) a fourth generation called TRUCKS (T cells Redirected for antigen-Unrestricted Cytokine-initiated Killing), where the transgene coding for a second-generation CAR-T is completed with a gene coding for a cytokine such as IL-12 or IL-15, for example (V. Wang et al, 2023) and most recently (v) fifth generation, which includes a truncated cytoplasmic IL-2Rβ domain, offering improved safety and controllability.

Although development started almost 40 years ago, it took almost 3 decades for the first CAR-T cell therapy product to be marketed. The first CAR-T cells were commercialized in 2017, it wasYescarta® (axicabtagene ciloleucel) from Kite/Gilead and Kymriah®  (tisagenlecleucel) from Novartis, following U.S. Food and Drug Administration (FDA) authorization under the Advanced Therapy Medicinal Product (ATMP) status. Then in 2018, both have been also approved by EMA (V. Vang et al, 2023). As of the beginning of 2026, there were 7 CAR-T therapies approved in total by FDA (R.Rosa et al, 2026).

Main area for CAR-T cell therapy as of today is hematological malignancies – certain forms of leukemia (ALL,  CLL),  multiple myeloma and different lymphomas where this therapy has shown exceptional effectiveness and these are indications where all 7 compounds approved to date are being used. Saying this, currently there is a lot of research related to potential use of CAR-T cell therapy in other indications – solid tumors (e.g renal, breast, colorectal, lung, ovarian cancers etc) as well as certain non-oncological conditions (SLE, Hemophilia, Diabetes, Systemic Sclerosis, Myositis, HIV, etc).

The development of CAR-T cell clinical trials has accelerated over the last 25 years. According to V. Wang et al and their analysis of cliniclatrials.gov data as of 2022, by that time trials were coming mainly from the United States (n = 377) and China (n = 636), while Europe (n = 58) was far behind these two leading countries. When we analyze Clinicaltrials. gov data as of today – situation is pretty much the same – for ongoing or not yet started studies initiated by the industry – China and US are leading the effort with Europe being seriously behind. According to different sources Europe lags in CAR-T cell therapy development and rollout due to fragmented market access, lower venture capital funding, and complex healthcare infrastructure hurdles.

Saying this, however we need to mention that overall conducting clinical research in CAR-T therapies regardless of the location is quite challenging and there are several reasons for this:

1. Advanced therapies are subject to stringent regulatory requirements that vary by region, including novel therapies that require approval through new regulatory pathways. For example, FDA in the USA issued their first guidance on cell therapy in 1998 and have since continued to issue updated guidance documents with the advance of cell technologies. Within the EU cell therapy products are bound to follow the Good Clinical Practice standards specific to advanced therapy medicinal products. Additionally, CAR-T cell treatments must comply with the guidelines of genetically modified organisms (GMOs). Sponsors must categorize these treatments as being under the 'contained use' or 'deliberate release' categories. The 'contained use' designation applies to procedures with stringent measures in place to prevent GMO exposure to the surroundings. Conversely, 'deliberate release' refers to the deliberate introduction of GMOs into the environment without specific containment protocols (M.Posa et al, 2026).

2. Complex manufacturing – CAR-T cell therapies are personalized treatments that are based on the T cells of an individual patient. The high and stringent regulatory requirements that are imposed for their clinical dissemination make their manufacturing process complicated.

3. Complex administration – multi-step medical process involving blood collection, lab re-engering during production and  then infusion

4. Immunogenicity and adverse effects – CAR-T cell therapies have been associated with major adversities such as cytokines release syndrome (CRS) and immune effector cells associatedneurotoxicity syndrome (ICANS) which has life threatening potential. Additional negative effects include hematologic disorders, severe infection, low blood pressure, low oxygen and acute kidney injury (M.Posa et al, 2026).

5. Product profile specifics often require review of additional national committees related to the impact of genetically modified products on the patient’s health (e.g in EU prior to the approval of a CAR T, some areas and countries are allowed to impose additional CAR T-specific requirements, in addition to more traditional regulation and ethical scrutiny)

6. Advanced therapy is novel for many regulatory agencies across the globe and this causes extra questions from the authorities.

7. Lack of awareness at the US or EU-based biotech companies about other countries’ regulatory requirements prevents leveraging the advantages of these countries’ contribution to the study recruitment boost.

With all mentioned above it’s evident that in such circumstances, when study conduct is challenging, while the urgent unmet need of curing serious life-threatening diseases CAR-T cell therapy has been targeting is obvious, it becomes even more important to make sure that studies are planned and organized properly to address all possible difficulties and ensure that they are being completed as fast as possible.

PVR team has a lot of experience running CAR-T studies (in some of countries where we operate, PVR was the first CRO to run CAR-T studies). We are well aware of all the challenges those studies can bring and have a proven track record of successful delivery of those complex trials in different indications including both studies in cancer and other pathologies. We clearly understandregulatory requirements and peculiarities in different countries, fully aware of patient pathways, have relationships with sites, able to provide dedicated project teams to make sure that studies are delivered in timely and cost-effective manner. We are well-positioned to deliver CAR-T studies in our regions and will welcome the opportunity to partner with biotech and pharma companies in advancing their CAR-T cell research with ultimate goal to bring new innovative therapies to patients in need faster.