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Key development considerations for cell therapies

What is a “cell therapy”? It is a phrase that has been used in nearly every recent oncology clinical conference. Cell therapies, such as CAR-Ts (chimeric antigen receptor T-cells), are not small molecules or a simple, straightforward biologic. They’re a whole new class of therapeutics!

How does CAR-T technology work?

In simplistic terms, it’s a method for enabling our immune system to fight debilitating diseases. CAR-T technology genetically engineers T cells (either a patient’s own or a donor’s) to express a chimeric antigen receptor targeting a specific tumor antigen.

CAR-Ts are engineered to identify and attach to specific antigens on the cancer cell surface (see Figure 1). The CAR-Ts can then proliferate and kill the cancer cells. The FDA has approved several CAR T-cell therapies including abecma (idecabtagene vicleucel), breyanzi (lisocabtagene maraleucel), kymriah (tisagenlecleucel), tecartus (brexucabtagene autoleucel), and yescarta (axicabtagene ciloleucel). These CAR-T therapeutics approvals have fueled a massive uptake in interest given the way it has revolutionized drug disease continuum. Part of the reason for this interest is the greater durability of efficacy expected with cell therapies compared with conventional treatments. Not surprisingly, the FDA has developed a guidance for industry on this subject to assist developers.

3D illustration of chimeric antigen receptor (CAR) T-cell therapy
Figure 1

A cursory search in the clinicaltrials.gov database reveals more than 100-cell therapy investigative treatments in clinical trials. One key aspect in product development is the consistent, within specification, product performance as it relates to chemistry, manufacturing, and scale-up. Cell therapy therapeutics have started to reimagine this time-valued manufacturing spectrum to produce consistently safe and quality medicines. Why is that? Let’s reflect on this aspect before launching into our 3 key development considerations.

What are the steps in CAR-T therapy?

Once a patient qualifies for the “procedure” (Figure 2) and arrives at a medical unit, they undergo a process called leukapheresis to isolate peripheral blood mononuclear cells. At this stage the “procedure” transitions into a “manufacturing” phase. In this phase, the patient undergoes chemotherapy during cellular processing. Genetic material is then transferred through viral vectors following cell expansion. After this step, the cells are infused into the patient following a process of lymphodepletion. So, as you can see, the traditional brick and mortar pharmaceutical manufacturing plant is replaced with a manufacturing process that takes place in the clinical center.

CAR T-cell therapy. Artificial leukocyte receptors are proteins that have been engineered for cancer immunotherapy (killing of tumor cells). genetically engineered
Figure 2

Here are 3 key considerations.

1. Clinical pharmacology strategy for CAR-T Therapeutics

The clinical pharmacology considerations for CAR-T therapeutics ordinarily involves defining the mechanism of action, assessing the on-target effects of the therapy, and characterizing the cellular kinetics of the new therapy. Some of the common translational strategies for such products are to better understand cellular kinetics and dynamics and whether there are key biological determinants underpinning responders vs non-responders.

For example, let’s take KYMRIAH. It was developed by transducing autologous T cells with a lentiviral vector encoding a chimeric antigen receptor (CAR) composed of a murine single chain antibody variable fragment (scFv) specific for CD19, linked to intracellular signaling domains from 4- 1BB (CD137) and CD3-zeta (here’s the summary basis of approval). One signaling domain enhances the expansion and persistence of KYMRIAH cells while the other initiates T-cell activation and antitumor activity. When CAR binds to CD19 positive target cells, it triggers anti-tumor activity, cellular proliferation, and persistence.

Conventional MIDD tools including population PK models can inform the program relating exposure with recovery and relating exposure with tumor burden. Given cellular dynamics is a key concern, adapted cellular kinetic models are usually a better mechanistic model to inform drug development decisions. A good example of a cellular kinetic model is shown below in Figure 3 (Adapted from Ogasawara et al., 2021).

図3:Cellular kinetic model of lisocabtagene maraleucel (Adapted from Ogasawara et al., 2021).

In Ogasawara’s model, C0 refers to initial transgene levels, Cmax is the maximum transgene levels, Fβ is the fraction of Cmax that appears in the β or terminal phase, HLα the initial (α phase) decline half-life, HLβ the terminal (β phase) half-life, Tdbl the doubling time during growth phase, Tgro the growth phase duration, Tlag the lag phase duration, and Tmax being the time to maximum transgene levels.

Traditional methods of sample collection may not provide the precision behind characterization of cellular kinetics. Recent attempts in quantifying cellular dynamics have included radiolabeling of CAR-T cells. Dual imaging of tumor and CAR-T cells can assist in interpreting antitumor responses.

2. Cell therapies dose selection strategy

When going into first-in-human studies, dose selection of cell therapies is mainly driven by safety considerations. When we start to collect clinical data, we can apply some of the typical exposure-response methods used for other drug types to support dose selection – we just need to think about things a little differently. Instead of exposure being defined by pharmacokinetic processes of absorption, distribution, metabolism, and excretion (ADME), exposure is defined by cellular kinetics, as the cells expand, contract, and persist. Once we understand and describe the cellular kinetics following injection of the cell therapy (Ogasawara et al., 2021), we can then link the characteristics of those kinetics to key efficacy and safety endpoints typical for exposure-response analyses. We can then seek a dosing regimen that provides an optimal benefit-risk balance.

Key factors that may impact dosing regimen selection for cell therapies include patient body weight and tumor burden. But we also should consider manufacturing process aspects of the cell therapy, as these can impact the cellular kinetics as well as the safety and efficacy profile.

Unlike conventional drug modalities, where higher doses usually mean higher efficacy, human participants who receive higher doses of CAR-T cells typically don’t experience greater CAR-T cellular expansion or persistence. This suggests that higher doses may not result in higher efficacy or durability in response and as such could render difficulties in interpreting dose and exposure/response relationships. Some of the key determinants of efficacy appear to be lymphodepletion and baseline tumor burden.

3. Cell therapy safety considerations

A cell therapy developer needs to assess many safety considerations as part of the clinical safety of the product. Once administered, the CAR-T cell proliferation rate can determine the extent and magnitude of the key safety issues of cytokine release syndrome (CRS) and neurotoxicity. These two safety issues may be life-threatening and typically arise within 28 days of infusion. Cytokine release storm (CRS) or macrophage activation syndrome is considered “on target” toxicity as the T cells expand and exert their biological effects. CRS is commonly managed by blocking the IL-6 receptor with tocilizumab.

Two types of neurotoxicity are associated with these products; those that are common and reversible (e.g., aphasia), and those that are much more severe (e.g., fatal cerebral edema). Prolonged B cell aplasia is also a known safety issue with these therapies and can be often managed by intravenous immunoglobulin. These safety issues are prominently featured on the package insert. The example below is from the KYMRIAH® (tisagenlecleucel) package insert.

KYMRIAH (tisagenlecleucel) package insert
Figure 4

There are several other approaches in development that are related to the concept of cell therapy.  These are TCRs (T-cell receptor-based therapies) which act a little differently as they use the T-cells natural ability to recognize antigens, meaning they can penetrate tumors and attach to internal parts of the cancer cell as well as to the cancer cell surface. Then we have NK (natural killer) cell therapies coming along, which may address some of the side effects one can get with CAR-Ts as highlighted above – but that is subject to another blog.

In conclusion, developing CAR-T therapeutics requires a clinical pharmacology/pharmacometrics strategy to elucidate the mechanism of action and explain biological effects in relation to efficacy and safety considerations. It also requires an understanding of immunology and cellular biology, as well as applied mathematical tools to develop a plausible understanding of cellular level kinetics and dynamics.

To learn more about best practices for cell therapeutics development, please watch this webinar.


  • Ogasawara K, Dodds M, et al. Population Cellular Kinetics of Lisocabtagene Maraleucel, an Autologous CD19‑Directed Chimeric Antigen Receptor T‑Cell Product, in Patients with Relapsed/Refractory Large B‑Cell Lymphoma. Clinical Pharmacokinetics. 2021 Dec;60(12):1621-1633.  doi: 10.1007/s40262-021-01039-5. Epub 2021 Jun 14.
  • FDA draft guidance, March 2022: Considerations for the development of CAR-T cell products

About the authors

Rajesh Krishna, PhD
By: Rajesh Krishna, PhD

Rajesh Krishna, PhDは、サターラ・ストラテジック・コンサルティングの医薬品開発科学特別研究員、ならびに希少疾患に関する統合プラクティス領域のリーダーです。医薬品業界とコンサルティングを合わせて約25年の経験を有し、40件以上の治験薬、200件以上の第1/1b相試験、および数件の新薬申請(new drug application、NDA)/生物製剤承認申請(biologicslicense application、BLA)に貢献してきました。Rajの臨床薬理ブログの執筆者でもあります

Kathryn Brown
By: Kathryn Brown

Kathrynは、サターラの統合された医薬品開発グループにおける、臨床薬理コンサルタント兼チームリードです。さらに、細胞療法、RNA技術、遺伝子療法、融合タンパク質、ADC、二重特異性抗体などの領域で、お客様に専門的なサポートを提供することに特化したComplex Biologics Integrated Practice Areaを主導しています。2020年にサターラに入社する以前は、20年以上、医薬品業界で臨床薬理および薬効評価に従事し、開発のあらゆる段階にわたり取り組んできました。

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