细胞疗法开发的主要考虑因素

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

CAR-Ts 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 approvals have fueled massive interest because they have revolutionized the drug-disease continuum. Cell therapies have greater durability of efficacy than conventional treatments. Not surprisingly, the FDA has developed a relevant guidance for industry to assist developers.

The clinicaltrials.gov database contains more than 100-cell therapy investigative treatments in clinical trials. One key aspect of 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 manufacturing to produce consistently safe and quality medicines.

Why is that? Let’s reflect on this aspect before launching into our 3 key development considerations.

Once a patient qualifies for the “procedure” (Figure 2) and arrives at the clinic, they undergo leukapheresis to isolate peripheral blood mononuclear cells. At this stage, the “procedure” transitions into a “manufacturing” phase. Thus, 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, manufacturing that occurs in the clinic replaces traditional pharmaceutical manufacturing.

Here are 3 key considerations.

The clinical pharmacology considerations for CAR-T therapeutics ordinarily involve:

• defining the mechanism of action,
• assessing the on-target effects of the therapy, and
• characterizing the cellular kinetics of the new therapy.

Some common translational strategies are to understand cellular kinetics and dynamics and whether biological determinants underpin 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. The other signaling domain 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 relate exposure with recovery and 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 in Figure 3 (Adapted from Ogasawara et al., 2021).

In Ogasawara’s model, these are the following parameters:

• C₀ refers to initial transgene levels,
• C_max is the maximum transgene levels,
• Fβ is the fraction of C_max that appears in the β or terminal phase,
• HLα the initial (α phase) decline half-life,
• HLβ the terminal (β phase) half-life,
• Tdbl is the doubling time during the growth phase,
• T_gro is the growth phase duration,
• T_lag is the lag phase duration, and
• T_max is the time to maximum transgene levels.

Traditional methods of sample collection may not provide precise 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.

When going into first-in-human studies, dose selection of cell therapies is driven by safety considerations. When we start to collect clinical data, we can apply exposure-response methods used for other drug types to support dose selection. But we do need to think about things a little differently!

Drug exposure is usually defined by pharmacokinetic processes of absorption, distribution, metabolism, and excretion (ADME). For cell therapies, 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 therapy (Ogasawara et al., 2021), we can then link the kinetics to efficacy and safety endpoints typical for exposure-response analyses. We can next seek a dosing regimen that optimizes the 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 the manufacturing process aspects of the cell therapy. These aspects can impact the cellular kinetics as well as the safety and efficacy profile.

For conventional drug modalities, higher doses usually mean higher efficacy. By contrast, patients who receive higher CAR-T cell doses typically don’t experience greater cellular expansion or persistence. This suggests that higher doses may not result in higher efficacy or durability in response.

As such, this phenomenon could complicate interpreting dose and exposure/response relationships. The key determinants of efficacy appear to be lymphodepletion and baseline tumor burden.

A cell therapy developer needs to assess many clinical safety considerations of the product. Once administered, the CAR-T cell proliferation rate can determine the extent and magnitude of the key safety issues: cytokine release syndrome (CRS) and neurotoxicity.

These safety issues may be life-threatening and typically arise within 28 days of infusion. CRS or macrophage activation syndrome is “on target” toxicity as the T cells expand and exert their 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. Patients often receive intravenous immunoglobulin to manage this complication.

The package insert highlights these safety issues. The example below is from the KYMRIAH® (tisagenlecleucel) package insert.

Figure 4

Several other approaches in development use the concept of cell therapy. These are TCRs (T-cell receptor-based therapies) which use the T-cells’ natural ability to recognize antigens. This means they can penetrate tumors and attach both the cancer cell’s inside and surface. In addition, NK (natural killer) cell therapies are coming along, which may address some of the side effects associated with CAR-Ts.

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