Views: 0 Author: Site Editor Publish Time: 2026-10-27 Origin: Site
Autoimmune R&D Series 01 | In vivo CAR-T and T-cell engagers
Originally published in Chinese on September 3, 2026. This commentary reflects information available as of September 2, 2026.
HKeyBio’s take. CAR T-cell therapy has provided important clinical proof of concept that deep B-cell depletion can translate into meaningful clinical benefit in selected severe, treatment-refractory autoimmune diseases. Further development should build on these results by improving clinical efficacy, the benefit–risk profile, treatment delivery, and access to care.
Summary. As of September 2, 2026, public reports indicated pauses in autoimmune disease trials of Novartis’s rapcabtagene autoleucel (rap-cel) and Bristol Myers Squibb’s zolacabtagene autoleucel (zola-cel). These developments highlighted the continuing importance of safety assessment and monitoring as autoimmune CAR-T development advances. They also raised a broader question for product development: how can a therapy achieve deep B-cell depletion or clinical remission while remaining manageable for patients, deliverable by treatment centers, and financially sustainable for healthcare systems?
For next-generation approaches, depth of B-cell depletion needs to be considered alongside the ability to understand the biological response, monitor treatment, and deliver care in clinical practice.
The reported trial pauses provide a timely context for assessing benefit and risk. [1] The clinical decision-making context differs between oncology and autoimmune diseases. Patients with life-threatening cancers and limited treatment options may accept substantial short-term treatment risks. In autoimmune disease, acceptable risk depends on disease severity, organ involvement, available therapies, and long-term treatment goals. In many settings, particularly where effective alternatives exist, the acceptable level of treatment-related risk may be lower than in advanced, treatment-refractory cancer.
Autologous cell manufacturing, lymphodepleting conditioning, and monitoring at specialized centers also influence treatment burden, patient acceptability, and access to care.
· Safety. Track CAR T-cell expansion, cytokine responses, cytopenias, infection risk, immunoglobulin levels, and organ-specific toxicities, with predefined criteria for intervention.
· Treatment delivery. Assess conditioning requirements, monitoring intensity, and the burden of care before and after clinical benefit emerges.
· Cost and supply. Consider individualized manufacturing, treatment-center capacity, and long-term follow-up. Pricing and reimbursement arrangements vary across products and healthcare systems.
HKeyBio’s perspective is that benefit–risk, treatment burden, and long-term access should be considered together when defining the target product profile. In vivo CAR-T and T-cell engagers warrant priority evaluation as next-generation approaches, with their potential advantages assessed through program-specific evidence.
In vivo CAR-T approaches aim to deliver genetic instructions encoding a chimeric antigen receptor (CAR) to T cells within the body. Messenger RNA delivered by lipid nanoparticles (mRNA-LNPs), other nonviral platforms, and viral vectors differ in expression duration, delivery properties, and manufacturing requirements. [2,3]
In B-cell-directed autoimmune programs, T-cell engagers (TCEs) typically bind CD3 on T cells and a target antigen on B cells or plasma cells, redirecting endogenous T cells to eliminate the target cells. [5] Both approaches offer potential alternatives to conventional ex vivo autologous CAR T-cell therapy. Product-specific studies can define how each approach contributes to safety, convenience, and accessibility in the intended clinical setting.
Figure 1. Routes for CAR gene delivery, including in vivo, ex vivo viral, and ex vivo nonviral approaches. Reproduced from Rossi and Breman (2024), Figure 1, under CC BY 4.0. [2] Expression duration depends on the delivery platform, payload design, and target-cell biology; the categories shown are schematic.
Table 1. Potential development advantages and key preclinical questions
Approach | Manufacturing and administration | Potential development value | Key preclinical questions |
Ex vivo autologous CAR-T | Patient T-cell collection, ex vivo engineering, and reinfusion. Many protocols include lymphodepleting conditioning. | Clinical proof of concept for deep B-cell depletion and immune reset in selected severe, treatment-refractory autoimmune diseases. | Characterize tissue depletion and its durability alongside conditioning requirements, CAR T-cell expansion, monitoring needs, infection risk, and recovery of immune function, in relation to disease severity. |
In vivo CAR-T | Targeted delivery of a CAR-encoding payload to T cells in vivo. mRNA-LNP platforms generally produce transient expression. | May reduce the need for patient-specific ex vivo cell manufacturing and support a more standardized supply model. | Assess delivery tropism, tissue distribution, cellular delivery efficiency, off-target transduction or expression, CAR expression and T-cell expansion kinetics, repeat dosing, and carrier immunogenicity. |
T-cell engagers | Bispecific or multispecific molecules link CD3 to a B-cell or plasma-cell antigen and recruit endogenous T cells. | Antibody-based TCEs can draw on established antibody manufacturing platforms and accumulated dosing experience. Different target choices may enable different patterns and depths of B-cell or plasma-cell depletion. | Assess cytokine release, tissue penetration, depletion in tissue compartments, step-up dosing, durability of response, hypogammaglobulinemia, and dosing strategy. |
The study endpoints should distinguish peripheral blood depletion from depletion in disease-relevant tissues and should track subsequent immune recovery. The appropriate endpoints depend on the target, delivery platform, and intended treatment schedule.
Effective B-cell depletion involves coordinated interactions among the therapeutic platform, effector cells, target cells, and the tissue environment. The delivery vehicle or engager must reach relevant cells and tissues, recognize its target, and activate the intended effector response. Target expression across relevant cell populations and tissues should also be characterized. The depth, duration, and tissue distribution of depletion, together with how cytokines, myeloid cells, and other immune networks amplify or constrain the response, all influence the outcome. A complementary set of models can address these questions. [4–6]
Confirm target binding, effector-cell dependence, target-cell killing, and cytokine release in systems appropriate to the candidate’s mechanism of action. For in vivo CAR-T, also establish which cells receive the payload and express the CAR. These experiments help define the mechanism and guide the choice of in vivo models.
Select models according to the question being addressed. Human immune system–reconstituted mice can support assessment of human target engagement, T-cell activity, and B-cell depletion. Interpretation should account for the extent of immune reconstitution, mouse–human cytokine compatibility, and the risk of xenogeneic graft-versus-host disease. Human target knock-in models and pharmacologically relevant surrogate systems can provide complementary evidence where appropriate. [4,6]
When target binding and functional activity, delivery tropism, and effector pathways are pharmacologically relevant, nonhuman primate (NHP) studies can characterize biodistribution, B-cell depletion and recovery, cytokine responses, and tissue safety. In vivo CAR-T programs additionally require assessment of cellular delivery, CAR expression, and CAR T-cell expansion and persistence. For viral delivery, assess transduction; for mRNA delivery, assess transfection and expression. The relevance of each endpoint should be established for the candidate and delivery platform.
HKeyBio can integrate human cell and tissue studies, appropriate mouse models, and pharmacologically relevant NHP studies into a preclinical evidence package tailored to the candidate’s mechanism of action. For in vivo CAR-T and TCE programs, study design should address cross-species binding and functional activity, delivery tropism where applicable, effector-cell involvement, tissue distribution, cytokine responses, pharmacokinetics and pharmacodynamics, and histopathological assessments. Model selection and endpoints should be confirmed against the molecular characteristics and development stage of each program.
1. Lupus Foundation of America. Novartis, Bristol Myers Squibb pause CAR-T trials for lupus and other autoimmune diseases for safety reviews. September 1, 2026. Source
2. Rossi M, Breman E. Engineering strategies to safely drive CAR T-cells into the future. Front Immunol. 2024;15:1411393. doi:10.3389/fimmu.2024.1411393
3. Razavi R, Kegel M, Muscat-Rivera J, Weissman D, Melamed JR. Harnessing mRNA-lipid nanoparticles as innovative therapies for autoimmune diseases. Mol Ther Methods Clin Dev. 2025;33(3):101566. doi:10.1016/j.omtm.2025.101566
4. Yue H, Bai L. Progress, implications, and challenges in using humanized immune system mice in CAR-T therapy—Application evaluation and improvement. Anim Models Exp Med. 2024;7(1):3–11. doi:10.1002/ame2.12353
5. Wincup C, Gatto M, Scherlinger M, Schett G, Hagen M. The why, what, who and when of B cell depletion in systemic lupus erythematosus: biological rationale, patient stratification and evolving therapeutic modalities. Rheumatology. 2026;65(8):keag416. doi:10.1093/rheumatology/keag416
6. Donnadieu E, et al. Time to evolve: predicting engineered T cell-associated toxicity with next-generation models. J Immunother Cancer. 2022;10(5):e003486. doi:10.1136/jitc-2021-003486
HKeyBio is a preclinical contract research organization specializing in autoimmune and allergic diseases, with end-to-end services for in vivo efficacy studies. Its core scientific team brings more than 20 years of experience in autoimmune drug discovery and development.
HKeyBio is ISO 9001 certified and operates an integrated research platform in Suzhou Industrial Park covering molecular biology, cell biology, pathology, small-animal studies, and analytical testing, alongside NHP study sites in Suzhou and Guangxi. The company has nearly 80 employees, and all project leaders hold a master’s or doctoral degree. The team’s cumulative experience includes support for more than 500 IND submissions in autoimmune disease development.
Our model portfolio includes more than 50 NHP models and more than 500 animal models of autoimmune and allergic diseases.
Author: HKeyBio Marketing Department | Scientific review and editing: Jing Yan
