Guest Column | June 27, 2025

Why 'Which Is Best?' Is The Wrong Question In CGT Development

By Jennifer Chain, Ph.D., CABP, cellular starting material expert

Hard choice or decision-GettyImages-2015287041

In the fast-evolving world of cell therapy, a common question keeps surfacing: “Which is best?” Autologous or allogeneic? T cells or NK cells? Fresh or cryopreserved? The instinct to seek a single “best” option is natural — but in reality, there’s rarely a universal winner.

The right choice depends on a complex interplay of biology, manufacturing, clinical need, and logistical practicality. As the field matures, what’s becoming clear is that successful therapies will emerge not from a one-size-fits-all model but from thoughtful alignment of the right technologies with the right indications. This article explores some of the most commonly debated either-or questions in cell therapy and resolves why the best answer should be “both.”

Auto vs. Allo

Which is better: autologous or allogeneic cell therapies?

Answering this question requires an analysis of the patient population, disease type, urgency of treatment, and practical considerations like manufacturing and cost. Ideally, auto and allo therapies will coexist, each serving distinct roles in the future of cell therapies.

Autologous therapies shine in cases where a personalized approach is essential.¹ These therapies are especially valuable for rare diseases, when immune rejection is a concern, and no off-the-shelf solution exists. The key strength of autologous treatments lies in the ability to precisely match a patient’s biology. But they come with trade-offs: they’re costly, slow to produce, and lack manufacturing standardization, making autologous therapies less suited for critically ill patients or widespread adoption.²

Allogeneic therapies, on the other hand, are built for scaling.³ These off-the-shelf treatments can be delivered quickly and efficiently to large numbers of patients with common symptoms.⁴ They offer lower costs and streamlined production, but they’re not without challenges. Immune rejection, graft-versus-host disease (GvHD), and variability in donor cells can limit their effectiveness if not accounted for during development.^4,5

Centralized vs. Decentralized

Which is better: centralized or decentralized manufacturing?

As developers are scrambling for scarce manufacturing slots, the best answer here ultimately depends on factors like product type, regulatory environment, cost, scalability, logistics, and quality control.

Centralized manufacturing involves collecting patient or donor material and shipping it to a central facility for processing, after which the therapy is returned to the patient. Benefits include streamlined quality control, efficient resource use, lower overall costs, access to a skilled workforce in one location, and simplified regulatory oversight.⁶ However, this model faces logistical hurdles in transporting materials and can create bottlenecks when compliance or quality issues arise and affect many therapies at once.⁷

Decentralized manufacturing (DCM) happens near or at the point of care, such as a regional facility or hospital. It reduces issues with transportation logistics, shortens vein-to-vein time, and spreads quality risk across multiple sites.^8,9 But DCM brings significant challenges: standardizing processes and ensuring consistent quality across batches are difficult, costs are higher due to the smaller scale, and it is difficult to find and retain trained staff across many sites.¹⁰ Regulatory oversight and monitoring also become more complex with the DCM model.^8,9

Both models play important roles in cell and gene therapy.

Centralized manufacturing is ideal for allogeneic and early-scale autologous therapies, especially when complex processes and strict quality control are needed.
DCM is better suited for autologous therapies requiring urgent patient access, where logistics issues could otherwise delay treatment.

Fresh vs. Cryopreserved

Which is better: fresh or cryopreserved cells?

This question remains a point of active debate in the cell therapy field, with strong opinions on both sides. The choice between fresh and cryopreserved cells ultimately depends on the therapeutic cell, type of therapy, logistical constraints, and clinical goals.

Fresh cells, whether used as starting material or as the final drug product, are generally believed to offer better viability, proliferation, and cytotoxic function than cryopreserved cells.^11,12 They avoid the stresses associated with freezing and thawing and can be administered to patients more rapidly after manufacturing. However, their short shelf life demands tight coordination across the entire supply chain. Fresh products also bring greater logistical complexity in transport and may exhibit more batch-to-batch variability.

In contrast, cryopreserved cells offer advantages in consistency, scalability, and flexibility.¹³ They simplify storage and transport and enable standardized manufacturing workflows. For allogeneic therapies, cryopreservation is especially valuable, allowing time for quality control testing and inventory management. While cryopreserved cells may show reduced viability and function immediately after thawing, some evidence suggests they can recover and perform comparably to fresh cells over time,^12-14 though this recovery may be dependent on cell type.¹⁵ A key drawback is the use of cryoprotectants like DMSO, which can cause toxicity and necessitate patient monitoring post-infusion.¹⁶

In the end, there is no one-size-fits-all answer.

Fresh cells may be favored when optimal biological performance is critical and timing is manageable.
Cryopreserved products are better suited for commercial-scale therapies that demand logistical efficiency and global reach.

Bone Marrow vs. Umbilical Cord Tissue vs. Adipose Tissue

Which is better: bone marrow, umbilical cord tissue, or adipose tissue for mesenchymal stromal cell therapy production?

The optimal tissue source for mesenchymal stromal cell (MSC) production depends on the intended application, donor characteristics, regulatory context, and manufacturing strategy.

Bone marrow-derived MSCs (BM-MSCs) are the most extensively studied and clinically validated.¹⁷ They have demonstrated strong immunomodulatory effects and tissue repair capabilities,¹⁸ making them especially suitable for autologous and immune-mediated therapies. However, bone marrow aspiration is invasive, yields relatively low numbers of MSCs, and donor age can negatively impact cell growth and therapeutic function.¹⁷

Umbilical cord tissue-derived MSCs (UCT-MSCs) are isolated from discarded birth tissue, offering a non-invasive, ethically favorable source.¹⁷ These cells have high proliferative capacity and are well suited for allogeneic, off-the-shelf products. However, UCT-MSCs have less clinical precedent than BM-MSCs, and variability in tissue processing can introduce manufacturing inconsistencies and affect product quality.

Adipose tissue-derived MSCs (AT-MSCs) are obtained through elective liposuction, a minimally invasive procedure that yields a large number of MSCs with robust proliferation potential.¹⁷AT-MSCs support large-scale expansion and show strong immunomodulatory functions, often matching or exceeding that of BM-MSCs .¹⁹ However, donor age, metabolic status, and health can affect MSC quality and consistency.¹⁷ Regulatory pathways with AT-MSCs remain more limited than for BM- and UCT-MSCs.

In short:

BM-MSCs are preferred when clinical history, immune modulation, or autologous use is critical.
UCT-MSCs are ideal for scalable, allogeneic therapies with high proliferative demands.
AT-MSCs are best suited for autologous or regenerative applications where high yield and minimally invasive collection are priorities, though variability and regulatory maturity must be considered.

T Cells vs. NK Cells

Which is better: T cells or NK cells?

While T cells have led the way in engineered cell therapies, natural killer (NK) cells are gaining attention as a powerful alternative. Each cell type offers unique advantages and limitations, and the optimal choice depends on the therapeutic target, treatment goals, and manufacturing strategy.

T cells are highly specific, recognizing antigens via their T cell receptors and mounting strong, targeted responses.²⁰ They generate immunological memory, enabling durable effects, which are especially important in cancer therapy. T cells have shown remarkable clinical success in autologous CAR-T treatments for B-cell malignancies.⁴ However, they carry risks such as cytokine release syndrome (CRS) and GvHD, particularly in allogeneic settings.^21,22

NK cells, by contrast, are part of the innate immune system and kill abnormal cells without prior sensitization or antigen-specific receptors.^23,24 This makes them inherently safer for allogeneic, off-the-shelf therapies, with minimal risk of GvHD.²² NK cells act quickly and are effective against aggressive tumors, but they lack long-term memory and typically do not persist as well in vivo.²⁵ They also pose manufacturing challenges due to lower expansion rates, and there is less clinical data supporting their efficacy.

To summarize:

T cells are best suited for therapies needing high specificity and long-term persistence.
NK cells offer broader, faster responses with a safer profile for allogeneic and off-the-shelf products. Rather than competing, these cell types will likely complement each other in future cellular immunotherapies.

Tscm vs. γδ T cells

What about two emerging, but rare, T cell populations, T stem cell memory (Tscm) and gamma delta (γδ) T cells for developing effective cell therapies? Tscm offer long-term persistence, self-renewal, and multipotent differentiation, which are ideal traits for durable, autologous CAR-T therapies.²⁶ However, they are rare in peripheral blood, limiting scalability for broader applications.

γδ T cells, by contrast, kill independently of antigen presentation, reducing the risk of GvHD.^27,28 They combine traits of both adaptive T cells and innate NK cells, making them promising for allogeneic off-the-shelf use. Yet, functional diversity among γδ T cell subsets presents manufacturing and reproducibility challenges.

In short, these cell types occupy distinct therapeutic niches.

Tscm excel in longevity and immune memory.
γδ T cells offer safety and scalability.

Fresh Healthy Donor Material vs. iPSC lines

Which is better: fresh starting material from healthy donors or induced pluripotent stem cell lines?

Groups developing therapies from both approaches are competing for the title of the “best off-the-shelf therapy.” But is it possible that both strategies could coexist?

Allogeneic therapies derived from healthy donor cellular starting material (CSM) — such as leukopaks or bone marrow — currently lead in clinical trials. Freshly collected CSM offers key advantages, including biologically mature cells that require no reprogramming or differentiation, which can simplify processing and shorten time to clinic.²⁹ Regulatory frameworks for donor-derived materials are well established, easing clinical translation. However, challenges include donor-to-donor variability in product quality and function, limited expansion capacity, and greater difficulty in genetic engineering due to cell maturity.^29-31

In contrast, allogeneic therapies using induced pluripotent stem cell (iPSC) lines are gaining traction for their potential to deliver highly consistent and scalable products.³² A single iPSC master cell bank can generate large, uniform batches of therapeutic cells, supporting long-term manufacturing and broad patient access.^32,33 Their immature state makes iPSCs easier to genetically engineer.³⁴ Yet, manufacturing remains complex, requiring both differentiation and genetic modification steps. Safety concerns, particularly regarding tumorigenicity, are not fully resolved, and regulatory pathways for iPSC-based therapies are still evolving, creating uncertainty in clinical development.

Each approach has its niche.

Fresh donor material is well suited for off-the-shelf T or NK cell therapies where rapid turnaround and process simplicity are priorities.
iPSC lines may ultimately prevail in applications demanding high scalability, genetic flexibility, and consistent dosing across large patient populations.

Ex Vivo vs. In Vivo

Which is better: ex vivo or in vivo cell therapy approaches?

The rise of in vivo CAR T therapies has sparked debate about the future of cell therapy manufacturing. Some suggest in vivo delivery could eventually replace traditional ex vivo approaches, but it’s more likely that both will play important roles moving forward.

Ex vivo therapies involve collecting cells from the patient or donor, modifying and expanding them in a controlled lab setting, then infusing them into the patient.¹ This enables precise editing, quality control, and customization for specific cancers. Ex vivo CAR-T therapies have an established clinical track record and defined regulatory frameworks. However, the process is costly, logistically complex, and time-consuming, particularly for autologous products, which require individualized manufacturing.

In vivo approaches deliver genetic material directly into the patient, enabling their own immune cells to be reprogrammed inside the body to fight a specific target,³⁵ similar to a vaccine. This eliminates the need for cell collection and lab-based manipulation, offering greater scalability and cost efficiency. But with these benefits come trade-offs: less control over where and how genetic material is integrated, limited safety data, and no standardized regulatory pathway yet.

In simple terms:

Ex vivo therapies remain best for applications needing precision and complex engineering.
In vivo therapies hold promise for more accessible, scalable treatments.

Both approaches are likely to coexist and future innovation may even combine them.

Conclusion

As the cell therapy landscape expands, the question of “which is best?” becomes less about competition and more about complementarity. Different approaches — whether centralized or decentralized manufacturing, bone marrow or other tissue sources, ex vivo or in vivo therapies — address different clinical and operational challenges.

What matters most is matching the right cell type, tissue source, and manufacturing approach to the therapeutic goal. Innovation will come not just from perfecting one approach but from developing flexible platforms that adapt to diverse patient needs.

Moving forward, collaboration, not rivalry, between these modalities will be key to building a truly robust, scalable, and patient-centered cell therapy ecosystem.

References:

About The Author:

Jennifer Chain, Ph.D., CABP, is a cellular therapy expert with 27 years of experience in T cell immunology, product development, blood banking, and consulting. She holds a Ph.D. in immunology and a Certified Advanced Biotherapies Professional credential from the Association for the Advancement of Blood and Biotherapies (AABB). She currently works as a consultant in the cellular starting material space, helping collection centers and cell therapy companies develop CSM collection and procurement programs as well as other strategic plans. Reach her on LinkedIn or CSM Consulting’s website, www.cellsmatter.com.

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