Autologous T-cell based therapies are today one of the most advanced type of cell and gene therapies in the race to demonstrate efficacy and commercialize.

While autologous immunotherapies hold a very promising future based on current commercially approved drugs and latest clinical trial results, allogeneic immunotherapies hold the potential to solve some of the scalability obstacles of autologous, though come with their own challenges.


Autologous and Allogeneic CAR-T treatment challenges


Whether you are developing an autologous or an allogeneic CAR-T therapy you will be focused on a similar goal, but will face very different obstacles, each with its own complexities.

Depil, S., Duchateau, P., Grupp, S. A., Mufti, G., & Poirot, L. (2020). ‘Off-the-shelf’ allogeneic CAR T cells: development and challenges. Nature Reviews Drug Discovery, 19(3), 185–199
Graham, C., Jozwik, A., Pepper, A., & Benjamin, R. (2018). Allogeneic CAR-T Cells: More than Ease of Access? Cells, 7(10), 155. https://doi.org/10.3390/cells7100155


Autologous CAR-T treatment challenges


The top four challenges we have identified for autologous CAR-T therapy developers are the quality and variability of the starting material, the inevitable disease progression from the time of tissue collection to treatment, the commercial viability of the treatment and the unexpected logistical challenges associated with harvesting and scheduling of manufacturing.

Depil, S., Duchateau, P., Grupp, S. A., Mufti, G., & Poirot, L. (2020). ‘Off-the-shelf’ allogeneic CAR T cells: development and challenges. Nature Reviews Drug Discovery, 19(3), 185–199
Graham, C., Jozwik, A., Pepper, A., & Benjamin, R. (2018). Allogeneic CAR-T Cells: More than Ease of Access? Cells, 7(10), 155. https://doi.org/10.3390/cells7100155

Quality of cells:

As cells are manufactured for each patient, it is not possible to produce a completely standardized end-product

Disease progression:

In the JULIET study, where Kymriah was used to treat relapsed, refractory DLBCL, 13% of patients never received the CAR-T cell product due to disease progression

Commercial viability:

The latest approved CAR-T cell products are priced at multiple hundreds of thousands of dollars and are not accessible to many patients who cannot afford them

Harvest & manufacturing issues:

It is not always possible to harvest and manufacture adequate lymphocyte numbers from patients who are typically lymphopenic from their disease or previous chemotherapy


Let's integrate your supply chain


Our solution starts by integrating your supply chain and manufacturing into a seamless vein-to-vein network, orchestrated centrally with a platform.

This is made possible through a series of key strategic partnerships and Lonza’s own MES (Manufacturing Execution System) MODA-ES. We have announced our partnerships with leading cell & gene therapy System Center Orchestrator (SCO) for vein-to-vein traceability (Vineti) and a leader in cell tissue transport, logistics & delivery (Cryoport).

Central to this vein-to-vein network is our manufacturing capability, enhanced by a number of automated, closed systems such as the Cocoon® device:

  • Single-use, highly customizable cassette can be tailored to a process providing flexibility when migrating to a closed, automated system
  • Flexible programming and in-process monitoring provides improved process control

Cocoon™ system for patient-scale cell therapy manufacturing

 

For more information on the Cocoon® device, visit this page.

 


Allogeneic T/NK-cell based immunotherapy challenges

Allogeneic T/NK-cell based immunotherapies have the potential to solve some of the major autologous challenges. One of these is donor variability, with a pool of well characterized donor tissues. Numerous hurdles still remain for allogeneic immunotherapy to address cell therapy commercial viability, including Cost Of Goods (COGs). 

Multiplex gene-editing:

  • Allogeneic T/NK-cell immunotherapies often require multiple gene editing steps
  • Combination of viral and non-viral methods based on efficiency, safety, IP and industrialization attributes
  • Knock-out of TCR (prevent GvHD) and HLA (prevent rejection) + the knock-in of CAR(s) and kill switches using either gene editing tools to control knock-in location or viral vector methods and transposon systems leading to random insertion but providing higher efficiency
  • Choice of licensed technologies needs to be based on their respective characteristics and the know-how of the product. TALEN and ZFN require to build a construct up-front, which can be used multiple times thereafter. CRISPR-based technologies could be more flexible, although they need a guide RNA oligonucleotide sequence for recognition

Downstream and scale:

  • Currently there are limited solutions for large volume processing for allogeneic immunotherapies.
  • Complex T-cell selection with heavy modification on desired T-cells + high patient safety concerns associated to the correct selection
  • Limited tools and GMP materials (e.g. magnetic beads could pose a supply concern); even more when scaling up
  • Current processing require several open manipulations and have limited scalability
  • Maximum number of duplications T-cells can sustain while avoiding exhaustion/senescence is a critical aspect to consider
  • In general, comprehensive large scale and robust technologies are yet to be developed (e.g. target T-cell isolation) 

A path forward

Best-in-class process development services

Our dedicated process development teams will help you to de-risk your manufacturing process before transferring it to GMP manufacturing and scale-up as appropriate. We are equipped to support the full analytical development lifecycle from new assay development to assay validation to supporting late stage products.

Customer's idea or process for therapy product Contact CDMORelease to clientContinuous assessment throughout the product IifecycleProcess and analytical developmentManufacture batches of safe, high quality product Medicine is delivered to patient

Best practices in process development characterization to address some of the key challenges for cell & gene therapy manufacturing include: Eliminate or minimize open / manual unit operations, optimize of sub-optimal unit operations, implement in-process control / decision points, scale-out / automation and process characterization.


Eliminate or minimize open, manual unit operationsProcess characterizationOptimization of suboptimal unit operationsScale out / automationImplement in- process control / decision points

Our bioassay services define, design, determine and deliver the critical quality attributes required for the success of your therapy.


In-process monitoring and decision points Define metrics and measure critical quality attributes Safety, Identity, Strength, Purity, Quality: SISPQ Qualify and validate methods (with QC) Specificity, accuracy, precision, linearity, range, LOD, LOQDevelopment stability testing and in-process hold points Assay developementAssay tech transferAssay validationAssay qualification DefineDesignDetermineDeliverCQA

Process development excellence

With our highly tailored, step-by-step approach to commercial readiness, you can be sure of a robust, reproducible and commercially viable Good Manufacturing Practice (GMP) process, de-risking your path to successful commercialization.

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Tissue sourcing & acquisition

Our in-house Bone Marrow Donor Program’s dedicated full-time staff can help you to navigate through the complexities of tissue sourcing to obtain the clinical and commercial starting material you need.

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Regulatory support dedicated to cell & gene therapy

Rely on a dedicated regulatory partner for the expertise and experience you need to de-risk your therapy's pathway.

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cell and gene therapies


our global network

Our global network of 4 centers of excellence spans across 3 continents to serve patients across the world. The sites in Pearland, TX (USA) and Geleen/Maastricht (NL) offer a fully integrated range of cell- and gene-therapy services including process development, bioassay services and clinical and commercial product supply as well as regulatory affairs consultancy for submission support. Our sites in Portsmouth, NH (USA) and Singapore (SG) serve both as clinical and commercial manufacturing sites for cell therapies.

Portsmouth, NH, USA

Clinical Manufacturing, Commercial Manufacturing, Cell and Gene Manufacturing

101 International Drive
Portsmouth, NH 03801
United States of America

Houston, TX, USA

Clinical Manufacturing, Commercial Manufacturing, Cell and Gene Manufacturing, Viral Vector Manufacturing

14905 Kirby Dr
Houston, TX 77047
United States of America

Tuas, Singapore

Production, Sales & Support

35 Tuas South Ave 6
Tuas 637377
Singapore

Geleen, The Netherlands

Clinical Manufacturing, Commercial Manufacturing, Cell and Gene Manufacturing, Process Development, Analytical Development

Urmonderbaan 20B
Geleen
Netherlands