Business Model

Business Model for the establishment and Commercialization of CAR Cell Technology and Major Supply Chains Involved

The typical CAR-T manufacturing process involves blood collection, apheresis, T-cell activation, gene modification, cell expansion, formulation and packaging, cryopreservation, and eventually injection into patients.

Apheresis collection:

As a mostly autologous cell-based therapy, the CAR-T, CAR-NK or CAR-M cell-manufacturing process starts from the collection of peripheral blood mononuclear cell from the patient, commonly achieved by a leukapheresis process.

Bottle Neck:

• Starting material sourcing itself has long been considered a bottleneck for the burgeoning cell therapy industry.
• The cell therapy manufacturing sector is facing two distinct challenges – the sheer volume of donors necessary to support a fast-growing industry and the mandate for a reliable, consistent product.
• When an autologous cell therapy is being developed, sourcing can be problematic. Patient donors are impacted by their disease and may be unable to donate sufficient healthy cells. Even when the target cell yield is sufficient, there is notorious variability in starting material from patient donors.
• As therapies scale up from small clinical trials to general use, the potential lag (and the accompanying cost) in sourcing appropriate material only grows larger.

Solution:

• Consenting physicians choose the appropriate window for collection based on treatment regimens to ensure the presence of sufficient numbers of T lymphocytes.
• Devices such as Haemonetics Cell Saver 5+, COBE2991, and Fresenius Kabi LOVO have the ability to remove gross red blood cells and platelet contaminants. 
• Terumo Elutra and Biosafe Sepax systems provide size-based cell fractionation for the depletion of monocytes and the isolation of lymphocytes.
• Instruments such as CliniMACS Plus and Prodigy systems allow the enrichment of specific subsets of T cells, such as CD4+, CD8+, CD25+, or CD62L+ T cells using Miltenyi beads post-cell washing.

Companies like:

1. Q2 Solutions offer the processing of peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) at their central laboratories across the world.
2. Terumo Blood and Cell Technologies provides devices to safely and efficiently process donated blood into blood products and to collect blood components needed for transfusions and cell therapy.
3. University of Nebraska Medical Center: The University of Nebraska Medical Center offers many products and services that can benefit the benchtop researcher as well as large pharmaceutical companies. The Elutriation Core Facility provides isolated human monocytes and lymphocytes from peripheral blood mononuclear cells (PBMCs) for various research needs

Raw material (Cells/chemical) suppliers:

CAR cell manufacturing involves the use of a variety of ancillary components such as one-time use disposables, culture medium, reagents for genetic modification, cytokines, formulation medium, and cryopreservation reagents

Bottle Neck

• There is need of backup vendors for critical materials to mitigate the risk of supply chain interruptions.
• Cost of raw materials hinders the mass production.

Preservation:

The processed cell source material can either be used directly for downstream procedure or cryopreserved for future use.

Bottle Neck

• Hypothermic temperature alone may not provide optimized protection, and cells may experience stresses from cold storage that can also lead to cell damage and cell death.
• The stability of fresh leukapheresis starting material is usually limited to a 24- to 48-hour window because of the decrease in cell viability over time in nonfrozen conditions.
• Any unforeseen shipment delays can reduce manufacturing success rates.
• Formation of intracellular ice crystals and cell stress during the crypreservation.

Solution

• Cryopreservation provides scheduling flexibility while significantly de-risking the logistical process.
• In order to keep the cells viable, they are transferred into single use bags, which in turn are placed into protective shells and subsequently frozen, shipped and stored at ultra-cold temperatures (cryopreservation).
• Cryopreservation will lead to a high-quality product with reduced vein-to-vein times, lower cost of goods, and minimal regulatory overburdening.
• Cell Freezing Reagents from SIGMAALDRCH:
• Preventing the formation of intracellular ice crystals and minimizing cell stress is paramount to maintaining cell viability during cryopreservation. They offer an extensive line of sterile-filtered, application-tested cryoprotectants like DMSO as well as ready-to-use cell freezing media with and without DMSO that are designed to maximize cell viability during the freezing and thawing processes.

Companies like:

• ZenBio: ZenBio can provide many different Human blood components to meet your research needs. Company also provides different types of serum.
• Akadeum: Akadeum’s product line is continually updated with new microbubble cell separation products. Find Cell Isolation products including T Cell Isolation Kits and B Cell Isolation Kits in both human and mouse species.

Low Temperature Transportation:

Cell therapies require a cold chain delivery as part of the production and delivery process. 

Bottle Neck

• The bottleneck for CAR T-cell therapy and similar cell and gene therapies is the logistic complexity of orchestrating each cog in the machinery of the process. 
• Often contract manufacturing organizations (CMOs) are involved during periods of high demand. Each institution has its own standard operating procedures (SOPs) and ways of storing and processing data. Therefore, real-time communication that works during comparably small clinical trials, is expected to collapse during massive scale up during commercialization.
• For the transportation of cell lines maintain ultralow constant temperature is typical task.

Solution:

• There are many companies offering dedicated cold chain courier services that can ensure both product quality and safety of these products.
• Linear and 2-D bar-coded cryovials are available from a range of suppliers in bulk or in a variety of formats including SBS 48-vial format (e.g., Fluidx) Source
• More recently RFID tags compatible with LN2 storage temperatures and capable of being retro-fitted to standard cryovials have been introduced (Cryogatt) Source
• Ultra-cold-resistant chips are being developed which, when fitted within individual cryovials, could store not only a detailed thermal history but also detailed batch information, test results, and other relevant quality documentation

Digital supply chain-As a technology for handling information in Value Chain

From the time when cells are removed from the patient to the time when they are returned, data is collected from sensors and transactional systems and fed into a digital twin (essentially a computer model) of the entire CAR T-cell therapy value chain.

• The digital twin provides a broad variety of analytical applications that support and optimize the treatment process, including scheduling, capacity planning, and manufacturing.
• The control tower tool provides visibility into such key parts of the process as scheduling as well as raw-material flow and inventory. It tracks KPIs and lays the foundation for more cutting-edge applications, such as enhanced decision making, advanced analytics, and collaborative planning integration.
• Some company partnered with software companies, such as Vineti and TrakCel, to offer digitized technology solutions that trace and track cell therapies with enhanced transparency.

Companies like:

• For non-vitrified material transportation on pellets of solid CO2 is the accepted practice. From a regulatory perspective, the containers used for transportation should be validated and the environment within the containers temperature monitored.
• Celyad,
• Cryoport, a provider of cold chain logistics for temperature-sensitive life sciences materials, is the logistics shipper for both of these products, which represent the first two commercialized CAR-T cell therapies now available for patients Source
• BuyPBMCs: Company stock a range of cryopreserved cells, all of which are ready for immediate domestic and international delivery through their network of distributors.
• SCTbio: SCTbio provides all services covering autologous or allogenic cell collections. Apheresis collection process focuses on harvest of peripheral blood mononuclear cells, e.g. T cells, monocytes, and other specific blood cell populations Full logistics services – shipping studies, validation of transport conditions, transport of apheresis product to manufacturing site.

Scale Up

• As the demand for CAR T cell cancer therapy increases, several closed and automated production platforms are being deployed, and others are in development.
• Automation could drastically reduce the cost of goods sold and make scaling out more feasible while reducing deviations in manufacturing.             

Bottle Neck

• The optimal production process is not yet defined.
• As CAR-T cell development geared up to larger, multicenter clinical trials, it became evident that a major issue facing developers was the insufficient number of target cells present in some collections; whether through insufficient collection volume, insufficient white blood cell counts or significant contamination with unwanted cell populations.
• Platforms require trained staff and stringent cleanroom environments, making them less desirable for commercial CAR T cell manufacturing intended for a large number of patients.

Solution:

Moving toward functionally closed and fully automated manufacturing platforms may enable production scalability and reduce potential human error.

Equipments involved and their suppliers:

CAR-T cell manufacturing currently requires GMP facilities with ISO5 cell processing clean rooms. The manufacturing facilities include complex and costly infrastructure and systems to support compliance with cGMP regulations.

Bottle Neck

• Standardizing leukapheresis collection equipment can be difficult since collection sites are not always part of the manufacturing process.
• For handling the equipment's no. of skilled labor required which ultimately increases the overall manufacturing costing.
• New equipment's also required extra space and new manufacturing site.
• Equipment like Density gradient centrifugation (DGC) is although effective, but it may require open processing which lead to increasing the chances of contamination; and may fail to isolate lymphocytes from cell fractions with similar densities, such as monocytes.

Solution

• To over come the need of new manufacturing site, a more efficient path forward may be to partner with commercial suppliers of human blood products with their own network of accredited leukapheresis collection centers. CAR-T manufacturers using a commercial supplier have the freedom to set their own quality requirements regarding acceptable leukocyte cell counts and purity. Since commercial suppliers utilize a network of clinics, they can often access a robust donor database that includes a wide selection of disease state products to facilitate patient matching. They can also assure that equipment, protocols and training are fully standardized across all clinical sites.
• The Spectra Optia® Apheresis System (Terumo BCT, Lakewood, CO, USA), is currently favored in the industry as a state-of-the-art cell collection platform, and most, though not all, modern hospitals and clinics utilize this equipment.

Companies like:

• Sartorius: Company with their innovative products and services, they enable pharmaceutical researchers and lab personnel to simplify workflows, minimize human errors and speed up their work. Company provides manufacturing solution for both cell, autologous as well as allogenic T-cell.
• WuXi Advanced Therapies’ Closed Process CAR-T Cell Therapy Platform combines several technologies, in-stock materials, and experienced technical staff. This one stop shop for manufacturing and testing offers cost and time savings for the CAR-T developer. Source
• NanoEntek's ADAM-MC2, ADAM-CellT, and Neon* can be used in the CAR-T manufacturing process. In addition,. ADAMⅡ-CDx** is all-in-one equipment that enables the CAR-T process to provide reasonable device prices and inspection costs compared to competing equipment.

Contract Reseach Organisation (CRO)

• Akadeum: Akadeum’s product line is continually updated with new microbubble cell separation products. Find Cell Isolation products including T Cell Isolation Kits and B Cell Isolation Kits in both human and mouse species.
• Nexcelom: Nexcelom has optimized a dual-fluorescence staining method for simple, accurate determination of concentration and viability. Samples stained with AO/PI can be analyzed with the Cellometer Auto 2000, or Cellometer K2 instruments using pre-optimized settings for PBMC analysis.
• Oxford BioMedica plc signed an agreement with Novartis for the commercial and clinical supply of lentiviral vectors used to generate CTL019 (tisagenlecleucel) and other undisclosed Chimeric Antigen Receptor T cell (CART) products.

Bottle Neck

• Maintaining stringent safety compliance according to the regulatory body is tough task for CRO
• Requirement of skilled laborer led to increase in the cost.

Government fund/support/initiatives/contribution

• Penn Medicine Awarded $14 Million NIH Grant to Apply CAR T Immunotherapies to Match More Patients in Need of Kidney Transplants
• The central government’s National Biopharma Mission-BIRAC has approved 19.15 Cr crore to the TMC-IIT Bombay team for conducting a first-in-human phase-1/2 clinical trial of the CAR-T cells. 
• The Ministry of Business, Innovation and Employment’s Partnership Scheme will contribute up to $4.9M over 5 years – 40% of the estimated cost – to help establish CAR T-cell manufacturing in New Zealand and develop new CAR T-cell therapies for clinical use.

Bottle Neck

Presence of complicated channels which become hurdle for the companies to reach the government.

Some Key Development in Japan

• Japan Medical and Research Development Agency (AMED) has launched The Initiative of Rare and Undiagnosed Disease (IRUD) which aims to support the diagnosis of patients with undiagnosed disease via data sharing and promote research into pathology that may lead to the development of new treatments and therapies. 
• J-TEC uses the CAR-T cell manufacturing technology jointly developed by Nagoya University and Shinshu University, which uses a low-priced vector based on natural enzymes to introduce the CAR gene, instead of the viral vector that has traditionally been used. 
• Fate Therapeutics (NASDAQ:FATE) said it expanded its cancer immunotherapy collaboration with Japan's Ono Pharmaceutical (OTCPK:OPHLY) (OTC:OPHLF) to include the development of chimeric antigen receptor (CAR) NK cell candidates
• Japan’s ministry for health has approved Abecma as a CAR T-cell therapy for adults with relapsed or refractory multiple myeloma who received at least three prior therapies. Source
• Daiichi Sankyo Authorizes the First YESCARTA® (Axicabtagene Ciloleucel) CAR T-cell Therapy Treatment Site in Japan.
• First iPSC-Derived CAR T-Cell Therapy Created by Kyoto University CiRA and Takeda Collaboration Enters Process Development Toward Clinical Testing.

Milestone Patents

 

Patentable Technologies/Possible grey areas

Bispecific/Multi-specific chimeric antigen receptor

A few patenting activity is observed in the manufacturing of bispecific or multi-specific chimeric antigen receptor. They present an improvement over different generations of chimeric antigen receptors by enhancing the T-cell cytotoxicity with low overall toxicity. Researchers are focusing now more on bispecific and tri-specific mAbs. So this area could also be exploited for patent filings.

Allogeneic T-cells expressing chimeric antigen receptor

A very limited patenting activity is observed on using allogenic CAR cells that would significantly alleviate the long engineering process associated with autologous therapy. Since 2017, only 3 autologous therapies have been approved and clinical trials for allogeneic CAR T-cell therapies are back on track. So this area could also be exploited for patent filings.

Liposomal nanoparticles carrying CAR modified cells

A few patenting activity is observed on using biodegradable liposome-based nanoparticles to carry immune-boosting cells along with therapeutic drugs. Solid tumors can be made more vulnerable to CAR expressing immune cells via efficient liposomal drug delivery. So this area could potentially be exploited for patent filings.

Managing immune rejection response in allogeneic CAR-cell therapy

There is no patenting observed on controlling the host-versus-graft reaction in case of allogenic CAR cell therapy. A patent disclosing a preparation of a universal chimeric antigen receptor comes close to overcome the immune rejection. So this area could potentially be exploited for patent filings.

Cytokine-induced cells expressing chimeric antigen receptor

A few patenting activity is observed in the manufacturing of fusion proteins expressing CAR along with cytokines that enhance their proliferation rate both in-vitro and in-vivo. A patent by “Southern Hospital Southern Medical University” discloses the manufacturing of a fusion protein expressing CAR fused with IN-15 cytokine, that maintains the modified CAR-cell number within patient’s body. So this area could also be exploited for patent filings.

Dosage of immune cells expressing chimeric antigen receptor

A few patenting activity is observed in the manufacturing of effective doses of allogeneic CAR-T cells for various cancer therapy. Dosing and re-dosing patients with allogeneic CAR-T cells such that it improves the overall efficacy, toxicity and exposure of CAR-cells itself, is an area still needs to be explored.

Programmable immune cells expressing chimeric antigen receptor

A few patenting activity is observed in the manufacturing of programmable immune cells expressing chimeric antigen receptor. The research is now being more focused on mitigating the higher risk of side effects causing causing cytokine storm and systemic neurotoxicity. So this area could also be exploited for patent filings.

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