Manufacturing

Our manufacturing process produces product candidates based on Universal Chimeric Antigen Receptor T-cells or, UCAR T-cells targeting cancer cells. Our approach is allogeneic, meaning that our UCART product candidates are made from thoroughly tested donor T-cells, unlike autologous CAR T-cell products, which are derived from individual patient samples.

The off-the-shelf strategy leads to lower production costs since our universal CAR T-cells derived from healthy donors can be manufactured to generate hundreds of doses that could benefit patients all over the world.

GMP Manufacturing & Solutions

GMP, or Good Manufacturing Practices, are a set of regulations applicable to the manufacturing of health product candidates, especially medicines intended for human use, such as UCART product candidates. A company is required to comply with GMP regulations in order to be granted a license from governmental regulatory agencies to manufacture pharmaceutical product candidates. The Manufacturing department takes manufacturing processes established at the R&D level, converts them to GMP, and ensures their deployment with GMP compliant raw materials and environments. The department is responsible for the manufacturing of clinical trial material (“CTM”), making it available for clinical studies, and also for the manufacturing of final GMP commercial cellular gene therapy products. The team interacts internally with different departments ranging from development and planning, to regulatory and legal, as well as externally with raw materials contractors or GMP manufacturing contract organizations, Lonza and MolMed.

Cellectis Proprietary Manufacturing Process

With more than 5 years of experience in allogeneic CAR-T manufacturing, we have utilized our validated TALEN® gene-editing technology and process development capabilities for the scalable manufacture of 5 Universal CAR-T product candidates (UCART). As a result, Cellectis has a quality control system in place for the 3 wholly controlled product candidates cleared by the U.S. Food and Drug Administration (FDA).

In addition, our process – powered by TALEN® and our proprietary PulseAgile electroporation technologies – inactivates genes in a highly efficient manner that avoids harming T-cells during processing. As a result, we can manufacture quality UCART products with high yields --and potentially in bulk. We expect that T-cells from one healthy donor, and one manufacturing run of UCART, could be used to create hundreds of doses of product and more when scaling up the process. These efficiencies may not only reduce costs to patients but also lead to competitive gross profit margins.

Cellectis is currently building 2 state-of-the-art manufacturing plants so that we will be fully equipped to manufacture our products in-house.

SMART
Starting MAterial Realization for CAR-T Products

  • ~14,000 sqft in-house manufacturing in Paris, France
  • Production of clinical and commercial starting materials
  • Operational "go-live" targeted in 2020

IMPACT
Innovative Manufacturing Plant for Allogeneic Cellular Therapies

  • ~82,000 sqft facility located in Raleigh, NC
  • Production of clinical and commercial UCART products
  • Operational "go-live" targeted in 2021

Manufacturing process

  1. Step 1: Frozen Leukopaks

    Blood is drawn from pre-selected donors. Red blood cells and platelets are filtered out leaving only the white blood cells behind. This is then put into freezer bags which we call leukopaks.

  2. Step 2: Thawed PBMCS

    The manufacturing process begins by thawing the frozen cells and selectively activating the T-cells.

  3. Step 3: TALEN-Mediated Gene Editing

    Chimeric antigen receptors (CAR) are engineered receptors that allow cells to bind to specific proteins. These are added to the T-cells with the help of lentiviral vector transduction, a virus-derived tool used to penetrate cells.

  4. Step 4: Lentivector Transduction

    Our proprietary Pulse Agile electroporation technology uses electrical pulses to create temporary pores in the CAR T-cells that make them permeable. This allows us to introduce the TALEN® (transcription activator-like effector nucleases) which are enzymes that have been engineered to cut specific sequences of DNA. In this case, a precise edit is made that eliminates the T-cell receptor (TCR). This is an important step since the TCR would normally trigger a rejection response from the patient’s immune system since the cells come from donors.

  5. Step 5: Cell Expansion

    The amount of gene-edited CAR T-cells are amplified using automated processes and special tools called bioreactors. This part of the process is also referred to as expansion.

  6. Step 6: Purification

    Gene-edited CAR T-cells are sorted and selected through our purification processes.

  7. Step 7: Fill and Finish

    Vials are filled with our allogeneic UCART product candidates. These are added to a solution, cryopreservation medium, that allows the cells to be preserved at very low temperatures.

  8. Step 8: Frozen UCART Product

    The vials are frozen and packaged so that they can be safely shipped to hospitals for patient administration.

Quality control checks are done all throughout the manufacturing process (in-process controls). These continuously assess the UCART product candidates on four key attributes: identity, safety, strength and stability.