"Off the Shelf" – The Next Step for Cell Therapy

With the robust efficacy of autologous CAR-T-cell therapies to date, the focus has shifted to commercial issues related to vein-to-vein time, manufacturing variability, shipping/chain-of-custody issues, and scalability over the long term. Allogeneic cell therapies (derived from a healthy donor) have the potential to address these issues by providing an enhanced speed to patient, availability, decreased cell variability, and streamlined manufacturing efficiencies. With a recent influx of investment in the space, biotechnology analyst Dr. Raj Prasad believes that the next phase of growth in the widespread use of cell therapies will be catalyzed by the successful development of these "off-the-shelf" modalities.

Companies developing allogeneic cell therapies are using various gene-editing technologies to prevent the expression of endogenous T-cell receptors (TCRs) to minimize the potential of graft-versus-host disease (GvHD) and graft rejection, including: 1) clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-Associated 9 (Cas9); 2) zinc finger nucleases ; 3) transcription activator-like effector nucleases (TALEN); 4) homing endonucleases; 5) megaTAL (meganuclease and TAL); 6) Cas-CLOVER; and 7) base editing.

Alternative allogeneic platforms being developed include: 1) short hairpin RNA and TCR-inhibitor molecules; 2) natural killer (NK) cells such as the master clonal induced pluripotent stem cell line approach, a placental-derived NK approach, and a CAR-NK platform; 3) allogeneic γδ T cells; and 4) Epstein-Barr virus T-cell bank platform.

TCRs consist of α and β chains that associate with the γ, δ, ε, and ζ chains of CD3 to form a TCR-CD3 complex. The TCR-CD3 complex normally mediates the physiological recognition of tumor antigens by T cells. When the TCR encounters a processed tumor antigen on the MHC (major histocompatibility complex, a set of cell surface proteins essential for the acquired immune system to identify foreign molecules), also called HLA (human leukocyte antigen) in humans, an immunological response is initiated. HLA class I molecules bind peptides from intracellular proteins—including tumor proteins—and present them to CD8+ T cells that respond by releasing cytokines and cytotoxic compounds that can kill cancerous cells and promote tumor control.

CARs are synthetic receptors that have been used to reprogram T cells to attack cancer; significant effects have been seen to date in types of leukemia and lymphoma. CARs are assembled by combining three components borrowed from immunoglobulin genes, the TCR-CD3 complex, and costimulatory receptors (such as CD28 or 4-1BB). The reengineering used to produce a CAR, combined with a target antigen, can result in sustained expansion and a functional and persistent response against cancer.

Commentary from former U.S. FDA Commissioner Dr. Scott Gottlieb served as a tailwind that underscores the potential for an off-the-shelf cell therapy revolution on the horizon. Specifically, in a statement published in mid-January 2019, Dr. Gottlieb and Dr. Peter Marks (CBER director) mentioned new guidance documents to be published later this year on certain advances in the manufacturing of CAR-T therapies that would not require redundant clinical trials, but instead would use existing technologies as proof of safety and efficacy. This would expedite clinical-bridging studies when minor changes in manufacturing have occurred. The agency also has noted its intention to hold a public meeting this year.

At this point, Dr. Prasad believes that it remains unclear whether there will be a substantial difference in efficiency between gene-editing technologies in the long term. Data readouts in the coming months and years will delineate which approaches will ultimately be successful, and he sees the commercial potential of allogeneic cell therapy in hematological malignancies representing an approximately $25 billion to $45 billion market opportunity in the next 3-5 years.

For a copy of the ""Off the Shelf" – The Next Step for Cell Therapy" report or for more information on the companies from Dr. Raj Prasad's coverage list, please contact your William Blair sales representative.