5:36 PM
Oct 18, 2018
 |  BC Innovations  |  Tools & Techniques

Allogeneic CARs on the horizon

How orthogonal technologies could make allogeneic cells the future of CAR Ts

With the first generation of autologous, personalized CAR T cell therapies on the market, the field is turning to allogeneic technologies to provide better scale and lower costs. But drug makers are learning that as they solve the first hurdle of graft-versus-host reactions, they need a way to avoid exacerbating the opposite problem, host-versus-graft.

There’s little dispute that while autologous CAR T cells have been transformational for a handful of blood cancers, they represent a sliver of the spectrum of possibilities that the technology might offer.

The hope is that allogeneic cells can broaden the reach of CAR T cells to more patients and more types of cancer. For example, allogeneic technology could provide off-the-shelf products -- rather than personalized ones -- comprising higher quality cells that don’t require the patient to be healthy enough to collect T cells. Allogeneic therapies are simpler to manufacture, more rapidly available to patients, and in the long term, cheaper to make.

The latest sign of allogeneic fervor was last week’s $324 million IPO from Allogene Therapeutics Inc., marking the largest biotech IPO on NASDAQ this year. The company, which had raised $420 million in private funding since it debuted in April, was formed by former Kite Pharma Inc. executives after Kite was acquired by Gilead Sciences Inc.

“When the guy who sold his autologous company to Gilead for $12 billion turns around and starts his own company six months later, you have to think he is on to something,” said Brad Loncar, CEO of the Loncar Fund.

“If you’re an autologous company, you have to at least be looking at allogeneic cells. If the technology works as well as autologous cells, it would make them obsolete.”

Brad Loncar, The Loncar Fund

All eight CAR T cell companies interviewed by BioCentury have allogeneic programs in clinical or preclinical development, including at least two that began as dedicated autologous cell therapy companies.

The driving force behind the progress comes from advances in orthogonal technologies, such as different forms of gene editing, genetic knockdown and cell engineering.

To transition from autologous to allogeneic cells, one of the principal needs is to control immune responses that prevent the donor cells from attacking the host and causing graft-versus-host disease (GvHD). The key molecule is the TCR -- the receptor on T cells that normally detects foreign cells.

In GvHD, TCRs on the transplanted donor CAR T cells recognize the patient as “foreign” and trigger the donor cells to attack the patient’s healthy tissues.

The dominant strategy for generating allogeneic cells is therefore to remove the TCR from the donor cells.

However, companies are discovering that as they eliminate expression of the TCR, they increase the chance that the host immune system will reject the donor cells before they kill the cancer.

Still, the field is likely to see progress given the amount of effort and profile of the players involved.

For example, in addition to Allogene’s executives from Kite, Merck & Co. Inc.’s CMO Roy Baynes, Memorial Sloan Kettering Cancer Center’s Michel Sadelain and the Children’s Hospital of Philadelphia’s Stephan Grupp recently joined the boards of allogeneic cell therapy companies Atara Biotherapeutics Inc., Fate Therapeutics Inc. and Cellectis S.A., respectively.

Loncar told BioCentury every CAR T player needs to be in the allogeneic space with some kind of technology.

“If you’re an autologous company, you have to at least be looking at allogeneic cells. If the technology works as well as autologous cells, it would make them obsolete,” said Loncar.

“There’s no dispute that allogeneic technologies are a much better way of doing this; it’s just a question of whether the technology can get there in terms of safety and efficacy,” he added.

Allogeneic edge

Allogeneic CAR Ts can improve upon the first generation cells in four primary ways: manufacturing speed, cost, cell quality and solid tumor penetration.

Chris Nowers, CEO of Cell Medica Ltd., told BioCentury the main limitation of autologous products is the challenging and expensive manufacturing process, which can delay treatments for up to six weeks and contributes to the high prices...

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