Cell Design Labs Envisions Robot Control of Tomorrow's CAR-T Therapies

Emerging Company Profile: San Francisco startup aligned with Kite Pharma believes T-cells may be programmed to reversibly activate and deactivate, greatly improving specificity, efficacy and safety of chimeric antigen receptor T-cell therapies.

Using a deal with CAR-T frontrunner Kite Pharma Inc. as a springboard, San Francisco-based start-up Cell Design Labs hopes to bring forward a new generation of specific, reversible T-cell therapies as an alternative to the imprecise, explosive nature of the candidates tested to date.

Kite Pharma, Juno Therapeutics Inc. and Novartis AG have been at the forefront of development for chimeric antigen receptor T-cell (CAR-T) therapies, and Kite is poised to bring the first product to market with plans to submit KTE-C19 for accelerated approval to treat advanced forms of non-Hodgkin lymphoma by the end of the year. (Also see "Kite Pharma Details CAR-T Therapy Launch, Floats Pricing Benchmarks" - Scrip, 19 Oct, 2016.)

One of the major downsides of CAR-T therapy has been the lack of control over the powerful therapies, which have been associated with the life-threatening side effect of cytokine-release syndrome as tumor cells are destroyed.

Developed over the last 20 years, CAR-T cells are not very targeted and do not allow control. Brian Atwood, CEO of Cell Design Labs and cofounder of Versant Ventures, likened current CAR-T therapies to first-generation cruise missiles that go to an address and blow up. Cell Design Labs envisions a treatment that "goes to an address and thinks for a while," Atwood said during an interview at the company's headquarters on the Mission Bay campus of the University of California, San Francisco (UCSF).

Brian Atwood, CEO, Cell Design Labs

The start-up licensed its throttle switch technology from the lab of UCSF Department of Cellular and Molecular Pharmacology Chair Wendell Lim. Current therapies don't take advantage of what cells can do – the ability to take in a lot of information and make decisions about what is and isn’t a tumor and launch a controlled program, Lim commented.

Robot Vision

Lim explained that he is not an immunologist or oncologist, but he was always interested in how cells make decisions, using receptors and signaling networks to act like little computers in the field of synthetic biology. (Also see "Synthetic Biology And The Computerization Of Drug Development" - In Vivo, 11 Oct, 2016.)

Lim and other researchers used synthetic biology approaches to focus on rewiring cells to change their behavior. That led them to think the knowledge and technology could be applied to the pioneering T-cell research by Carl June at the University of Pennsylvania. (Also see "A New Industry-Academic Model: Novartis And Penn Make A Splash In Cancer Immunotherapy" - In Vivo, 26 Nov, 2012.)

Lim published preclinical data in the journal Cell on Sept. 29 for the synthetic Notch receptor, or synNotch, that Cell Design Labs developed to allow programming of T-cells.

But Lim uses a different metaphor that Atwood to explain what the company is developing: self-driving cars. Cell Design Labs is looking at how to make autonomous cells more precise and sophisticated so they recognize various aspects of where they are in the body. That precision may allow the user – the physician – to communicate and direct the cells remotely, the researcher explained.

The company says its technology could enable CAR-T cells to be reversibly ramped up and down at will "You could give pulsatile treatments by ramping up cellular activity in different temporal patterns," Lim said.

Wendell Lim, Scientific Founder, Cell Design Labs

Proliferation of T-cells may cause hyper immune responses, including cytokine-release syndrome, but Lim says the company’s throttle switch will go a long way to address those problems.

Currently, there are no other "switch" technologies that allow for titratable and reversible control of T-cell function and therefore anti-tumor activity. Cell Design Labs says its switch maintains therapeutic levels of T-cells due to the broad dynamic range of the switch and the fast reversible off function.

"The closest competitor's approach is not titratable or reversible and has a very narrow dynamic range. The biology results in an irreversible loss of CAR-T cells from the patient with no ability for control and therefore a loss of patient management," the company said.

The start-up also says that its approach is unique, because it offers precise control of the activity of anti-tumor CAR-T cells using an (undisclosed) FDA-approved small molecule drug in patients with various malignancies.

"This control capability creates a therapeutic which therefore has the potential to be used to mitigate safety issues like those currently observed in CAR clinical studies – for example, cytokine-release syndrome," according to the company.

Cell Design Labs

Location: San Francisco

R&D focus: Company develops disruptive cell-based therapies for cancer and other devastating diseases developed at and licensed from Wendell Lim at the University of California, San Francisco. Offers proprietary technology platform for custom cell engineering that can be used by partners and collaborators and for development of proprietary anti-cancer therapies.

Founding Date: June 2016

Management team: Founded by Wendell Lim (UCSF), Brian Atwood (Versant Ventures) and Fred Cohen (TPG Biotechnology). Board also includes Andrew Allen (Gritstone Oncology), Brook Byers and Beth Seidenberg (Kleiner Perkins Caufield & Byers), and Arie Belldegrun and David Chang (Kite Pharma).

Financing to date: At time of founding, company announced $34.4m in financing from Kleiner Perkins Caufield and Byers, Kite Pharma, Osage University Partners, Mission Bay Ventures and a group of private investors. Deal with Kite, announced at time of founding, included undisclosed upfront and milestone payments plus royalties.

Cell Design Labs launched in June with $34.4m from Kleiner Perkins Caufield & Byers, Mission Bay Ventures and other investors (see box). The company simultaneously announced a deal with Kite Pharma to develop precision-controlled CAR-T therapies built with its molecular on/off switch technology. Terms were not disclosed, but involved upfront and milestone payments plus royalties. The deal gave Kite exclusive rights to develop the technology in acute myeloid leukemia (AML) and an option for an exclusive deal to develop the technology for other B-cell malignancies.

Targeting Acute Myeloid Leukemia

During an Oct. 18 R&D day for investors, Kite introduced KITE-796, which will be developed with the Cell Design Labs technology, as a next generation CAR-T therapy targeting CLL-1 for AML.

To reduce off-target toxicity, it's important that the target not be present in non-hematopoietic stem cells or non-hematopoietic cells, which is the case with CLL-1 in AML, Kite Chief Medical Officer David Chang explained during the company’s R&D presentation.

Also, with AML, "there has to be a way to regenerate white blood cells, which are essential for functioning of a normal human being," he said.

"So, our focus really was trying to develop CLL-1 CAR without having to use the rescue allogeneic stem cell transplantation, which is the current approach with other chimeric antigen receptor programs in this space," Chang said.

Kite's candidate is being developed as a standalone therapy with a control switch that can reversibly shut down and reactivate CAR-T cells. The company plans to take KITE-796 into the clinic in 2018.

The CAR-T field grew up in an ad hoc manner and opened the door for synthetic biology approaches. The startup's initial plan is to solve the unmet needs of CAR-T cells, but Cell Design Labs says that if it can learn to systematically engineer cells, there are many therapeutic areas in which it could have an impact and hopefully become a transformative company, Lim said. Potential applications include autoimmune diseases, degenerative disease and orphan indications, in addition to cancer.

"There is a very large strategic landscape we can play in from the business development point of view," Atwood said.

Cell Design Labs has been asked whether the Kite deal takes away a large part of its operating space, but Atwood said it doesn't, because the agreement is limited to AML and B-cell malignancies.

"From our point of view working with [Kite] in one tightly focused disease area was perfectly ideal," as all other targets are open for deal-making, Atwood said.

Solid Tumors On Agenda

As opposed to looking for one magic bullet – tumor versus non-tumor – ideally T-cells would detect a molecular signature encompassing a number of targets. Detecting two or three antigens brings a huge increase in discrimination specificity and could allow the company to move beyond B-cell malignancies into solid tumors. In a way, the technology is like a "Chinese menu" – there are lots of targets and combinations of targets, Atwood said.

Cell Design Labs sees Cellectis and Bellicum as competitors, but also as potential collaborators.

"The platform lends itself to a really interesting business development strategy," Atwood added.

Lim also noted that the platform isn’t limited to autologous CAR-T therapies like Kite’s. It could be applied to allogeneic, or off-the shelf, products. The technology is "kind of agnostic," he said.

Cell Design Labs sees the Kite deal and Lim's recent publication about the synNotch technology as important milestones as it builds out the company with about 20 employees. Lim's paper "completely lays out what the company is about from a technology point of view," Atwood said.

The next milestones, include getting Cell Design’s own proprietary candidate into the clinic. Preclinical work is already under way.

"If you look at the history of CAR-T cells the first success became evident with a few patients. If we are really fortunate we would begin to see efficacy in 2018, but I'm not going to predict that," Atwood said.

The execs declined to comment on what disease their first candidate will target. Areas of high unmet need could be targeted, but so could diseases where PD-1 inhibitors are available and working, but the response rate has much room for improvement.

And while Cell Design Labs is building collaborations to finance its own programs and maintain its position as a standalone operation, Atwood said the company expects to go public eventually, depending on how the stock market is doing.

Experience at other CAR-T companies shows that manufacturing is feasible for a small firm in the earliest stages of clinical development, but as the company moves to later stages and larger trials, it will need to consider bringing on a partner for its in-house programs. For the time being, Cell Design Labs is looking to secure another collaboration similar to the Kite deal.

In addition to Juno, Kite and Novartis, Cell Design Labs sees Cellectis SA and Bellicum Pharmaceuticals Inc. as competitors – tough competitors in some circumstances, "but also potential collaborators," Atwood said.