Biotech veteran Gilman is back, heading up next-gen CAR-T startup Obsidian

Obsidian pieces
Obsidian wants to make immunotherapy available to all patients with cancer.

Michael Gilman went into retirement when Bristol-Myers Squibb bought out his Padlock Therapeutics venture last year, but has made a comeback at the helm of a new company promising to transform cell and gene therapies.

The Cambridge, MA-based startup—Obsidian Therapeutics—just came out of stealth with a $49.5 million series A that will fund the development of a technology that Gilman said could transform new therapies like CAR-T by making them more controlled and safer for patients.

Michael Gilman
Michael Gilman

Gilman joined the board of Obsidian after the $600 million buyout of Padlock by BMS, but “utterly failing at retirement” led him to take the CEO role at the company in October 2016, a move that has only just been revealed.

According to Gilman, CAR-T cells exist “on a therapeutic knife edge, teetering between profound efficacy and brutal toxicity [and] they need to be tamed.”

Obsidian is setting out to bring the technology into line thanks to a platform developed by its scientific founder Professor Thomas Wandless, a leading researcher in chemical and systems biology. In a nutshell, it is based on two elements: a biological “cassette” that is installed in the gene vector and a small-molecule drug that controls the activity of the cassette and, as a consequence, the activity of the modified gene sequence. The controlling molecules—or destabilizing domains (DDs)—are all off-the-shelf, orally active generic molecules.

It’s an approach similar to one piloted at ARIAD, one of Gilman’s earlier employers, but was side-lined for various reasons including the death of gene therapy recipient Jesse Gelsinger in 1999, which set back the field for a decade, and was eventually licensed out.

“With all the promising results with CAR-T and gene therapies, the problem now is that once cell and gene are administered to the patient, the physician surrenders all control,” Gilman told FierceBiotech. “The cells are on their own. We can only respond to any havoc they create and manage any unintended and sometimes severe consequences with the best medical response possible.”

Toxicity has already spelled the end for some CAR-T candidates, including Juno Therapeutics’ JCAR015 which was shelved earlier this year.

So how could Obsidian’s approach help? One way would be to control expression of the CAR on the cell surface and so modulate the degree of antigen-stimulated proliferation. That means the cells could start with low receptor expression, which could then be increased until a clinical signal is detected, and the dose held for the duration of treatment.

Moreover, like other cancer treatments, we could cycle therapy on and off, giving both the cells and the patients a periodic rest, which is likely to lead to more tolerable and durable therapy,” said the CEO.

CAR-T cells could also be equipped with a mechanism to allow their activity to be dialed up and down at will. That would allow the physician to keep the therapeutic cells alive and active, even after antigen-driven signaling has subsided—something Gilman said is important because persistence of the therapeutic cells is critical to long-lasting remissions or cures.

Other uses of the platform could include eliminating the “brutal” pre-conditioning regimens needed by first-generation CAR-T therapies, which could make them an option for sicker patients.

“These are some of the actual products in development at Obsidian. Our whiteboards are filled with many more ideas—and that’s just for novel next-generation CAR-T products,” said Gilman.

For now, Obsidian plans to apply its approach to in-house programs as it plans to develop its own CAR therapies, and while it does not rule out collaborating with other CAR-T players said its funding is sufficient to implement its current business plan.

Current projects are focusing on the dynamic control of CAR receptor expression, a membrane-bound IL-15 construct to enhance the persistence of therapeutic cells, and tightly regulated secretion of IL-12, a cytokine admired for its ability to stimulate anti-tumor immunity but also feared for its lethal toxicity. All of these are in preclinical development and the company isn’t predicting yet when clinical trials could start.

Our time in stealth mode allowed us to advance the technology platform, build some exciting prototypes, assemble an outstanding team, and move into some great office and lab space in Cambridge. Now, we’ve reach a point where our technology has advanced significantly—and the CAR-T field has become so exciting—that we felt the time was right to engage more broadly with thought leaders in the space.”

Obsidian has also just announced a research collaboration with Crystal Mackall, M.D., at Stanford University, a team that worked with Wandless to show that DDs make it possible to modulate CAR expression in T cells and that doing so alleviates the functional exhaustion caused by chronic CAR signaling.

Mackall is tasked with installing Obsidian’s DDs into CAR vectors with the goal of creating novel CAR-T products that can be taken to patients, and will make a presentation on CAR-T at the American Society of Hematology meeting on Dec. 9 that will include a rundown of Obsidian’s platform.

It’s very cool to be able to take another run at this. It’s rare to have the opportunity to take a second crack at something important,” said Gilman.

The series A financing was led by GV, with participation from Atlas Ventures, Takeda Ventures, Vertex Ventures HC, Amgen Ventures, Alexandria Venture Investments and ShangPharma Investment Group.