Epidarex, Sofinnova double down on a parallel take on 3rd-gen CAR-T — aiming straight at ovarian cancer

2021-10-21

When John Maher treated the first head and neck cancer patient at Guy’s Hospital in London with his pan-ErbB CAR-T back in 2015, he was among a small club of researchers convinced they had an answer to the challenges that had kept those engineered T cells — wildly successful in hematological cancers — either too dangerous or out of reach for patients with solid tumors. The field has blossomed since then, with a proliferation of technologies that promise to address any number of challenges identified as unique to solid tumors. And Maher himself has rethought his approach and come up with a new CAR-T platform to generate the next slate of candidates. Now that the first candidate is nearing the end of Phase I, his biotech spinout, Leucid Bio, will have almost $16 million (£11.5 million) to take those new programs into the clinic. T4, as the CAR-T Maher has administered to 18 patients with squamous cell cancer of the head and neck is known, belongs to the second generation, explained Leucid Bio CEO Artin Moussavi. Those CARs consist of a binding receptor on the surface membrane, a series of signaling domains, plus one of two costimulatory domains: CD28 or 4-1BB. It was a structure Maher knew well after working as part of Michel Sadelain’s Memorial Sloan Kettering team behind a crucial part of what became Bristol Myers Squibb’s CD19 CAR-T, Breyanzi. As scientists moved into the third generation of CARs, they combined the two costimulatory domains in hopes of getting more powerful T cell activation. But in his own research, Maher concluded that the way most of his peers did it — putting the CD28 and 4-1BB on top of each other — didn’t quite enhance the potency as much as expected. So he tried a different configuration, arranging the two costimulatory domains in a parallel fashion, close to the cell surface, and getting rid of the zeta chain signaling. “What he discovered there was he was getting far better potency, far better signaling but wasn’t inducing a senescence or an overstimulation and was able to stimulate those cells to kill tumor cell lines — many more cycles than the second generation or third generation CAR,” Moussavi said. Over the past few years, Maher — who juggles several jobs teaching and seeing patients at King’s College London and Eastbourne Hospital while also serving as Leucid’s CSO — has moved that technology from in vitro studies to in vivo preclinical models. They call it pCAR, short for parallel CAR. “It’s a platform,” Moussavi said. “It gives us the ability to add in auxiliary technologies that will enhance its efficacy against particular challenges in solid tumor space. So with ovarian cancer, we’re introducing homing enhancements. We’re also introducing our experience in terms of route of administration.” Although it technically falls behind T4 (or LEU-001), LEU-011 — the autologous CAR-T being positioned for platinum-resistant ovarian cancer — is now Leucid’s lead program. The biotech has developed a pCAR version of T4 as well as additional technologies to support allogeneic CAR-T in the future. “I don’t believe there is one technology on its own that will overcome all the barriers for a particular indication,” he said. “So I see this as an evolution in the CAR-T field.” The Series A financing should fund a Phase I for ‘011 AND get the allogeneic programs ready for further testing, the CEO said. Epidarex and Sofinnova, which had provided the seed funding to sustain the company up to this point, were back for this round, joined by new investors Vulpes Investment Management, 2Invest and Future Fund of the British Business Bank. Thanks to a close relationship with Guy’s Hospital (where the team of fewer than 20 is based), Leucid gets its clinical drug supply from a GMP manufacturing suite there. And don’t look for the splash money on production any time soon. “We’re not trying to reinvent the wheel in terms of elaborate manufacturing,” Moussavi said. “What we’re trying to do is to make sure that we have a very cost-effective manufacturing system that’s scalable.”

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