Jefferies 2024 – Cargo tries again with an old idea

Some biotech ideas never die. One such is firicabtagene autoleucel, Cargo Therapeutics' lead Car-T project, which is now on at least its fifth iteration of ownership, and which in this guise will next year face a key catalyst: readout of the Firce-1 trial that could lead to its US filing.

An important question is why none of the previous owners of the anti-CD22 construct now known as firi-cel, including legacy companies of Bristol Myers Squibb, had any luck with it. The space Cargo is targeting is important – lymphoma patients who relapse after standard anti-CD19 Car-T therapy – and investors already have expectations for next year's data.

That's because Stanford University, from which Cargo licensed firi-cel, ran its own phase 1 study in a CD19 Car-relapsed DLBCL setting, and the data are published for all to see. The headline number is a 52% complete response rate among 29 patients, with 75% of CR patients still in response at 12 months.

Six-month OS

That bodes well in a setting where median life expectancy is six months, Cargo's chief executive, Gina Chapman, told the Jefferies London healthcare conference on Wednesday.

Cargo's Firce-1 study aims to treat 101 patients with firi-cel, and has so far dosed 57. Its first data, from an interim analysis, are expected in the first half of 2025, and if these are positive they will lead to talks with the FDA about approvability.

The question is what a positive result would look like. Chapman said the "bar set by Stanford is a helpful result", but Jefferies analysts expect a CR rate of around 40%, meaning below Stanford's but above the 38% that Roche's anti-CD20 T-cell engager Columvi has shown in a subset of Car-T-relapsed patients in its registrational DLBCL dataset.

Firce-1 is expected to include some patients who have relapsed on second-line Car-T – Yescarta and Breyanzi recently became available here – and these would likely be fitter than those in Stanford's trial, who had all relapsed from Car-T therapy given in the salvage setting of third line or later.

Either way, patients who relapse after a CD19 Car represent an important opportunity, and until the advent of T-cell engagers like Columvi they had few options. CD22 has long been considered a promising target here, being expressed on B cells even after patients relapse through loss of the CD19 antigen, but so far this has come to nothing.

10-year history

Indeed, the construct used by firi-cel is itself the result of such early work, with a convoluted history dating back over 10 years to trials initially undertaken at the NCI by a team including Dr Crystal Mackall, and signed over under a CRADA to the private biotech Opus Bio, run by Douglas Lind and financed by Biomark Capital.

In December 2014 Opus signed a licensing deal with Juno Therapeutics, which took over the NCI CRADA and continued clinical development of the project, coding it JCAR018.

However, in 2016 Mackall ended a 27-year career with the NCI and moved to Stanford University, where she continued clinical work on the anti-CD22 Car under a separate IND. As for Juno, in 2018 that company was sold to Celgene, which in turn was acquired by Bristol Myers Squibb a year later.

At some point either Juno or Celgene stopped work on JCAR018, and in 2020 the NCI put out a notice seeking a new licensee for the autologous anti-CD22 Car. An allogeneic iteration of the anti-CD22 Car, now coded SC262, was separately picked up from the NCI by Sana, a company co-founded by Juno's former chief executive Hans Bishop.

Meanwhile, Mackall's work on the anti-CD22 Car was spun into Syncopation Life Sciences, later renamed Cargo Therapeutics, where it gained the INN firi-cel, and Cargo debuted on Nasdaq in a November 2023 IPO that raised $280m.

It's curious why JCAR018 was discontinued, and notable that firi-cel seems to be relatively unencumbered: Cargo's IPO filing noted royalty obligations to the NCI and Stanford, but none to Bristol, or the former owners of Juno or Celgene.

Selected cell therapies for DLBCL patients relapsed after a CD19 Car

Notes: *KITE-753 uses fast manufacturing; **allogeneic; ^uses gamma-delta T cells; ^^uses NK cells. Source: OncologyPipeline.