Make or break time for Caribou

Caribou Biosciences, which disappointed with its allogeneic Car-T project CB-010 at ASCO 2024, will soon have a chance to redeem itself. In the first half the company will report more data from the phase 1 Antler lymphoma trial – this time using a human leukocyte antigen (HLA) matching strategy.

The group turned to this plan after seeing lacklustre all-comer results in Antler, which dashed Caribou’s hopes of rivalling autologous Car-T. Success will see Caribou begin a pivotal study in second-line LBCL later this year – but another letdown could see CB-010 heading for the scrapheap.

Even if Caribou does prevail there will still be questions about the HLA matching approach, not least around practicality: the company has said that 13 different batches of CB-010 would need to be available off the shelf, to be able to provide a partially matched HLA product to around 90% of lymphoma patients.

The limited post hoc data available so far on an HLA-matched product suggest efficacy no better than standard autologous Car-T therapy, and investors don’t have much faith in the next update: Caribou’s stock has sunk even further since ASCO, and is now at an all-time low of $0.98.

Uncompetitive?

In common with approved autologous Car-Ts like Gilead’s Yescarta and Bristol Myers Squibb’s Breyanzi, CB-010 targets CD19. Allogeneic Car-Ts are being developed to improve convenience and lower costs, but have been dogged by a lack of durability.

CB-010 employs PD-1 knockout, designed to prevent premature T-cell exhaustion and improve persistence. However, data released from Antler so far have suggested that the product isn’t competitive versus autologous Car-T.

Cross-trial comparison with CD19 Car-T in 2nd-line LBCL

Note: *2L LBCLC subgroup. Source: ASCO 2024 & product labels.

Caribou has therefore turned to the HLA matching strategy. HLA is a marker used by the body’s immune system to ascertain what is self and what is foreign. Caribou believes that the better the match the longer it will take before CB-010 is cleared by a patient’s immune system.

At ASCO the company presented a retrospective analysis showing that, among 13 patients with four or more matching HLA alleles, PFS was 14.4 months, versus 2.8 months in patients with three or fewer matches.

Now Caribou aims to show prospectively that HLA matching matters, and has enrolled around 20 additional second-line LBCL patients with four or more HLA matches, who received the go-forward dose of 80 million Car-T cells.

It’s these patients that will feature in the first-half update, with around three to six months of follow-up, according to Evercore ISI analysts. The company will hope to get closer to the benchmark set by autologous Car-T.

As for safety, so far there have been no cases of grade 3 or higher cytokine release syndrome, but Evercore flagged immune effector cell-associated neurotoxicity syndrome (ICANS) and infections as adverse events of interest, particularly as CB-010 uses an enhanced lymphodepletion regimen.