ONCT在RoR1 CAR-T上的分析，出自Twitter上的@brendan_49
挺有意思的分析，市场现在完全没有对ROR1 CAR-T进行估值。如果ROR1这个靶点如果证实有效的话，ONCT的前途不可限量。
The rationale for ROR1 as CAR-T target:
1) Expression restricted to fetus and tumors. If ADC's are safe CARs should be too.
2) ADCs nabbed monotherapy CRs in MCL.
3) Diverse tumors evolve to express ROR1 as they advance.
4) W/in heterogeneous ROR1 found on tumor stem-cells.
Re #4, if it's true that tumor stem cells often rely on ROR1 to maintain their pathological stemness, and stemness confers flexibility for relapse, then responses to ROR1 inhibition should be durable. See durability below. Ibrutinib monotherapy median DoR is 17.5 months.
data is still maturing. Note that three PRs converted to CR at 7, 9, and 12 months. Only one PR progressed. And multiple PRs are yet young. Today: 7/15 CR. Ultimately? Could be 10/15. ROR1 inhibition induces differentiation more than cytotoxicity. It's gentle/gradual MoA.
Advantage of diff modalities for targeting ROR1:
Naked antibody: attractive safety in combos w/ hints of reducing ibrutinib toxicity (maybe by inducing differentiation of cells that would've otherwise been killed by ibrutinib).
ADC: More potent than naked antibody, probably safe enough to combine w/ same treatments as naked antibody, maybe effective enough in combo that preclude necessity for CAR-T, especially if tumors are too heterogenous for CAR-T monotherapy to work.
CAR-T: ROR1 is not expressed on healthy tissue so why not hit it with the bazooka? And if tumor stem cells - which resist existing SoC - do indeed rely on ROR1, then a potent ROR-1 CAR-T + cytotoxic SoC combo could overcome the problem of solid tumor heterogeneity for real CRs.
$ONCT's ROR1 CAR-T hits the clinic mid-2021. The only other ROR1 CAR-T is Juno's, which initiated in 2016. When data? Dunno. But note the breadth of signal finding: lung, breast, heme, and "malignant solid neoplasm". Q: did Merck/Boehringer know what Juno's seen?