Thread by @Prof_Oak_

Interrupting the #Omicron coverage flooding your feed for some under-the-radar ASH abstracts to which I'm looking forward. Collectively, these aren't the "stock moving" headliners that will get broader attention, but are sleepers with important & far-reaching implications (1/24)

In the non-viral delivery world, first HSC-tropic LNP data in NHPs from $BEAM, showing up to ~19% "transduction" at doses up to 1mg/kg. Recall, we've seen directionally similar efficacy data from $NTLA, but doses were not disclosed (2/24)

ash.confex.com/ash/2021/webpr…

Bone marrow is likely the next frontier for LNPs, and is looking increasingly tractable with cell-selective activity afforded by lineage-specific gene expression (eg BCL11a). Potency needs to improve, but BM-directed LNP could truly be an end-game of sorts for SCD / B-thal (3/24)

Next-up: $NVS's second act in auto CAR-T, including the unveiling of a short TAT mfg process (24 hrs in culture - probably 7-10 days in total). Emphasis is on T-cell phenotype (naive enrichment), allowing for lower doses (~5-15M across two studies) wit consistent efficacy (4/24)

75% ORR in each CD19 (75% CR) & BCMA (50% CR) in small n at sub-maximal doses; updates at ASH. To my surprise, $NVS also disclosed BCMAxCD19, CD123, EGFR CARs in 3Q earning presentation, all of which are already in Phase 1 (5/24)
ash.confex.com/ash/2021/webpr…
ash.confex.com/ash/2021/webpr…

Moving to new targets & exciting academic data. The thematic overlay has shifted to ID'ing strategies for SOC CAR-T (eg, CD19, BCMA) r/r pts. Intg implications for trial design / putative efficacy bar for CTx players going forward, particularly as incumbents move earlier (6/24)

GRPC5D had its coming out party as a hot new target at ASH 2020 with initial $JNJ bispecific data. We now have an early look at a CAR-T format from MSKCC (collab w/ $BMY) showing an 83% ORR and 42% VGPR+... (7/24)

(likely to continue deepening) in 12 pts of 3+3, 50% of whom were BCMA CAR-T exposed. Nail changes (25% Gr1) popping up as a class-effect

Target is real, but utility will be defined by efficacy in BCMA-experienced - looking for this at ASH (8/24)

ash.confex.com/ash/2021/webpr…

In CD19 land, CD37 may emerge as a promising target. From Marcela Maus' lab at MGH, FIH study achieved a 75% ORR / 50% CR in 4 NHL / TCL patients, 2 of whom had relapsed following CD19. Of note, BM aplasia observed in 2 of 4, rescued by transplant (9/24)

ash.confex.com/ash/2021/webpr…

Not much crowding in CD37 - this is the only CAR-T program I'm aware of, though $GMAB / $ABBV also have a bispecific (GEN3009) in a FIH trial (10/24)

clinicaltrials.gov/ct2/show/NCT04…

Stanford has been active in a similar setting via an IST evaluating a CD22 CAR specifically in CD19-relapsed pts. Some encouraging data from this trial had previously been published, but abstract contains some incremental disclosure, and we'll get a further update at ASH (11/24)

Data are the most encouraging I've seen in a post-CD19 setting. ORR / CR of 86% / 67% CR in 21 pts. All CRs remain in remission at mean follow-up of 7.3 months. However, 24% experienced macrophage activation syndrome - tox signal to watch (12/24)

ash.confex.com/ash/2021/webpr…

On BCMA side, much noise has been made of potential for GSi combination to boost efficacy. The initial dataset that put some heft behind this hypothesis was the Fred Hutch GSi + BCMA CAR-T combo data from ASH 2019. At #ASH21, we'll get an update from that same trial (13/24)

Efficacy has come down a bit - abstract ORR is 89% in 18 pts, with 77% ≥ VGPR and 44% CR. March 2021 cut-off so should get much more data in presentation

However, there is an interesting divergence in outcomes for BCMA-naive vs. BCMA-exposed... (14/24)

Overall mPFS is 11 months - within this, mPFS NR for BCMA-naive (n=11), but merely 2M for BCMA-exposed (n=7) (15/24)

ash.confex.com/ash/2021/webpr…

Hope to see some data on response kinetics and molecular characteristics of relapse among subgroups, but for now, appears GSi combo may not be sufficient to rescue efficacy of sequential anti-BCMA treatment. Relevant for $SWTX, $AYLA (16/24)

Finally, relevant to $AFMD, CD30 CAR-T from UNC, showing early evidence of DOR in HL, but relative lack of efficacy in small n w/ CTCL

Of note, construct co-expresses a chemokine receptor, CCR4 - efficacy contribution not obvious but translational data should be intg (17/24)

In 8 HL pts, most of whom were treated at DL1, achieved 6 CRs (75%), 2 PRs. 5 remain in CR, with one CR out 2.5 yrs. mPFS NR at 12.7M follow up. CTCL efficacy poor - 1 SD, 1 PD (18/24)

ash.confex.com/ash/2021/webpr…

Expanding into the transplant space, encouraging to see manipulated grafts improve upon SOC allo transplant. In this case, anticipating new data from Orca Bio, which is developing a precision manufactured allo graft (precise ratio of donor lymphocyte / HSC subsets)... (19/24)

Initial data was presented at ASH 2020, but generated some controversy as a single-center study run at Stanford. The ASH 2021 abstract contains new data from a multi-center trial that looks comparable to the Stanford data set, and looks MUCH better than SOC (20/24)

Across both studies, GRFS, RFS, and OS at 12M were 72%, 78%, and 91%, which compare favorably to SOC control (33%, 71% and 78%, respectively). Abstract mentions immune reconstitution differences related to IL-2 - looking for an explanation here (21/24)

ash.confex.com/ash/2021/webpr…

Couple quick hitters that are interesting areas of research. Firstly, multiple abstracts documenting relationship b/w BL gut microbiome and CAR-T response, including this one from MSKCC (22/24)

ash.confex.com/ash/2021/webpr…

Second, iPSC-derived platelets from Kyoto University, in development for aplastic anemia - already dosing in humans!

A few companies in this space, including Platelet Bio, but much earlier in development (23/24)

ash.confex.com/ash/2021/webpr…

Should be a fun ASH - much to dig into, even beyond the headliners. Let me know what stands out to you - welcome any additions to this list (24/24)