'Why we have evolved so many cytokines for so few transcriptional regulators is not entirely known, but it suggests that the diversity in cell types that can send a signal and cell types that can receive them is more important than diversity in transcriptional programs.'

We had visitors @moffittnews.bsky.social today!

Paper in Cell finds that YTHDF2 degrades CD19 and MHC II mRNA while promoting ATP synthesis in B cell malignancies. Could be a mediator of resistance to CD19-targeted therapies.

Two incredibly important abstracts presented by @moffittnews.bsky.social myeloma investigators at #ASH24. 1/3

Lawrence David (Duke) presents “FoodSeq” - everything we eat is alive and has a genome. Some DNA remains undigested. By 16S seq of stool, he can see everything we have eaten, with an alpha diversity “diet diversity” score. Followed diets of transplant patients just by following stool samples! #ASH24

Controversial opinion: in lymphoma, investigators will subcategorize into many clusters and claim a biology for one of the clusters. This is fine, but it is nearly impossible to validate this data or do a clinical trial. If there are 5-10 clusters, we need 5-10x the number of patients.

Trang Vu (Ruella lab/Vittoria bio) shows that KO of CD5 in CAR T cells leads to better function by increasing JAK/STAT signaling. Clinical trial in T cell lymphoma underway. #ASH24

Sleiman (Saar Gill lab UPenn) presents an EGFR-tagged IL-2 that can only bind to their CAR T cells and not non-CAR cells. In a macaque model, saw CRS and B cell aplasia without needing lymphodepleting chemotherapy. “Cis-targeted IL-2”. #ASH24

Josh Brody (Mt Sinai) shows that most lymphoma biopsies have a few CD20 negative cells (some more than others). They have a plasmablastic phenotype and may be targetable. Q - do patients who relapse after bispecifics and are CD20 neg have a more plasmablastic phenotype in their relapsed lymphoma?

David Stahl (Cologne) shows that myeloid cells in the DLBCL TME express CSFR1 and have poor patient outcomes after CAR T. Axatilimab is a GVHD drug that blocks CSFR1 and could improve outcomes. Interestingly, CSF1 ligand may be from Tregs. #ASH24

Kelvin Mo (Stanford) shows that M2 macrophages in the DLBCL TME produce CCL8/CCL13 and have a high IFN signature, associating with poor clinical outcomes after CART. At Moffitt we have a clinical trial of a JAK inhibitor that we think will reduce myeloid IFN in highly inflamed CAR T patients.

Fascinating work by Bacchisio Ziccheddu and Francesco Maura (UMiami) outlining that tumor loss of MHC I (with resultant NK inhibition) associates with relapse after CAR T in patients treated by us at Moffitt. Suggests that CAR T needs to recruit other aspects of immunity to work!

Fascinating study where they label CAR T cells and follow their trafficking in patients! Immediate biodistribution is to the liver and spleen, and they can see whether the Car goes into extramedullary masses. What explains differences between patients?

One person’s immunodeficiency could be another person’s lymphoma target