These data will be important in future clinical development of BTK degraders and considering new modalities to target. Thank you to @bloodcancerunited.bsky.social, @ascocancer.bsky.social, @mskcancercenter.bsky.social, NCI, and the CLL Society for their support.

Importantly, this mutation confers a profound fitness disadvantage in the absence of selection pressure from BTK-targeting agents & co-treatment with BCL2 inhibitors mitigates the expansion of BTK A428D in the setting of BTK degrader treatment:

We functionally, biochemically, & structurally characterize a very unique mutation in BTK (BTK A428D) which is rarely seen in CLL patients but selected for under the specific pressure of BTK degraders. BTKA428D confers cross-resistance to all FDA-approved BTK inhibitors and degraders in development:

Excited to announce a new paper out today in Cancer Discovery @aacrjournals.bsky.social on clinical mechanisms of resistance to BTK degraders. Led by @quinnsievers.bsky.social and part of our ongoing collaboration with Meghan Thompson, Nurix Therapeutics & Justin Taylor (U. Miami):

We identify a mechanism for clonal expansion of MDS through local immunosuppressive effects of MDS mutant cells through secretion of TGFb, as well as cell intrinsic effects as mutant cells themselves have dampened recognition of TGFb (gorgeous art by @DrawImpacts):

Through the use of custom probes we track clonal populations of T cells over time and space in the marrow and identify SF3B1 mutant cells in situ. These studies enabled differential gene expression and niche analyses of clonal cells in tissue:

Now across a cohort of 41 patients with MDS and 15 bone marrow biopsies from age-matched normal individuals we capture 5.7M cells and identified new cellular niches characteristic of human MDS & lymphoid aggregates unique to MDS marrow:

Led by Susan DeWolf, Rob Stanley, Beatrice Zhang, Kimon Argyropoulos, Stephen Martis & collab with Ben Greenbaum. Prior studies have identified important roles for the microenvironment in MDS but transcriptomic studies of the native marrow in patients with MDS have been limited to date:

Excited to present the first pre-print from our group, an investigation the human bone marrow microenvironments in patients with myelodysplastic syndromes (MDS) and normal age-matched subjects using Xenium genotype-informed spatial transcriptomics: www.biorxiv.org/content/10.6...

Armoring CAR-T cells with IL-18 led to antigen gain on AML, durable remission, and protection from AML rechallenge. These data thereby identify a CAR-T cell platform which addresses prior limitations in tumor-selectivity and safety for patients with acute leukemias.

Anti-U5 snRNP200 CAR-T cells were effective in human and syngeneic models of AML as well as B-cell acute lymphoblastic leukemia (B-ALL), a setting where surface U5 snRNP200 is also present.

We used autoantibodies responsible for graft-versus-leukemia to create CAR-T cells. We generated CAR-T cells against one such antigen - U5 snRNP200, an RNA helicase localized to the surface of AML but not normal hematopoietic precursors. Described here:

Collaboration with @DaniyanMd and led by Takeshi Fujino & Jen Lewis. Developing CAR T cells for AML has been challenging due to a lack of known AML-associated antigens that spare normal hematopoietic precursor cells.

Excited to announce a new paper out now in Cancer Discovery @aacrjournals.bsky.social on a unique CAR T cell platform that eliminates AML and B-ALL without harming vital endogenous immune cells or other normal human tissues: pubmed.ncbi.nlm.nih.gov/42059863/

We are now excited to move this forward in prospective trials of patients with CDK4/6 independent cancers & high leukemia risk. Thank you to the Neil Hirsch Foundation, @break-cancer.bsky.social , @ash.hematology.org , LLS, Edward P. Evans MDS Foundation, NCI, NHLBI, and V Foundation for support.

Similarly, in a mouse model of TP53 mutant clonal hematopoiesis, we found that contemporaneous administration of a CDK4/6 inhibitor with platinum chemotherapy mitigated p53 mutant cell expansion with chemotherapy:

The development of therapy-related myeloid neoplasms is one of the most dangerous complications of cancer-directed therapy. Here we identify across 4 randomized trials that short-term CDK4/6 inhibition mitigates clonal expansion of TP53 mutant hematopoietic cells during cytotoxic chemotherapy.

Importantly both mice and patients with class 3 MEK mutations respond to ERK inhibition with Ulixertinib. Through FDA compassionate use and help of @BioMedValley, we treated 5 MEK1 E102_I103del mutant patients with Ulixertinib and saw partial or complete responses:

We then created a conditional knockin mouse model of the most common MEK mutation – MEK1 E102_I103del and fund that these mice develop a high penetrance histiocytosis affecting the skin and hematopoietic organs:

Now across an international cohort of 498 patients we identify that RAF-independent MEK mutations (which are common amongst histiocytosis patients) are associated with progression to MEK inhibition:

It turns out that ARHGAP45 also encodes the first identified minor histocompatibility antigen (HA-1) and we present a new cell therapeutic approach to target HA-1 and upregulate ARHGAP45 derived epitopes. Thanks to @LLSusa, @theNCI, @MSKCancerCenter for their support.

Excited to announce a new paper in ‪@aacrjournals.bsky.social‬ with Junwei Shi and Tony Daniyan. We perform screens of GAPs and GEFs in AML and discover a hematopoietic-specific GAP (ARHGAP45) required in a variety of hematologic malignancies: aacrjournals.org/cancerdiscov...

Excited to announce our annual New York City Edward P. Evans MDS Centers Symposium across @mskcancercenter.bsky.socia & @columbiacancer.bsky.social. This year to be held at @mskcancercenter.bsky.socia. See this flyer below and register here: forms.fillout.com/t/1wX3dGmym4us

We are excited to develop this as a novel cell therapy for myeloid leukemia patients with mutations in splicing factors. Thank you to @break-cancer.bsky.social, ASH, LLS, Edward P. Evans MDS Foundation, NCI, NHLBI, and @parkerici.bsky.social for support.

Importantly we were able to identify neoantigen-specific CD8 T cells in patients with active MDS and AML. However, these neoantigen specific T cells had clear evidence of dysfunction, likely explaining the initiation/maintenance of these malignancies.

We now find that MDS and AML patients with mutations in the splicing machinery create endogenous mis-splicing derived immunogenic peptides which are shared across patients (“public”) and were used to isolate tumor-selective TCRs.

In 2021 in collaboration with the Bradley lab we identified that pharmacologic modulation of splicing creates bona fide RNA mis-splicing derived neoantigens which can augment immune checkpoint blockade efficacy in syngeneic solid tumor models:

Mutations in genes encoding RNA splicing factors occur in 50-80% of patients with myelodysplastic neoplasms and create stereotyped changes in RNA splicing consistent across patients.

This is part of a long-standing collaboration with Rob Bradley’s lab ‪@fredhutch.bsky.social‬ and with amazing TCR discovery expertise from Chris Klebanoff’s lab @klebanofflab.bsky.social @mskcancercenter.bsky.social‬‬. Also incredible help from Jeff Molldrem @mdanderson.bsky.social‬‬‬‬‬