Blake Smith

MD-PhD student @Harvard @MIT | interested in all things immuno, chem bio, viruses, IM, heme/onc, art hist | @Yale '16, NY native | @runthelistpod

[Connor Dobson @ItsVirusTime]

It’s hard not to get addicted to this.

From side conversations with @MEBirnbaum to an incredible result for patients. So proud of the Kelonia team for all the hard work it took to make this real.

[Blake Smith @_blake_smith]

Check out @Steph_Gaglione's amazing preprint introducing a highly scalable (and inexpensive) approach to TCR synthesis that enables library-on-library screening of TCRs + antigens 👇!

[Stephanie Gaglione @Steph_Gaglione]

Thrilled to share our preprint! We introduce TCRAFT, a method to assemble tens of thousands of TCRs at <$1 each, unlocking high-throughput functional TCR screening from single-cell data.
🧵@kochinstitute @MEBirnbaum @MITChemE @MIT

https://t.co/zifGBP4p7k

[Blake Smith @_blake_smith]

@dylanvneel @harvardneuromds @MGHNeuroSci @BWHNeurology congrats Dylan! this is such great news 👏

[Blake Smith @_blake_smith]

here's a peek of Dr. Perez showing this work - how diverse CAR libraries (inputs) can be leveraged to generate useful datasets that describe differential CAR phenotypes (outputs) at his thesis defense yesterday 👇

super lucky to be your lab mate & play a small part in this work!

[Blake Smith @_blake_smith]

An incredibly impressive body of work from the newly-minted PhD @calebrperez comparing clinical candidate CAR-T architectures head-to-head at single cell resolution, shedding light on mechanisms of differential CAR-T efficacy in vivo with insights into better construct design 🚗

[Caleb Perez @calebrperez]

Excited to share some of my PhD work was pre-printed! Using single-cell sequencing, we took a deep look at a library of CAR signaling architectures to try to identify signal-intrinsic drivers of CAR-T function🧵👇 @MEBirnbaum @kochinstitute @MITdeptofBE

https://t.co/DHbwlFQlnB

[Blake Smith @_blake_smith]

In sum, Dezfulian et al. have successfully re-centaured T cell antigen discovery around CD4+ T cells 😉

https://t.co/v5CTgyZqMh

[Blake Smith @_blake_smith]

The authors then applied their TScan-II methodology to uncover antigens in cancer, autoimmunity, & infectious disease across many different MHC class II alleles & TCRs

Their screens uncovered antigens recognized by clonally-expanded CD4+ T cells from Sjögren's syndrome patients

[Blake Smith @_blake_smith]

For their last trick🪄, the authors introduced the candidate human TCR antigen-binding variable region atop a murine TCR constant region resulting in a human-mouse hybrid TCR that reduces cross-reactivity with the endogenous TCR

They termed these chimeras "centaur T cells"🏃🐎

[Blake Smith @_blake_smith]

For the T cell side of the equation, they made use of the granule-releasing properties of primary CD8+ T cells, but introduced a CD4 co-receptor alongside a candidate T cell receptor (TCR) of interest

But what if the introduced TCR mispairs with the endogenous CD8+ T cell's TCR?

[Blake Smith @_blake_smith]

Wrote a Spotlight piece together w/ lab mate @amandaochan & @MEBirnbaum covering an impressive new methodology from @elledge_stephen's group that enables MHC class II antigen discovery for CD4+ T cells called TScan-II

https://t.co/v5CTgyZqMh

[Blake Smith @_blake_smith]

They also needed to introduce a reporter of T cell antigen recognition

The reporter is an infrared fluorescent protein (IFP) that only becomes fluorescent upon exposure to cytotoxic granzyme B (GzB), representing a functional & sortable readout of cognate CD4+ T cell recognition

[Blake Smith @_blake_smith]

But to do so, the authors needed to engineer both the antigen presenting cells (APCs), alongside the primary T cells used

For the APCs, they modified HEK-293 cells (eHEK-293-II) to lack MHC class I, but present MHC class II allele(s) of interest alongside appropriate machinery

[Blake Smith @_blake_smith]

TScan-II allows for genome-scale interrogation of MHC class II antigens using endogenous processing & presentation machinery of antigen libraries, alongside physiological T cell activation & degranulation (GzB) 👇

https://t.co/nVCO97nd9L

[Blake Smith @_blake_smith]

new @runthelistpod episode is now out hosted on @MHMedical's AccessMedicine webpage!

best part about it?

you can search for key words & phrases to more easily listen to high-yield content 🤯

https://t.co/gk4dowcBPG

[RunTheList @runthelistpod]

We're back with another pod🎙️!

Ep 97: Approach to Dysphagia

https://t.co/i96iBINONn

Host @NavinKumarMD discusses dysphagia workup w/ RTL's own @WalkerReddMD

[Vinod BalachandranMD @TheVinodLab]

1. ENTER #mRNAvaccines for #pancreaticcancer! Long-term #PDAC survivor story PART3.

"Do #PDACs REALLY have vaccine neoantigens (NAs)"? (aren’t they lowly mutated?)

If each patient = own NAs, how do you vaccinate?

Maybe mRNA? But how?

@Nature https://t.co/d1SgGgdVHq

👇🏽 [1/32]

[Blake Smith @_blake_smith]

@blhorton https://t.co/SYk9RB0mvL

happy to put you in touch with the first author too if you want!

[Blake Smith @_blake_smith]

So excited to be at #SITC22 in Boston hearing from some of the giants in the field!

[Blake Smith @_blake_smith]

@leah_pierson 🔥

[Blake Smith @_blake_smith]

@ESmithMDPhD @DanaFarber this is so incredibly exciting, congrats to you @ESmithMDPhD & your team! such an amazing turnaround from the 2019 publication to now 👏

[Blake Smith @_blake_smith]

@DanB0nD1 congrats Dan! awesome work as always 👏