Elena Sotillo: Engineering CAR-T cells for combination therapy with CD47 blockade

Elena Sotillo, Senior Research Scientist at Stanford Cancer Institute, shared on LinkedIn:

“New paper out in Nature (and Open Access) from Crystal Mackall lab about engineering CAR-T cells suitable for combination therapy with CD47 blockade.

The story started in pre-covid times, when then postdoc Johanna Theruvath wondered if anti-CD47 antibodies would synergize with CAR-T cells. It made sense that harnessing the almighty power of macrophages would enhance the antitumor activity of CAR-T cells… but the opposite happened:

Macrophages were killing not only tumor cells, but also CAR-T cells!!!

At that time Sean Yamada-Hunter joined the lab and, exploiting his protein engineer background, he suggested to design CAR-T cells with a modified version of CD47 (47E) that still signals ‘don’t eat me’, but is invisible to CD47 targeting antibodies.

With help from Brianna McIntosh from the Cochran lab, they identified a single amino acid change in CD47 that did the trick!! CAR or TCR specific T cells engineered with the new 47E didn’t get eaten upon anti-CD47 treatment and T cell therapies could finally synergize and eradicated tumors that were resistant to single therapies.

Along the way we discovered that:

1) The balance of ‘eat-me’ and ‘don’t eat me’ signals expressed by CAR-T cells fluctuates with T cell activation and with time in culture.

2) That we can detect molecules of CAR mRNA inside myeloid cells, as well as observe histiocytes engulfing lymphocytes, in samples from patients receiving CAR-T cells, suggesting that CAR-T phagocytosis could limit therapeutic efficacy.

3) That activated CAR-Ts attract and recruit macrophages to the tumor site, and they ‘talk’ to each other and

4) That CAR-T phagocytosis is soooo quick and effective upon CD47 blockade, that in models of CAR-T induced toxicity, anti-CD47 antibodies could be used as safety-switches.

Needless to say, but important to remember, this paper showcases the result of incredible team effort.”

Additional information.
Source: Elena Sotillo/LinkedIn