Who I'm Reading Today

https://www.science.org/content/blog-post/hiding-way-down-there

Quick preface: For those who have asked, my in-laws in Iran are (so far) all OK, but we are all of course in an extremely dangerous, stupid, and random situation right now. So yes, it does feel a bit odd to be writing about science and medical topics when there are so many other things going on (and going off) in the world. But this is one way I keep my own equilibrium, and I hope that that word of new discoveries and things that actually seem to be working out for the future can perhaps do the same for you. 

I’ve written here a number of times about chimeric antigen receptor T (CAR-T) cells a number of times here, going back to the first startling reports of their clinical efficacy. What’s been apparent for years now is the difficulty of getting them to work against solid tumors - that is, ones that are not based on circulating populations of aberrant blood cells. There are a number of reasons for this, and surely more that we haven’t worked out yet, but a big one has been the lack of “clean targets” for the T cells. Ideally you want a surface antigen protein that is expressed primarily by tumor cells and not by normal tissue, and you want a given tumor to express it all the way through.

Remember, most solid tumors are heterogeneous mixtures of mutated cancer cells, all fighting it out with each other for resources and room to grow, with new mutations appearing all the time. Single-cell sequencing techniques have made this vividly clear over the years, and this also helps explain why anticancer therapy is so difficult: you may come up with a method to kill off 70, 80, 95% of the cells in a tumor, but you will leave behind a resistant remnant that now is free to expand, its competition having been conveniently removed. And so the tumor recurs some weeks or months later, and this time in an even harder-to-treat form.

The surface protein CD70 is apparently not present in the great majority of adult tissues (except for some differentiating immune cell lines), but it does show up in tumors - to a degree. There are cells in many tumor types that are positive for CD70, but they also contain plenty of cells that appear not to be expressing that it at all. This new paper explores the hypothesis that these supposedly negative cells may in fact still be expressing CD70, but at a level too low for the usual methods of detection - and that means at a level too low for conventional CAR-T cells to recognize them, too. The authors find that the CD70 expression is epigenetically silenced by the methylase enzyme EZH2, which trimethylates lysine residues on histone H3 in the chromatin of these cells. That shuts expression down almost completely, but not quite. When compared to actual CD70 knockout cell lines under stringent detection conditions, they still show some low levels.

The team then went on to try out one of the higher-sensitivity CAR-T platforms, the “HLA-independent T cell” (HIT) receptor design, aimed at CD70 with the hopes that these could go on to eliminate these low-expression cells. They prepared xenografts in animals taken from extremely resistant human tumors, and treatment with the CD70-HIT T cells showed very strong activity against pancreatic and ovarian tumors, and they propose a chromatin-accessibility assay to determine if a given tumor could be sensitive to this sort of CD70 attack. The authors note that at least 20 solid tumor types have been found to express the protein heterogeneously, and suggest that many (perhaps all) of these are in fact still expressing very low levels of CD70 and could be candidates for such treatment.

This could be very good news indeed, and it also opens up a hunt for more such hidden targets that we have been missing. The combination of these and new methods to produce more active T cells is something we should keep an eye out for in clinical trials, and I look forward to following what happens!

https://www.science.org/content/blog-post/hiding-way-down-there