Use TCR seq as a prediction before and during PD-1/PDL-1 antibody treatment?


#1

There are many papers out there show that there are relations between TCR status and the prognosis of PD-1/PDL-1 treatments. I am wondering why the pharmaceutical companies of immunotherapy drugs, such as, Merck, Roche or BMS only just use IHC staining of PDL1 expression level as an indicator to predict the prognosis of the treatment in the clinical and clinical trails. Any reasons we can think about?


#2

Dear Tao_Sun,
This is peter from Repertoire Genesis.
Please find the links below for your reference.
http://www.repertoire.co.jp/en/technology.html
We have many evidence, showing that PD-1/PDL-1 increases TCR diversity when suppress tumor growth. And I am Immune repertoire analysis will replace IHC staining or FACS sooner.
I hope this helps you.


#3

Excuse me, but the link you’ve posted provides no info on “evidence, showing that PD-1/PDL-1 increases TCR diversity when suppress tumor growth”, it rather looks like an advertising…


#4

I would like to share our information with others and hope to help each other. Please let me know if you want to see our data.


#5

I really would like to! Thanks!


#6

Sure any data/results that answer the OP question are welcome. I’ve just noted that your first post doesn’t contain any info directly related to the question


#7

Can you link to those articles you mention as showing relationship between TCR status and PD-1 inhibition prognosis?

Taking a guess on your question the reason could be that there is no well defined exhaustive set of TCR sequences related to cancer specific epitope and therefore it is hard to exclude an individual from PD-1 treatment on that piece of evidence.

On the other hand if tumor cells are expressing PD-L1 they are likely to respond to PD-1 inhibition and if they don’t express PD-L1 at all, well then there is a clear cut case where PD-1 inhibition is useless.

From the other end of the spectrum, don’t underestimate how conservative pharma/biotech are in their approaches. Rep-Seq of TCR is still a new technology in their eyes and therefore associated with significant risk and trouble (such as convincing FDA/EMA to use this instead of the well known immunohistochemistry that all the rest are using).


#8

It is not totally clear to me what you mean when you write:[quote=“Peterche, post:2, topic:308”]
PD-1/PDL-1 increases TCR diversity when suppress tumor growth
[/quote]

Maybe you could make it more explicit to me what you mean here?

In general (not only in this case) I hear the word diversity being thrown around a lot but I rarely find it very informative unless there is a clear definition of what diversity is and how it relates to the repertoire. Increased diversity in a TCR repertoire might as well mean that your are exposed to plenty of bugs (living with animals, having kids etc.), or going the other way around, that you have low diversity because of a recent massive clonal expansion caused by an infection.

The last is what is hoped for when treating with PD-1 inhibitors. In this case T cells recognising tumor specific epitopes are relieved from suppression and will therefore expand to take up a large part of the T cells and then dealing with the tumor. So then succesful PD-1 inhibition would be reflected in a temporarily lower diversity TCR repertoire.


#9

Here are some paper examples that have some clues about this concept.

PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–571
CTLA4 blockade broadens the peripheral T-cell receptor repertoire. Clin Cancer Res 2014;20:2424–32.
A liquid biopsy for cancer immunotherapy. Nat Med. 2016 Apr 6;22(4):340-1. doi: 10.1038/nm.4074.
Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat. Med. doi:10.1038/nm.4051
Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641–645 (2014)


#10

Yep. All the titles seems to imply that the articles are about the PD-1 inhibition and its potential to enable T cell response against tumor specific antigens. Exciting stuff, but I don’t see how TCR sequencing before PD-1 blockade can predict the response and therefore it is hard to use it as a biomarker.


#11

Now that the topic is set and immune checkpoint blockades stand in such shinny lights I also think it is relevant to remind about the side effects that are logically tied to the unleashing of T cells. It is not surprising to see that autoimmune diseases are found correlated with checkpoint inhibition:

http://cancerimmunolres.aacrjournals.org/content/early/2016/04/13/2326-6066.CIR-15-0123



#12

I read those papers long time ago, but if I didn’t remember the data wrong, they have found that the responders have the higher diversity of T cells in blood before treatment with CTLA4 antibody drug.


#13

Which brings me back to my point on diversity and what this actually is. In this case it seems to mean a repertoire containing TCRs able to recognising tumor epitopes. The problem here is that a “diverse” TCR repertoire is only correlated with better response. There is no direction on the correlation, meaning that diversity could be caused by a thousand other things or just by chance not contain an potent TCR against tumor epitopes.

Concluding on that, I perfectly understand why TCR sequencing is not likely to replace immunohistochemistry simply because it gives no clear answers, contrary to high vs. low tumor expression of PD-L1.