I'll second Plotinus in suggesting the importance of the recent Zhao/Lui article on the MDPI website. And of course a big shout-out to twinter, who brought it to our attention in the first place. Here are some of the quotes in the paper that got my attention:
"We hypothesized that a specific chemokine receptor might exist that uniquely marks and is associated with the accumulation or retention of dysfunctional, terminally exhausted T cells within the TME, thus directly contributing to PD-1 blockade poor response." They go on to say "Based on transcriptomic profiling, we characterize a potential regulatory axis whereby crosstalk between myeloid cells and T cells via the CCL3/4-CCR5 axis is associated with T cell dysfunction..." They conclude the paper by saying "These findings deepen our understanding of ICI response and provide bioinformatic insights into the development of novel combination immunotherapies targeting CCR5, which warrants further experimental and functional validation."
Sounds to me like they are talking about CCR5-positive T cells as a potential biomarker in solid tumors, with the implication that an immediate use of a CCR5 inhibitor and an ICI is warranted. In other words... no waiting around for your PD-1/PDL-1 levels to reach a certain threshold. If your T cells are CCR5+ then you are eligible for the combination therapy... because locking down CCR5 will prevent T cell exhaustion and let the ICI do it's thing. And you would get leronlimab in the body right away so it can do it's thing on metastasis, macrophage polarization, etc. And didn't we see that 100% of the 66 patients enrolled in the mCRC trial were CCR5+?
That's the way I interpret it, though they do say at one point "These findings identify CCR5 expression as a marker associated with dysfunctional CD8+ T cell states rather than establishing a direct mechanistic role in resistance." So perhaps these authors aren't ready to go that far. Maybe a test for elevated CCL3/4 would also be required. But doesn't the Pestell article on T cell exhaustion in TNBC prove the "direct mechanistic role in resistance" in CCR5+ T cells?
I thought the Creatv Bio people were going to come up with biomarkers that will guide the use of leronlimab in solid tumors, maybe even find a reliable marker of metastasis... There is still time, of course. But it looks like other scientists are identifying additional biomarkers that would entail the early use of leronlimab and an ICI. The more the merrier!
But am I missing something here? I am no scientist, and could certainly miss something obvious. So any responses would be appreciated. But it seems to me that if you put 2 and 2 together... you get 22!
I'll leave it at that. With thanks again to twinter.
"We hypothesized that a specific chemokine receptor might exist that uniquely marks and is associated with the accumulation or retention of dysfunctional, terminally exhausted T cells within the TME, thus directly contributing to PD-1 blockade poor response." They go on to say "Based on transcriptomic profiling, we characterize a potential regulatory axis whereby crosstalk between myeloid cells and T cells via the CCL3/4-CCR5 axis is associated with T cell dysfunction..." They conclude the paper by saying "These findings deepen our understanding of ICI response and provide bioinformatic insights into the development of novel combination immunotherapies targeting CCR5, which warrants further experimental and functional validation."
Sounds to me like they are talking about CCR5-positive T cells as a potential biomarker in solid tumors, with the implication that an immediate use of a CCR5 inhibitor and an ICI is warranted. In other words... no waiting around for your PD-1/PDL-1 levels to reach a certain threshold. If your T cells are CCR5+ then you are eligible for the combination therapy... because locking down CCR5 will prevent T cell exhaustion and let the ICI do it's thing. And you would get leronlimab in the body right away so it can do it's thing on metastasis, macrophage polarization, etc. And didn't we see that 100% of the 66 patients enrolled in the mCRC trial were CCR5+?
That's the way I interpret it, though they do say at one point "These findings identify CCR5 expression as a marker associated with dysfunctional CD8+ T cell states rather than establishing a direct mechanistic role in resistance." So perhaps these authors aren't ready to go that far. Maybe a test for elevated CCL3/4 would also be required. But doesn't the Pestell article on T cell exhaustion in TNBC prove the "direct mechanistic role in resistance" in CCR5+ T cells?
I thought the Creatv Bio people were going to come up with biomarkers that will guide the use of leronlimab in solid tumors, maybe even find a reliable marker of metastasis... There is still time, of course. But it looks like other scientists are identifying additional biomarkers that would entail the early use of leronlimab and an ICI. The more the merrier!
But am I missing something here? I am no scientist, and could certainly miss something obvious. So any responses would be appreciated. But it seems to me that if you put 2 and 2 together... you get 22!
I'll leave it at that. With thanks again to twinter.
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