Nice find! There is a lot of scientific stuff in
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Posted On: 07/15/2019 10:45:01 AM
Nice find! There is a lot of scientific stuff in here that I'm not going to pretend to understand. I took away mostly positive information (as I have previously researching CCR5 in cancer), but have a couple of questions I hoping someone here can help clarify?
Does leronlimab block macrophages? I'm not sure if this is where leronlimab differs from maraviroc in that it binds to CCR5 at a precise point to block attaching to the CCR5 receptor vs. maraviroc buries and blocks the entire receptor (not a specific point and my understanding why leronlimab allows for auto immune functions and maraviroc does not)?
Also, it needs to be pointed out that in the MARACON trial, there was no direct relationship between patchy or nonpatchy expression patterns and response to CCR5 inhibition in terms of the extent of selective tumor necrosis (Figure 2(f)), which also seems to indicate that the Maraviroc-mediated tumor cell death in this study did not exclusively rely on CCR5 expression by cancer cells but most likely centered on macrophages. This is line with our previously published results, where Maraviroc-mediated tumor cell death was relying on the presence of functional macrophages in tissue cultures of liver metastases(page 10).
I apologize in advance if this is an unintelligent question. Most of the article seems to confirm that CCR5 plays a role in cancer metastasis. The below excerpt seems more along the lines of where I think CYDY is heading in cancer in that stopping or delaying progression and improve overall survival for patients with high CCR5 expression.
Low mRNA expression of CCR5 – that we approximate using patchiness (supplemental Figure 4) – is linked to a longer relapse-free survival and disease-specific survival (Figure 4). Interestingly, however, this effect only appears after a certain amount of time (around 2 years) during which low CCR5-expressing metastases are associated with a poorer profile of RFS (Figure 4(b-c)). Does this indicate that this is the timeframe for a CCR5-associated relapse to become visible? This timeframe of the first two years after curative resection nicely fits into the clinical observations.58 But this also brings up another important aspect: do we need a trial utilizing CCR5 inhibition in the adjuvant setting15,42? Can we prevent metastatic homing or at least delay the relapse and progression? Based on our data this could be considered, especially as this is reinforced by the trend towards overall survival advantage (Figure 4) in patients with high CCR5 expression (page 10).
Does leronlimab block macrophages? I'm not sure if this is where leronlimab differs from maraviroc in that it binds to CCR5 at a precise point to block attaching to the CCR5 receptor vs. maraviroc buries and blocks the entire receptor (not a specific point and my understanding why leronlimab allows for auto immune functions and maraviroc does not)?
Also, it needs to be pointed out that in the MARACON trial, there was no direct relationship between patchy or nonpatchy expression patterns and response to CCR5 inhibition in terms of the extent of selective tumor necrosis (Figure 2(f)), which also seems to indicate that the Maraviroc-mediated tumor cell death in this study did not exclusively rely on CCR5 expression by cancer cells but most likely centered on macrophages. This is line with our previously published results, where Maraviroc-mediated tumor cell death was relying on the presence of functional macrophages in tissue cultures of liver metastases(page 10).
I apologize in advance if this is an unintelligent question. Most of the article seems to confirm that CCR5 plays a role in cancer metastasis. The below excerpt seems more along the lines of where I think CYDY is heading in cancer in that stopping or delaying progression and improve overall survival for patients with high CCR5 expression.
Low mRNA expression of CCR5 – that we approximate using patchiness (supplemental Figure 4) – is linked to a longer relapse-free survival and disease-specific survival (Figure 4). Interestingly, however, this effect only appears after a certain amount of time (around 2 years) during which low CCR5-expressing metastases are associated with a poorer profile of RFS (Figure 4(b-c)). Does this indicate that this is the timeframe for a CCR5-associated relapse to become visible? This timeframe of the first two years after curative resection nicely fits into the clinical observations.58 But this also brings up another important aspect: do we need a trial utilizing CCR5 inhibition in the adjuvant setting15,42? Can we prevent metastatic homing or at least delay the relapse and progression? Based on our data this could be considered, especially as this is reinforced by the trend towards overall survival advantage (Figure 4) in patients with high CCR5 expression (page 10).
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