[color=rgb(3, 3, 3)]The All-Important Number[/color]
Our recent narrative has been that we are able to turn COLD tumor HOT. But, what does this mean?, well … 100’s of articles have been written about this from a scientific point of view.
For us, investors, only one number matters: CPS (Combined Positive Score).
The reason for this is simple: A higher number increases the likelihood of a patient responding to PD 1/PD L1 checkpoint inhibitors.
i.e Merck, Bristol-Myers Squibb and/or Roche/Genentech will not use pembrolizumab (Keytruda) , nivolumab (Opdivo), atezolizumab (Tecentriq, this one not approved anymore in the U.S.) respectively without a minimum score.
Different cancers use different CPS cutoffs (1, 10, etc.) for treatment decisions. For our case, in a TNBC environment CPS ≥ 10 strongly correlates with responses.
This is why the FDA approvals for TNBC immunotherapy use CPS (only PD-L1 scoring system accepted by them) and the FDA-approved cutoffs by cancer type are used industry-wide. In our case, we have to upregulate to this number to say: the tumor now is HOT (and go whistling to the bank).
So, how do we get there ??
The CPS formula is:
CPS=100* (PD L1 positive tumor cells + lymphocytes + macrophages)/Total viable tumor cells
So basically this is a percentage of all cells showing PD-L1 (both, tumor and immune) divided by total tumor cells. If this number goes above 100 it is capped at this number.
The idea is to capture the best description of the tumor-immune interface, which is what immunotherapy actually targets.
The good news is that this is especially relevant to the CCR5 positive TNBC biology as TAMs can express more PD L1 than tumor cells, is strongly immunosuppressive and (TAM PD L1) predicts response to PD 1/PD L1 blockade. This is because the PD-L1 biology is dominated by immune cells, not tumor cells, explaining why these are added at the numerator of the formula.
In our case, CCR5 activation drives the recruitment of monocytes, the differentiation into M2-like macrophages and the upregulation of PD L1 on these macrophages resulting in increased expression on immune cells.
All well and good. But: can we obtain CPS > 10 ???. Unfortunately, CYDY reports in relation to PD-L1 have been based in Relative Fluorescence Units (RFU) which do not play any role in calculating PD L1 CPS. RFU measure signal intensity but is not used for clinical PD L1 scoring in pathology. Regulators (FDA, EMA) require standardized assays, reproducible scoring and compatibility with routine pathology labs of which RFU is not. Think of it as an “analog” count vs a “digital count”. In addition, there are no validated clinical studies out there showing a correlation between RFU and CPS (not meaning this does not exist, simply there has not been implicit need)
It is obvious from the patients treated by ICI after LL treatment, that their doctors somehow ascertained that this treatment would be beneficial, so, arguably, at some point there were CPS measurement(s) larger than 10 giving green light for the treatment.
The poster on the AACC conference depicts either RFUs or fold changes in CCR5+CD8+ PD1+ T cells in macaques lymph nodes and it is not possible to calculate from this a “synthetic” CPS score.
So, I am “salivating” at the prospect of CYDY publishing more definite results but this time using CPS scores. I really hope this is what we are measuring (as far as PD-L1 goes) in all our trials.
I see a beautiful correlation between "one finger" followed by a zero and the minimum of the CPS scores we are going to measure in our trial(s) ... which will lead to the SP breaking this relation and going to much higher levels ...
GLTYA
20
