The interesting discussion on PD-1/ PD-L1 axis and

The interesting discussion on PD-1/ PD-L1 axis and CCR5 in Oncology reminds me of when I "discovered" CCR5 had applications in Oncology. I had invested a small sum due to HIV but, then when I made the connection with Cancer I went all-in. Still today I believe this is the BIG prize.

https://investorshangout.com/post/view?id=5758573

This is Looong time ago. In interest of the conversation, and with the intent of adding some "gas to the fire" I am including some cut-and-paste from previous communications.

Credit to Ohm who understood the effect and proposed way back that trials should be started to test this pathway, before this was even a possibility (company was working on HIV exclusively then).

Below some snippets either from the company itself, Ohm or some other contributors (including myself)

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Downregulates programmed death ligand 1 ( PD-L1 helps protect against attacks by T-cells). Downregulates angiogenesis (growth of blood vessels) throughout the tumor by limiting chemokine signaling which helps kill off the tumor. Reduces collagen deposition, fibronectin, and tenascin C which tumors use to grow and survive. Suppresses expression of immunosuppressive myeloid cells, immunosuppressive myeloid cells keep T-cells from attacking tumors. Shuts down tyrosine kinase receptors which reduces tumor cell proliferation. Downregulation of interleukin 6, which reduces tumor growth.

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Leronlimab's MOAs for cancer - Inhibits angiogenesis, shuts down cancer reappearing through collagen downregulation, Stops the recruitment of Tregs to tumor sites (Tregs promote tumor immunity), inhibits tumor cell dna repair, inhibits IL-13 a tumor protectant, downregulates IL-4 (IL-4 promotes tumor immunity), upregulates IFN-gamma promoting tumor cell death, downregulates PD-1/PD-L1 , polarization of macrophages , downregulates calcium channel signalling, blocks CCL5 shutting down pathways for CTCs.

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A very interesting topic is the fact that Leronlimab can potentiate and, arguably, replace Keytruda. From a hypothesis letter (Blockade of CCR5 in melanoma: An alternative immune checkpoint modulator) in the link:

https://onlinelibrary.wiley.com/doi/pdf/10.1111/exd.14065

“For instance, Pembrolizumab, an anti- PD-1 antibody, showed over 34% progression-free survival at 6 months vs 16% progression-free survival on chemotherapy in an early clinical trial of pembrolizumab. The mechanisms of action of immunotherapy encompass blocking PD-1/PDL-1 and CTLA-4 receptors, which mediate the interaction of melanoma and T cells. Blockade of these pathways allows T cells to mount an immune response against melanoma cells. Immunotherapy is widely used as no other therapy provides long-term survival benefit (40% of patients alive at 3 years) even after stopping the medication. However, a significant downside of immunotherapy is toxicity. Immune side effects manifest in all organs and systems including skin rashes, pneumonitis, colitis, hepatitis, nephritis, encephalitis, endocrine and rheumatologic side effects and reactivation of immune diseases.

Therefore, pursuing treatment alternatives with fewer side effects is warranted.

The paper goes on to add:

“The addition of CCR5 blockade could help decrease the dose of PD1 inhibitors and therefore improve the side effect profile, which is a major obstacle to the use of immunotherapy. While anti- PD-1/PD-L1 enables T-cell anti-tumor activity, blockade of CCR5 can prevent MDSCs and T-regs immune modulation and prevent neutrophilic-mediated inflammation in the tumor microenvironment.”

The point here is that little has been done on Melanoma with Leronlimab, this is a common condition and Keytruda has serious adverse effects. The Hypotesis letter rightly points out that there is urgent need to start a trial with Leronlimab (well, with a CCR5 antagonist) for Melanoma.

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You all have a great weekend.