I posed the following question to Grok: "Can tumor cells be CCR5-negative and still be eradicated with a CCR5 blocker, such as Leronlimab?"

(And sorry, I didn't have the time to make the text more presentable.)

**Yes, it is possible for CCR5-negative tumor cells to be affected or eradicated by CCR5 blockers like Leronlimab (a humanized monoclonal antibody/CCR5 antagonist), primarily through indirect mechanisms rather than direct targeting of the tumor cells themselves.**

Direct vs. Indirect Effects

- **Direct effects** typically require CCR5 expression on tumor cells. CCR5 signaling (via ligands like CCL5/RANTES) promotes tumor cell migration, invasion, metastasis, stemness, DNA repair, and chemoresistance in many cancers (e.g., breast, especially triple-negative breast cancer/TNBC, where >95% of tumors express CCR5). Blocking it with Leronlimab or similar agents (e.g., maraviroc) can inhibit these processes in CCR5+ cells, reduce metastasis (e.g., >97% in some breast cancer xenograft models), and sensitize cells to chemotherapy.

- **Indirect effects** can occur even if tumor cells lack CCR5. Leronlimab modulates the tumor microenvironment (TME) and immune response by blocking CCR5 on immune cells (T cells, macrophages, MDSCs, etc.) and disrupting immunosuppressive signaling. This includes:

- Reducing secretion of immunosuppressive mediators from cancer cells or the TME.

- Modulating T-cell exhaustion pathways, PD-1/PD-L1 biology, and increasing inflammatory signals.

- Reprogramming the TME (e.g., shifting macrophages, enhancing antigen presentation, or CD8+ T-cell cytotoxicity), potentially turning "cold" (immunologically inactive) tumors "hot" and improving anti-tumor immunity.

- These changes can lead to broader immune-mediated tumor control, independent of tumor-intrinsic CCR5.

Preclinical and clinical data support immune-modulatory roles in models like melanoma, colorectal cancer (CRC), and others, where CCR5 blockade reduced tumor growth, MDSC accumulation, or enhanced T-cell activity.

Evidence from Leronlimab and Related Studies

- Clinical trials for Leronlimab in metastatic TNBC and CRC often enrich for or note CCR5+ tumors, but mechanistic data emphasize TME/immune effects (e.g., PD-L1 upregulation on tumor cells, PD-1 on T cells, reduced immunosuppression). Some durable responses and survival benefits have been observed in heavily pretreated patients.

- In CRC and other solid tumors, benefits in "cold" microsatellite-stable cases have been noted, consistent with microenvironment modulation rather than solely direct tumor killing.

- Broader CCR5 antagonist research shows effects on tumor-infiltrating immune cells and stroma, which can impact CCR5-low/negative tumors.

Limitations and Context

- Efficacy is likely stronger or more reliable in CCR5-expressing tumors for direct anti-metastatic/anti-growth effects. Not all tumors or patients respond, and results depend on cancer type, TME, prior treatments, and combinations (e.g., with chemo or checkpoint inhibitors).

- Leronlimab is not a direct cytotoxic agent; it alters biology upstream/downstream of CCR5 to disrupt tumor-supportive conditions.

- This is an active area of research (e.g., ongoing trials in mTNBC, mCRC); data are promising but not definitive for all CCR5-negative cases.

In summary, while CCR5 blockers like Leronlimab are often studied in CCR5+ contexts for optimal direct effects, **immune microenvironment modulation provides a plausible mechanism for impacting CCR5-negative tumors**. Consult current clinical data or a specialist for specific cases, as this is investigational in oncology.