Jake, I have a precise & published answer to give you.
The short version: the early TNBC long-term survivors all received an ICI alongside or following leronlimab. That is not a coincidence. It is a prediction in the mechanism which the published biology now explains with specificity. Whether CLOVER patients can fare better without an ICI depends on which of leronlimab's four activity layers are doing the work in each individual patient's tumor, and the answer differs by patient.
The longer version follows.
The four patients in the early mTNBC cohort who are currently alive without evidence of disease after 42, 48, 49, and 52 months each had four prior lines of systemic therapy and were treated with leronlimab either in combination with, or subsequently with, checkpoint inhibitors: pembrolizumab or atezolizumab.
This was published in ESMO Open in 2025 and it answers your question directly. The durable complete responses in the early TNBC cohort were not generated by leronlimab alone. They were generated by leronlimab in a setting where a checkpoint inhibitor was also present, either concurrently or sequentially. The patients who received leronlimab without an ICI did not achieve the same durable outcomes. The Dolezal, Khan, and Lalezari peer-reviewed case report documenting 60.9 months of sustained disease-free survival used atezolizumab as the ICI partner specifically. https://www.merck.com/news/fda-approves-merck...cer-whose/
The explanation for why the ICI was required in those patients is now documented at single-cell resolution in the May 30, 2026 CCR5+ CD8+ T cell exhaustion paper. Leronlimab opens the upstream gate by blocking CCR5-mediated myeloid suppressive cell recruitment and reversing the exhaustion architecture imposed on tumor-infiltrating CD8+ T cells. But opening the gate does not independently activate the cytotoxic T cells waiting on the other side of it. The reinvigorated T cells still carry the PD-1 brake. Leronlimab upregulates PD-L1 expression on the tumor cell surface, as documented in the AACR IO February 2026 presentation, which is counterintuitive until you understand that PD-L1 upregulation is the tumor's way of signaling that the immune system is now pressing against it. Without an ICI releasing the PD-1 brake on those reinvigorated T cells, the gate is open but the T cells cannot execute the kill. The ICI is what converts the opened gate into a completed cytotoxic event.
This is exactly why the Dolezal, Khan, and Lalezari case report is so important: PD-L1 levels rose from 276 to 796 relative fluorescence units after leronlimab was added to atezolizumab. Leronlimab created the immunological conditions under which the ICI could function in a tumor previously classified as PD-L1 low and ICI-ineligible. The ICI then released the brake on the T cells that leronlimab had rescued from the exhaustion pipeline. The two mechanisms completed each other.
Now to your direct question about CLOVER: can CLOVER patients fare better without an ICI given that the backbone is TAS-102 plus bevacizumab rather than a checkpoint inhibitor?
The answer is: yes, for a distinct reason, and it is the fourth activity layer.
CLOVER patients are not receiving an ICI. They are receiving a DNA-damaging chemotherapy backbone in TAS-102, whose trifluridine component incorporates into tumor cell DNA and causes lethal strand breaks. As established in the previous reply, leronlimab's CCR5-dependent disruption of CEP131, KHDRBS1, and MAPK6 cell cycle regulators compromises the tumor cell's ability to repair those strand breaks and survive. The fourth activity layer is not dependent on having functional T cells present to complete a cytotoxic event. It operates directly at the tumor cell's metabolic and proliferative machinery. The Seahorse metabolic profiling from the AACR Brain Cancer poster confirmed this: CCR5 inhibition reduces oxygen consumption rate dose-dependently, meaning the tumor cell cannot fuel its repair response even when the immune architecture is not the primary therapeutic lever being pulled.
So the CLOVER patients occupy a different position than the early TNBC compassionate use patients. The early TNBC patients needed an ICI to complete the kill because leronlimab's primary therapeutic contribution in that setting was immune architecture conversion, opening a gate that required an activated T cell to walk through it and execute.
The CLOVER patients have a DNA-damaging chemotherapy agent doing the killing work directly, and leronlimab's fourth activity layer is impairing the tumor cell's capacity to survive that damage at the metabolic and cell cycle level simultaneously.
The immune architecture benefits of CCR5 blockade are still present and still valuable in CLOVER, but they are not the rate-limiting step for RECIST response the way they were in the early TNBC monotherapy context.
The historical ORR for TAS-102 plus bevacizumab alone in this population from the SUNLIGHT phase 3 trial was 6.3 percent. That is the benchmark the fourth activity layer needs to improve upon at RECIST. Whether it does so in sufficient numbers to constitute a meaningful ORR is what October at ESMO answers. https://www.sciencedirect.com/science/article...2822000877
The early TNBC survivors needed leronlimab plus ICI because the mechanism required both gates to be addressed simultaneously. The CLOVER patients need leronlimab plus DNA-damaging chemotherapy because the mechanism in that combination addresses both the tumor's metabolic survival capacity and its immunological evasion architecture, without requiring a functional T cell kill to register a RECIST response. Different backbone, different rate-limiting step, same upstream gate providing the contribution.
Your friend asked the right question. The published biology answers it completely.
The short version: the early TNBC long-term survivors all received an ICI alongside or following leronlimab. That is not a coincidence. It is a prediction in the mechanism which the published biology now explains with specificity. Whether CLOVER patients can fare better without an ICI depends on which of leronlimab's four activity layers are doing the work in each individual patient's tumor, and the answer differs by patient.
The longer version follows.
The four patients in the early mTNBC cohort who are currently alive without evidence of disease after 42, 48, 49, and 52 months each had four prior lines of systemic therapy and were treated with leronlimab either in combination with, or subsequently with, checkpoint inhibitors: pembrolizumab or atezolizumab.
This was published in ESMO Open in 2025 and it answers your question directly. The durable complete responses in the early TNBC cohort were not generated by leronlimab alone. They were generated by leronlimab in a setting where a checkpoint inhibitor was also present, either concurrently or sequentially. The patients who received leronlimab without an ICI did not achieve the same durable outcomes. The Dolezal, Khan, and Lalezari peer-reviewed case report documenting 60.9 months of sustained disease-free survival used atezolizumab as the ICI partner specifically. https://www.merck.com/news/fda-approves-merck...cer-whose/
The explanation for why the ICI was required in those patients is now documented at single-cell resolution in the May 30, 2026 CCR5+ CD8+ T cell exhaustion paper. Leronlimab opens the upstream gate by blocking CCR5-mediated myeloid suppressive cell recruitment and reversing the exhaustion architecture imposed on tumor-infiltrating CD8+ T cells. But opening the gate does not independently activate the cytotoxic T cells waiting on the other side of it. The reinvigorated T cells still carry the PD-1 brake. Leronlimab upregulates PD-L1 expression on the tumor cell surface, as documented in the AACR IO February 2026 presentation, which is counterintuitive until you understand that PD-L1 upregulation is the tumor's way of signaling that the immune system is now pressing against it. Without an ICI releasing the PD-1 brake on those reinvigorated T cells, the gate is open but the T cells cannot execute the kill. The ICI is what converts the opened gate into a completed cytotoxic event.
This is exactly why the Dolezal, Khan, and Lalezari case report is so important: PD-L1 levels rose from 276 to 796 relative fluorescence units after leronlimab was added to atezolizumab. Leronlimab created the immunological conditions under which the ICI could function in a tumor previously classified as PD-L1 low and ICI-ineligible. The ICI then released the brake on the T cells that leronlimab had rescued from the exhaustion pipeline. The two mechanisms completed each other.
Now to your direct question about CLOVER: can CLOVER patients fare better without an ICI given that the backbone is TAS-102 plus bevacizumab rather than a checkpoint inhibitor?
The answer is: yes, for a distinct reason, and it is the fourth activity layer.
CLOVER patients are not receiving an ICI. They are receiving a DNA-damaging chemotherapy backbone in TAS-102, whose trifluridine component incorporates into tumor cell DNA and causes lethal strand breaks. As established in the previous reply, leronlimab's CCR5-dependent disruption of CEP131, KHDRBS1, and MAPK6 cell cycle regulators compromises the tumor cell's ability to repair those strand breaks and survive. The fourth activity layer is not dependent on having functional T cells present to complete a cytotoxic event. It operates directly at the tumor cell's metabolic and proliferative machinery. The Seahorse metabolic profiling from the AACR Brain Cancer poster confirmed this: CCR5 inhibition reduces oxygen consumption rate dose-dependently, meaning the tumor cell cannot fuel its repair response even when the immune architecture is not the primary therapeutic lever being pulled.
So the CLOVER patients occupy a different position than the early TNBC compassionate use patients. The early TNBC patients needed an ICI to complete the kill because leronlimab's primary therapeutic contribution in that setting was immune architecture conversion, opening a gate that required an activated T cell to walk through it and execute.
The CLOVER patients have a DNA-damaging chemotherapy agent doing the killing work directly, and leronlimab's fourth activity layer is impairing the tumor cell's capacity to survive that damage at the metabolic and cell cycle level simultaneously.
The immune architecture benefits of CCR5 blockade are still present and still valuable in CLOVER, but they are not the rate-limiting step for RECIST response the way they were in the early TNBC monotherapy context.
The historical ORR for TAS-102 plus bevacizumab alone in this population from the SUNLIGHT phase 3 trial was 6.3 percent. That is the benchmark the fourth activity layer needs to improve upon at RECIST. Whether it does so in sufficient numbers to constitute a meaningful ORR is what October at ESMO answers. https://www.sciencedirect.com/science/article...2822000877
The early TNBC survivors needed leronlimab plus ICI because the mechanism required both gates to be addressed simultaneously. The CLOVER patients need leronlimab plus DNA-damaging chemotherapy because the mechanism in that combination addresses both the tumor's metabolic survival capacity and its immunological evasion architecture, without requiring a functional T cell kill to register a RECIST response. Different backbone, different rate-limiting step, same upstream gate providing the contribution.
Your friend asked the right question. The published biology answers it completely.
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