Although metastatic Triple-Negative Breast Cancer (“mTNBC”) typically has a poor prognosis, we recently announced promising survival rates as observed in a group of 28 patients with advanced mTNBC. Overall survival rates at 12, 24, 36, and 48 months after treatment with leronlimab compare favorably with reported life expectancy after treatment with current approved therapies. Further, CytoDyn has also confirmed that five of these patients remain alive today, over four years later. 

A retrospective review of the underlying clinical data indicated that leronlimab treatment correlated with increased expression of an immune cell protein or “checkpoint inhibitor” known as programmed death-ligand 1 (“PD-L1”) on patient’s circulating tumor cells (“CTCs”). The retrospective results indicate that 15/17 (88%) of patients who received a weekly dose of 525 mg or higher experienced a significant increase in PD-L1 expression on their CTCs over a 30-to-90-day period after starting leronlimab. Increasing expression of PD-L1 can be likened to turning “cold” tumors “hot”, elevating PD-L1 levels to the level necessary for patients to potentially derive benefit from further treatment with a class of drugs known as immune checkpoint inhibitors (“ICIs”). The clinical significance of the increase in PD-L1 was further driven home by the confirmation that 5/5 (100%) of patients who demonstrated a significant increase in PD-L1 expression while receiving leronlimab and received an ICI remain alive today.

The above survival observations and underlying retrospective data collectively suggest a potential paradigm shift in solid tumor oncology involving leronlimab’s novel mechanism of action in conjunction with ICIs. For more information on leronlimab as a “prime-and-pair agent” with ICIs, please select the drop-down link directly below.

The survival observations and retrospective data from the CytoDyn’s prior clinical trials suggest the potential paradigm shift in solid tumor oncology therapy. For more information on the promising observations and data from CytoDyn’s prior clinical trials, please select the drop-down link directly above. 

To help understand this prospective new paradigm, the following is an explanation of the basic science and our working theory at this time.

For a cancer tumor to form in the body, it has to essentially blind the immune system to its development so it can grow unimpaired. It does this by hijacking CCR5, a protein receptor on the surface of certain immune cells. Through CCR5 signaling, the tumor commandeers host macrophages, a type of white blood cell which would otherwise attack the cancer cells, to help the tumor build a surrounding area or “microenvironment” to support its growth, including a blood supply that provides necessary nutrients. The growing tumor also uses CCR5 signaling to recruit immunosuppressive cells to the local environment that keep the microenvironment “cold” and the host immune system at bay.  

As to the above processes, it appears leronlimab has the ability to disrupt the CCR5 signaling that both promotes the cancer tumor’s growth and protects its microenvironment from the host immune response. By disrupting CCR5 signaling, leronlimab allows the host immune system (CD8+ cells) to identify the cancer cells as a threat and attack them in what has now become a “hot” or inflamed microenvironment (expressing various inflammatory cytokines). In addition to its potential synergy with ICIs, leronlimab alone has demonstrated anti-metastatic activity by blocking CCR5-mediated signaling pathways that are known to facilitate tumor cell migration, invasion, and the establishment of metastatic niches. 

To counter the pressure of an attack from the host immune system, the cancer, at least as evidenced on the CTCs, has a secondary line of defense: expressing a protein called PD-L1 and hijacking its relationship to its receptor, PD-1. Ordinarily, PD-1 acts as the immune system’s “off switch”, binding with PD-L1 on functioning immune cells and preventing them from being so strong they kill healthy cells in the body. Cancer cells capitalize on this system by expressing PD-L1 and binding to the “off switch” on the invading host immune cells, in turn slowing an immune response, thereby protecting the tumor. 

As observed in patients who were fortunate enough to receive a PD-L1 antibody called an immune checkpoint inhibitor (“ICI”) in our prior studies, this “secondary defense” of the tumor can be thwarted. The antibody prevents the PD-L1 protein from binding to the “off switch” (PD-1), keeping the immune system “on” and allowing the host immune attack on the cancer to continue. Typically, patients who have tumors with higher levels of PD-L1 expression derive the most benefit from treatment with an ICI, given there are more opportunities for the antibody to block connections to the “off” switch and allow the immune system to fight the cancer cells. 

As to this process, preliminary data indicates that leronlimab has the ability to induce higher levels of PD-L1 expression in solid tumor cancer cells. This opens potential new treatment pathways for patients with low PD-L1 levels that would have otherwise been unable to derive benefit from an ICI.

The foregoing sequence is a novel working theory, however, our data first presented at ESMO Breast Cancer Annual Congress (“ESMO”) suggests that this is what happened in the five patients who are alive today. 

The key findings from our presentation at ESMO in May 2025 included the following (ESMO Breast Cancer Annual Congress, May 14-17, 2025 Poster #369P):

• PD-L1 Upregulation:16/21 (76%) of patients showed a significant increase in PD-L1 expression on CTCs within 30-90 days after starting leronlimab, regardless of dose. This suggests that the tumor microenvironment was turned from “cold” to “hot” (from protected against host immune invasion to under host immune attack). Even more remarkably, this shift from “cold” to “hot” occurred in 15/17 (88%) patients who received weekly leronlimab doses of 525 mg or higher. Turning “cold” tumors “hot” means that far more patients with TNBC (and potentially other solid tumors) may become eligible for a class of drugs known as anti-PD-1/anti-PD-L1 treatments and collectively referred to as Immune Checkpoint Inhibitors (ICIs). 
• Long Term Survival:The clinical significance of the increase in PD-L1 observed on the CTCs was driven home by the confirmation that 5/5 (100%) of patients who demonstrated a significant increase in PD-L1 expression while receiving leronlimab and received an ICI are alive today, 4+ years later. More remarkably, four of these individuals (80%) are currently identified as having no ongoing evidence of disease, while the 5^th patient is described as having “stable disease.” To underscore the clinical significance of these results, unfortunately none of the 23 patients who didn’t induce significant PD-L1 expression or didn’t receive an ICI with leronlimab are alive today. 
  

Leronlimab’s Mechanism of Action for Immuno-oncology

C-C chemokine receptor type 5 (“CCR5”) is a protein found on the surface of certain cells that play a role in the body’s immune system. It is believed that CCR5, in particular, may play an integral role in tumor progression in a variety of cancers, and increased CCR5 expression is an indicator of disease status and/or progression in several cancers. For example, CCR5 is overexpressed in breast cancer, prostate cancer, colorectal carcinoma, melanoma, head and neck cancer, gastric cancer, esophageal cancer, pancreatic cancer, as well as other tumors.¹

Working Theory:

• CCR5 is overexpressed in a number of solid-tumor cancers, where it plays a critical role in tumor cell migration, invasion, and metastasis through its regulation of chemotaxis and cell signaling.
• CCR5 also orchestrates the recruitment of immunosuppressive cells (e.g., regulatory T cells and M2 macrophages) into the tumor microenvironment (TME), contributing to immune evasion.
• By binding and blocking CCR5, leronlimab disrupts both tumor progression and immunosuppressive signaling, creating an opportunity to enhance anti-tumor immunity.

The combined observations and retrospective clinical data – from the mechanistic role of CCR5 in tumor biology, biomarker shifts indicative of immune priming, and early clinical outcomes including durable remissions in ICI-treated patients – seems to support leronlimab can play a role in the direct inhibition of tumor progression and metastasis, as well as activation of the tumor microenvironment to enable effective immunotherapy.

We believe the Company’s clinical observations to date provide a compelling rationale for the continued prospective development of Leronlimab in mTNBC and other CCR5-overexpressing solid tumors, and that leronlimab has potential as both a direct anti-cancer agent via CCR5 inhibition and a modulator of the tumor microenvironment to enhance immunotherapy responsiveness.

¹ _{Velasco-Velázquez M, Jiao X, De La Fuente M, Pestell TG, Ertel A, Lisanti MP, Pestell RG. CCR5 antagonist blocks metastasis of basal breast cancer cells. Cancer Res. 2012 Aug 1;72(15):3839-50. doi: 10.1158/0008-5472.CAN-11-3917. Epub 2012 May 25. PMID: 22637726.}

Read More on CCR5

Dr. Richard Pestell, our Lead Consultant – Preclinical and Clinical Oncology, has published preclinical data demonstrating that leronlimab both prevented the metastatic spread of TNBC and caused reversal of established metastases in mice. These important observations speak to two different mechanisms by which leronlimab's blockade of the CCR5 receptor appears to impact cancer: the first involves the role that CCR5 plays in cell migration and how that receptor is hijacked by cancer cells to promote the spread of distant metastases; the second speaks to the direct anti-cancer activity of leronlimab on an established tumor itself and, in particular, the surrounding microenvironment. To follow up on these preclinical observations, we conducted three clinical studies in patients with mTNBC and other solid tumors starting in 2019. 

In 2025, we announced our retrospective analyses of pooled follow-up data from the 28 patients with mTNBC enrolled across these studies, forming the basis for leronlimab’s stand-alone activity in three important ways:

1. Promising survival rates: Overall survival rates at years 1, 2, 3, and 4 (35.7%, 21.4%, 17.9%, and 17.9%) compare favorably with previous studies of patients with advanced mTNBC. In particular, the long-term survival rates of 17.9% at both years 3 and 4 are very exciting, considering other studies exploring potential mTNBC treatments typically don’t even report survival rates out to three years. Moreover, the survival rate of 17.9% at year 4 was calculated without removing or “censoring” patients who dropped out for any reason, meaning it is presented in a more conservative manner. 
2. Impact on advanced disease: Patients in our study population had failed a median of two prior lines of treatment afterdeveloping metastatic disease, and a majority had cancer in other organs (64% had visceral metastases and 29% had brain metastases at entry into the studies). Despite that, the median overall survival (“mOS”) of 6.8 months for all 28 patients (9.7 months for the 18 patients receiving > 525 mg) appears comparable to current standard of care. This makes our results especially promising, given our study population had, generally speaking, more advanced disease than typical clinical populations. Given our survival observations and working theory on the mechanism of action, we are excited to explore leronlimab as an earlier line of therapy with the idea that earlier treatment could serve to save more lives.
3. Decreased CTC levels: The decline in circulating tumor cells (“CTCs”) observed in most patients after as little as one dose of leronlimab was significantly associated with both progression-free and overall survival. Leronlimab’s rapid and prognostically significant impact on CTCs, which appears to reflect activity within the primary tumor itself, provides important evidence of leronlimab’s activity as a stand-alone agent. Confirming the full extent of leronlimab’s activity on the primary tumor is on our short list of clinical priorities in the coming months.