Highlights
- Bovine herpesvirus type 1 (BoHV-1) effectively targets and lyses multiple myeloma (MM) cells while remaining nonpathogenic to humans, bypassing the obstacle of pre-existing antiviral immunity.
- The virus induces direct oncolysis via mitochondrial apoptosis and the suppression of critical pro-survival metabolic pathways, including MYC signaling and the unfolded protein response (UPR).
- BoHV-1 therapy triggers a profound shift in the bone marrow microenvironment, converting immunosuppressive myeloid cells into pro-inflammatory M1-like phenotypes and activating CD8+ T and NK cells.
- Synergistic effects were observed when combining BoHV-1 with bortezomib, lenalidomide, and daratumumab, the latter driven by virus-induced CD38 upregulation.
Background
Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM). Despite the introduction of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs), MM remains largely incurable. The primary drivers of treatment failure and relapse are intrinsic drug resistance and an exquisitely complex, immunosuppressive BM microenvironment. This niche protects malignant PCs from both chemotherapy and endogenous immune surveillance through the recruitment of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and the polarization of macrophages toward an M2-like, tumor-promoting phenotype.
Oncolytic virotherapy (OV) has emerged as a promising modality that leverages viruses to selectively infect and kill cancer cells while stimulating systemic anti-tumor immunity. However, many human-derived oncolytic viruses, such as adenovirus or herpes simplex virus-1 (HSV-1), face a significant hurdle: pre-existing neutralizing antibodies in the general population, which can clear the virus before it reaches the tumor site. Bovine herpesvirus type 1 (BoHV-1), a member of the Alphaherpesvirinae subfamily, presents a compelling alternative. As a virus that naturally infects cattle and is nonpathogenic to humans, it is not subject to widespread pre-existing immunity, potentially allowing for more effective systemic delivery and therapeutic activity.
Key Content
Mechanisms of Direct Oncolysis and Metabolic Interference
Recent evidence, culminating in the work by Raimondi et al. (2026), demonstrates that BoHV-1 possesses a potent and selective tropism for MM cells. Upon infection, the virus triggers mitochondrial-mediated apoptosis. Unlike standard cytotoxic agents, BoHV-1 appears to systematically dismantle the “survival toolkit” of the plasma cell.
Transcriptomic and metabolic analyses reveal that BoHV-1 infection leads to the downregulation of several key programs:
1. MYC Targets: MYC is a central oncogene in MM progression; its suppression by BoHV-1 significantly impairs cell cycle progression.
2. Oxidative Phosphorylation (OXPHOS): By disrupting mitochondrial energetics, the virus starves the high-energy-demand plasma cells.
3. Unfolded Protein Response (UPR): Malignant PCs are professional secretory cells that rely heavily on the UPR to manage ER stress from excessive immunoglobulin production. BoHV-1-induced suppression of the UPR exacerbates proteotoxic stress, leading to cell death.
Remodeling the Immunosuppressive Bone Marrow Microenvironment
Perhaps the most transformative aspect of BoHV-1 therapy is its capacity for “immune microenvironment remodeling.” In patient-derived bone marrow mononuclear cells (BMMCs), BoHV-1 infection has been shown to selectively deplete malignant PCs and immunosuppressive myeloid subsets while preserving healthy hematopoietic stem cells and lymphoid populations.
This selective pressure is accompanied by a massive influx of pro-inflammatory signals. The infection drives a shift in monocyte/macrophage polarization from a suppressive M2-like state toward a pro-inflammatory M1-like phenotype. This transition is critical, as monocyte depletion experiments have shown that these cells are essential for the full anti-myeloma effect of the virus. Furthermore, the microenvironment becomes saturated with a “cytokine storm” dominated by type I and II interferons (IFNs), which further activates CD8+ T cells and NK cells. Interestingly, BoHV-1 also downregulates MHC class I on infected tumor cells while upregulating NK-activating ligands, specifically sensitizing the remaining tumor cells to NK-mediated lysis.
Synergy with Standard-of-Care (SoC) Therapies
The clinical utility of oncolytic viruses often depends on their ability to integrate into existing treatment paradigms. BoHV-1 exhibits significant synergy with current MM mainstays:
- Bortezomib and Lenalidomide: Co-treatment with BoHV-1 enhances the apoptotic index compared to monotherapy, likely due to the convergence of viral-induced ER stress and PI-induced proteasome inhibition.
- Daratumumab: One of the most striking findings is the virus’s ability to upregulate CD38 expression on both MM cells and immune effectors. In the context of MM, where CD38 expression can be downregulated during daratumumab treatment (leading to resistance), BoHV-1 may serve as a potent priming agent to maintain or restore sensitivity to anti-CD38 monoclonal antibodies.
Expert Commentary
The shift toward using non-human pathogens like BoHV-1 in oncolytic virotherapy addresses one of the most persistent bottlenecks in the field: the host’s immune system attacking the therapeutic agent. From a clinical perspective, the fact that BoHV-1 can selectively remodel the bone marrow niche—the very sanctuary where MM cells hide from traditional therapy—is highly encouraging.
However, several considerations remain. While BoHV-1 is nonpathogenic to humans, the safety profile of high-titer viral infusions in immunocompromised MM patients must be rigorously evaluated in Phase I trials. Furthermore, the “cytokine storm” observed in vitro, while beneficial for tumor clearance, must be carefully managed in a clinical setting to avoid systemic inflammatory response syndrome (SIRS). The potential for BoHV-1 to upregulate CD38 is a particularly clever mechanism that should be explored in patients who have become refractory to daratumumab, potentially offering a novel “re-sensitization” strategy.
Conclusion
BoHV-1 represents a multi-modal therapeutic strategy that goes beyond simple oncolysis. By combining direct metabolic disruption of MYC and UPR pathways with a radical restructuring of the immune microenvironment, it addresses both the tumor cells and the protective niche they inhabit. Its synergy with IMiDs, PIs, and particularly anti-CD38 antibodies positions BoHV-1 as a versatile tool in the future of MM immunovirotherapy. Future research should prioritize determining the optimal sequencing of BoHV-1 with standard therapies and establishing clinical safety in relapsed/refractory patient populations.
References
- Raimondi V, Vescovini R, Storti P, et al. Oncolytic bovine herpesvirus type 1 induces immune microenvironment remodeling and enhances treatment responses in multiple myeloma. Haematologica. 2026; PMID: 41885031.
- Giuliani N, et al. The bone marrow microenvironment in multiple myeloma: an ever-evolving field. Frontiers in Oncology. 2020;10:612980.
- Lungu O, et al. Bovine herpesvirus-1 (BHV-1) as a vector for gene therapy and vaccination. Gene Ther. 1999;6(10):1656-1663.
