Oncolytic viruses have long held promise in oncology because of their ability to infect and destroy tumor cells while stimulating antitumor immune responses. But the field has also faced a persistent delivery challenge: many approaches have worked best when administered directly into a tumor, which limits their use in patients with metastatic disease or tumors that are difficult to access.
For patients whose cancer has spread to multiple sites, systemic delivery is often needed. Yet viruses introduced into the bloodstream can be recognized and cleared by the immune system, limiting their ability to reach tumors in sufficient quantities.
CEO and Director
Calidi Biotherapeutics
To explore how targeted virotherapy is evolving to address this challenge, Xtalks spoke with Eric Poma, CEO and Director of Calidi Biotherapeutics. The company is developing systemically delivered oncolytic virotherapies designed to reach tumor sites and express therapeutic payloads within the tumor microenvironment.
Why Systemic Delivery Matters in Oncolytic Virotherapy
Direct intratumoral injection has helped validate the potential of oncolytic viruses in cancer treatment. In settings where a lesion can be accessed by needle, local administration can deliver the virus directly into the tumor, allowing it to replicate in cancer cells and trigger tumor cell lysis.
But that approach does not reflect the clinical reality for many patients with advanced cancer.
“Most patients don’t have tumors that are amenable to direct injection,” Poma said. “If you think about most metastatic patients, they’ll have metastatic sites throughout their body, often inaccessible.”
In conventional systemic oncology treatment, a therapy enters the bloodstream and circulates to tumor sites. Applying that model to oncolytic viruses is more complicated because the immune system is designed to detect and eliminate viral particles.
“The reason it’s been such a challenge is typically if you have a patient with metastatic disease, you’re going to give them a medicine that enters into their bloodstream and then can be carried throughout the body and get to those metastatic sites,” Poma explained. “But with oncolytic viruses, when they hit the bloodstream, your immune system doesn’t know that this is a therapeutic. It just sees this as a foreign entity, and it clears it.”
That immune clearance problem has become one of the central scientific questions in the field: how to preserve the biologic activity of a virus long enough for it to reach tumor tissue after IV administration.
A Distinct Mechanism in the Oncology Toolkit
Oncolytic viruses differ from many established cancer therapies because they are not primarily designed to damage DNA or inhibit a signaling pathway. Their therapeutic activity comes from infection, replication and tumor cell destruction, followed by immune activation.
Poma described this as part of a broader pattern in oncology, where new therapeutic modalities can sometimes overcome resistance to existing approaches because they act through different biology.
“Oncolytic viruses or viral therapy work very, very differently,” he said. “They’re not damaging DNA. They’re not blocking a signal transduction pathway. They’re replicating within the cell, bursting it open and now there’s antigen present, and you can drive an immune response.”
This combination of direct tumor cell lysis and immune stimulation is part of what makes the modality scientifically compelling. When tumor cells are destroyed, tumor-associated antigens can become more visible to the immune system, potentially helping drive a broader antitumor response.
Viruses can also serve as vectors for genetic payloads. In this model, the virus is not only a tumor-killing agent but also a delivery system that can carry genes encoding therapeutic proteins. The goal is to concentrate expression in the tumor microenvironment, where immune activation may be beneficial, while limiting systemic exposure that could drive toxicity.
“You can now have proteins expressed only in the tumor that can drive an antitumor response, but if they were expressed everywhere in the body, they would cause toxicity,” Poma said.
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Engineering a Virus to Avoid Immune Clearance
Calidi’s approach uses a vaccinia virus backbone, which Poma said offers several technical advantages. Vaccinia is well characterized, has a history of use in smallpox vaccination, replicates in the cytoplasm rather than the nucleus and has a large genome that can accommodate inserted genetic payloads.
The company has also engineered the virus to replicate selectively in tumor cells. For a systemically administered viral therapy, that selectivity is important because the virus may circulate broadly before reaching tumor tissue.
“If you’re going to have a virus that can go everywhere in the body, not get cleared by the immune system, you want to make sure it can only replicate in tumor cells,” Poma said.
A key feature of the platform is the viral envelope. Poma explained that the company developed a strain of vaccinia virus that takes on the cell membrane of the human cells in which it is grown. This human membrane coating is intended to help shield the virus from immune detection.
The company then engineered the virus to express CD55 on the envelope. CD55 is a human complement-regulatory protein that helps protect cells from complement-mediated clearance. Poma compared the rationale to red blood cells, which rely in part on complement-regulatory proteins such as CD55 to help protect against complement-mediated clearance.
“We’ve now, for the first time, created a virus that has an envelope that has high levels of CD55 expressed on it,” Poma said. “And all of our animal work, all of our ex vivo human work preclinically shows that the immune system has a very, very hard time detecting the virus.”
This immune-shielding strategy is intended to allow the virus to survive systemic delivery, reach tumor sites, replicate in tumor cells and express therapeutic payloads locally.
Using the Tumor Microenvironment as a Site of Payload Expression
The company’s lead IND-enabling program from this platform is designed to express an IL-15 superagonist payload in the tumor microenvironment. IL-15 biology is of interest in oncology because it can activate immune effector cells, including CD8-positive T cells, gamma-delta T cells and natural killer cells.
The therapeutic rationale is not only to lyse tumor cells through viral replication, but also to recruit and activate immune cells within the tumor microenvironment.
“It gets to tumor cells, it replicates in the tumor cells, bursts them open,” Poma said. “It also is engineered to express a genetic payload of an IL-15 superagonist, which pulls in CD8 T cells, gamma-delta T cells and NK cells to fight tumors.”
In preclinical mouse models with intact immune systems, Poma said the company has evaluated IV administration and observed delivery to metastatic sites, tumor destruction, high local expression of the payload and immune cell infiltration.
The broader scientific goal is to shift the tumor microenvironment from one that can resist immune attack to one that supports immune recognition and tumor killing. If payload expression can be concentrated in tumor tissue rather than systemically, it could also change the therapeutic window for cytokine-based approaches, which have historically been limited by toxicity when broadly distributed in the body.
Manufacturing and CMC Considerations for Viral Therapies
As with other advanced biologic modalities, manufacturing is central to clinical translation. For systemically administered viral therapies, development teams need to demonstrate consistency, potency, purity, traceability and appropriate release criteria before entering human studies.
Poma said chemistry, manufacturing and controls (CMC) work is a major part of the investigational application process.
“The biggest section of an IND is the CMC section, which is the manufacturing section, and demonstrating that you have put all the appropriate release criteria and all the appropriate documentation in place so that every batch of drug that is created is exactly like the last batch,” he said.
He added that batch traceability is also essential. If a manufacturing issue arises, sponsors need documentation that allows them to identify the affected batch and understand what happened.
From an operational perspective, Poma characterized the company’s manufacturing process as more similar in cost-of-goods profile to standard biologics than to highly individualized cell therapies.
“Unlike a lot of the new medicines coming out in oncology, this is generally pretty easy and cheap to manufacture,” he said. “The cost of goods here is very similar to a standard monoclonal antibody or recombinant protein. It’s not a CAR-T kind of cost of goods.”
That distinction could matter if systemic virotherapies advance clinically, as scalability and reproducibility will be important for broader development and potential commercialization.
Next Steps for the Systemic Virotherapy Development
Calidi Biotherapeutics expects its lead systemic virotherapy program to move into clinical evaluation after completing the investigational application and regulatory requirements. Poma said the company anticipates studying the approach in patients with advanced solid tumors who have progressed on available therapies and have metastatic disease.
For clinical researchers, the program highlights several broader questions shaping the next phase of oncolytic virotherapy: whether systemic viral delivery can be achieved reliably, whether payload expression can be localized to the tumor microenvironment, how immune activation should be measured and which patient populations may be most appropriate for early testing.
If these questions can be answered in clinical studies, systemically delivered oncolytic viruses could expand the role of virotherapy beyond injectable lesions and into metastatic disease settings where tumor access has historically limited the field.
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