Oncolytic Virotherapy for Pancreatic Cancer: Overcoming Obstacles in Oncolytic Virus Delivery
Reporter: Aviva Lev-Ari, PhD, RN
UPDATED: 07/02/2026
Source: https://www.cellandgene.com/doc/why-improving-drug-delivery-remains-a-major-opportunity-in-oncology
Why Improving Drug Delivery Remains A Major Opportunity In Oncology
By Eric Poma, Ph.D., CEO of Calidi Biotherapeutics
Cancer treatment has advanced significantly over the last two decades, with immunotherapies, targeted therapies, and cell therapies changing the standard of care across various cancer and tumor types. Despite this progress, effectively delivering therapies to tumors while minimizing systemic toxicity remains a challenge for the industry, limiting lifesaving outcomes in oncology.
Many therapies struggle to reach metastatic tumors, while others may activate a broad immune response rather than localized one, increasing the risk of side effects and limiting therapeutic concentration at the tumor site. As a result, there remains significant unmet need for treatment approaches capable of selectively reaching tumors and driving therapeutic activity within the tumor microenvironment.
Cancer is one of the leading causes of death worldwide, accounting for nearly 10 million deaths in 2020 according to the World Health Organization. In many advanced cancers, outcomes remain poor even as new therapies continue to emerge. Non-small cell lung cancer, for example, has an estimated five-year survival rate of approximately 30%, with outcomes declining significantly in metastatic disease. Head and neck cancers also continue to present major treatment challenges, particularly in later-stage disease.
One area receiving renewed attention is virotherapy, particularly systemically delivered oncolytic viruses engineered to selectively target tumors and modify the tumor microenvironment.
The Limits Of Conventional Drug Delivery In Oncology
Traditional oncologic drug delivery approaches often face competing priorities. Therapies must reach sufficient concentration within tumors to generate meaningful activity while maintaining low enough concentration in healthy tissue to avoid excessive exposure.
Tumors are biologically heterogeneous; differences in vascularization, immune composition, stromal barriers, and receptor expression can all affect whether a therapy successfully reaches the tumor site. Additionally, the immune system itself can limit therapeutic delivery. Biologic therapies introduced systemically may be rapidly identified and cleared before reaching their intended target. Alternatively, many immunotherapies rely on systemic immune activation. While these approaches can produce meaningful responses, they may also generate inflammatory toxicities that limit dosing flexibility or patient eligibility.
Why The Tumor Microenvironment Matters
The tumor microenvironment has become an increasingly important focus in cancer research because of the central role it plays in disease progression and therapeutic response. Tumors interact continuously with immune cells, stromal cells, blood vessels, and signaling molecules within their surrounding environment. In many cancers, this microenvironment suppresses immune activity and creates conditions that help tumors avoid destruction. For this reason, many next-generation oncology strategies aim to kill tumor cells directly and alter the tumor microenvironment in ways that support stronger anti-tumor immune responses.
Therapeutic payloads intended to stimulate immune activity within tumors have limited benefit if they cannot reach sufficient concentrations at the tumor site. On the other hand, therapies that circulate broadly throughout the body may increase immunogenic toxicity without producing the intended local effect.
The Evolution Of Oncolytic Virotherapy
For years, oncolytic virotherapy has been studied as a potential mechanism for selectively targeting cancer cells. Early approaches focused primarily on engineering viruses capable of infecting and killing tumor cells while sparing healthy tissue. The field reached a major inflection point with the growing recognition that oncolytic viruses could do more than directly destroy tumor cells. Researchers increasingly demonstrated that these therapies could also stimulate anti-tumor immune responses, shifting development efforts toward platforms designed to combine tumor lysis, immune activation, and targeted delivery. However, one of the longstanding challenges in systemic virotherapy is immune clearance, as many viral therapies struggle to persist in circulation long enough to effectively reach tumors following intravenous administration.
Calidi’s RedTail platform uses an engineered enveloped oncolytic virus designed to evade immune clearance and improve delivery to tumor tissue. Once at the tumor site, the therapy induces tumor cell lysis while delivering genetic payloads directly within the tumor microenvironment. This design enables systemic administration with selective tumor targeting.
Advancing Targeted Payload Delivery
Calidi’s lead program, CLD-401, is engineered to evade immune clearance by utilizing a human envelope combined with overexpression of CD55. It is intended for systemic administration, with the ability to home to the tumor cells, where it induces cell lysis and delivers an IL-15 superagonist within the tumor microenvironment.
IL-15 is a cytokine associated with activation of CD8 T-cells, gamma delta T cells, and natural killer (NK) cells. Preclinical data evaluating IL-15 expression and immune changes within the tumor microenvironment demonstrated recruitment and activation of NK, NK-T, and gamma delta T cells. Further analysis showed low circulating levels of IL-15, with high intratumoral expression observed. These data showcase the goal: increase immune activation in a way that concentrates activity within tumors while reducing systemic exposure.
Systemic Delivery And Metastatic Disease
Therapies capable of effectively reaching tumor metastases continue to represent a major area of unmet need. Localized therapies administered directly into tumors may offer advantages in accessible lesions but face limitations in widespread metastatic disease.
Developing systemically delivered therapies that can successfully navigate circulation, avoid premature immune clearance, and selectively reach tumors has historically been difficult. Technologies designed to improve systemic tumor targeting may help expand treatment options for cancers where metastases are difficult to access directly. Calidi’s approach focuses on systemic delivery to distal tumor sites, including metastatic disease.
Looking Ahead
The broader oncology landscape continues to evolve toward more targeted and biologically informed treatment approaches. Advances in genomics, immunology, and genetic engineering are creating new opportunities to rethink how therapies are delivered and activated within tumors.
Drug delivery also remains a foundational challenge that continues to influence therapeutic outcomes across oncology. Improving delivery efficiency may help unlock the potential of existing therapeutic mechanisms while also enabling entirely new treatment approaches.
The oncolytic virotherapy field continues to advance as researchers explore ways to improve tumor targeting, payload delivery, and systemic administration. While substantial work remains ahead across the field, recent advances suggest that the next phase of oncologic innovation depends on identifying new therapeutic targets and improving how therapies reach tumors in the first place.
Original article
Reporter: Aviva Lev-Ari, PhD, RN
We covered MGH’s Innovation on Tumor targeted therapy in Pancreatic Cancer in
Pancreatic Cancer Targeted Treatment?
Curator: Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2016/05/18/pancreatic-cancer-targeted-treatment/
Below, we report on the State of the Science for Overcoming Obstacles in Oncolytic Virus Delivery and provide the source for all the references used
ONCOLYTIC VIROTHERAPY FOR PANCREATIC CANCER
Adenovirus
ONYX-015 was the first TOV used in a clinical trial for pancreatic cancer. ONYX-015 was administered intratumourally under endoscopic ultrasound-guidance into patients with locally advanced adenocarcinoma of the pancreas or metastatic disease in phase I/II trials[132]. The treatment was well-tolerated in most patients, however no objective responses were seen with ONYX-015 as a single agent and only 2/21 patients experienced mild responses when combined with gemcitabine[132]. A second adenovirus vector carries a deletion in the E1A gene[133]. E1A normally binds to the retinoblastoma protein, forcing cells to prematurely enter the S phase of the cell cycle. Since most pancreatic cancers harbor a mutation in CDKN2A[134], the E1A protein is unnecessary for entry of the TOV into cancer cells. Furthermore a double-deleted (E1A and E1B19) adenovirus demonstrated increase potency and selectivity in pancreatic cancer models[135,136]. This demonstrates that TOVs can be genetically engineered to increase selectivity and efficacy while maintaining their potency. Adenovirus selectivity has also been improved by engineering tumour-specific promoters such as a human CEA promoter[137] or by substituting the adenovirus serotype 5 fiber knob with the fiber knob from serotype 3[138]. The potency of TOVs can also be improved further by engineering them with therapeutic genes that stimulate the immune system and/or improve direct oncolysis. Adenovirus ZD55-IL-24 expressing IL-24 locally in pancreatic tumours in immune competent mice inhibited tumour growth and induced a stronger T cell response compared to its backbone virus, as measured by IL-6 and IFN-γ levels[139].
HSV
Two oncolytic HSV-1 vectors are currently in clinical trials for the treatment of pancreatic cancer. HF10 is a non-engineered, naturally occurring oncolytic HSV that demonstrated regression in 1/6 of the patients treated[140,141]. OncoVex GM-CSF is a ∆34.5 and ICP47-deleted mutant expressing GM-CSF, whereby the deletions allow for tumour-selective replication and inhibition of protein-kinase R activation, respectively[142]. Phase I/II trials in various solid tumours demonstrated OncoVex GM-CSF to be well-tolerated at high and repeated doses[143,144]. A phase I clinical trial with OncoVex GM-CSF in patients with unresectable pancreatic cancer is underway.
Poxviruses
The most widely studied poxvirus is VV, which is highly immunogenic and produces a strong cytotoxic T cell response[145] and circulating neutralizing antibodies which can be detected decades later[146]. For its crucial role in the eradication of smallpox, much has been learned about its potential role in immunotherapy today. The Lister strain of vaccinia remarkably showed no replication degradation even under the hypoxic conditions of PDAC[147]. A second Lister strain, thymidine kinase-deleted replicating VV armed with IL-10 demonstrated superior and long-lasting antitumour immunity in both a subcutaneous pancreatic cancer model and a Kras-p53 mutant-transgenic pancreatic cancer model after systemic delivery compared to its unarmed backbone virus[148]. Myxoma virus, a rabbit-specific poxvirus combined with gemcitabine resulted in 100% long-term survival in Pan02-engrafted immunocompetent intraperitoneal dissemination models of pancreatic cancer[149]. The only poxvirus to be tested in clinical trials is a non-replicative VV that expresses the pancreatic TAAs CEA and MUC-2[150]. The vaccine also includes a triad of costimulatory molecules, B7.1 (CD80), ICAM-1 (intra-cellular adhesion molecule-1) and LFA-3 (leukocyte function-associated antigen-3) (TRICOM) (PANVAC-VF)[150]. GM-CSF was also used as an adjuvant following each vaccination of PANVAC-VF. Phase I trials demonstrated antigen-specific antitumour responses in 62.5% of patients enrolled and antibody responses against VV was observed in all ten patients, which was associated with an increase in survival (15.1 mo vs 3.9 mo)[48]. A phase III clinical trial for the treatment of metastatic pancreatic cancer after failing treatment with gemcitabine, however, was terminated after failing to reach its primary efficacy endpoint[151].
Other pre-clinical TOVs for pancreatic cancer therapy
Parvovirus, measles virus and reovirus have also demonstrated pre-clinical activity in pancreatic cancer models. Parvoviruses particularly demonstrated enhanced IL-2-activated NK responses against PDAC cells[152,153]. An armed measles virus (MV), MV-purine nucleoside phosphorylase (PNP)-anti-prostate stem cell antigen, that expresses the prodrug convertase PNP, which then activates the prodrug fludarabine, was shown to enhance the oncolytic efficacy of the virus in gemcitabine-resistant PDAC cells[154]. Reovirus is another promising TOV for pancreatic cancer therapy, particularly because its selectivity depends on the cellular activity of Ras, which is constitutively active in pancreatic cancer[155]. Reolysin® (Oncolytics Biotech Inc., Calgary, AB, Canada) a reovirus administered intraportally resulted in decreased metastatic tumour volumes in the liver of immunocompetent animal models[156,157]. A phase II study of Reolysin® in combination with gemcitabine in patients with advanced PDAC has been completed (clinicaltrials.gov: NCT00998322). A two-armed randomized phase II study of carboplatin and paclitaxel plus Reolysin® vs carboplatin and paclitaxel alone in recurrent or metastatic pancreatic cancer is currently being conducted by the United States National Cancer Institute (NCI-8601/OSU-10045).
RATIONALIZING VIRO-IMMUNE-CHECKPOINT COMBINATION THERAPY
A understanding how antitumour immunity is regulated allows us to recognize barriers against effective immunotherapy delivery and furthermore, allow for the development of rational combination therapies aiming targeting these mechanisms[108,158,159]. This approach allows therapies to work synergistically and also has the potential to benefit a broader patient population[108]. Tumours have evolved to avoid immune recognition and/or destruction at every stage in the antitumour response, therefore targeting more than one immune resistance mechanism will enhance antitumour immunity.
An important immunological barrier in cancer immunotherapy is the tolerance towards self-antigens. Tumours downregulate their antigenicity through various mechanisms in response to selective pressure by the immune system, a process called “immunoediting”[37]. Therefore, in order to raise an effective antitumour response, the immunological tolerance must be broken to allow tumour antigen-specific cytotoxic T cell responses[158]. This can be achieved by increasing the tumour load and/or enhance antigen presentation[108]. TOVs can initiate selective infection and replication in the tumour bed, exposing TAA, disrupting the immunotolerance employed by the tumour while re-engaging adaptive immune effector responses[39]. Combining an agent that can cause disruption to the tumour bed i.e., an oncolytic virus, with a novel antitumour immunomodulating agent such as anti-PD-1/PD-L1 antibodies can maximize immune-stimulating and immune-recruiting inflammatory responses[39]. Specifically, TOV lysis induces the release of tumour antigens into the microenvironment, which are then cross-presented to T cells in the draining lymph nodes by APCs[159] (Figure (Figure1).1). This allows T cell infiltration to the tumour bed. Next, T cell dysfunction must be reversed[108,158]. Immune checkpoint inhibitors alleviate immunosuppression, allowing the elimination of the tumour by the adaptive immune system[70]. TOVs in combination with immune checkpoint inhibitors can therefore potentiate and activate the immune system synergistically, ultimately creating a pro-inflammatory environment. Pre-existing TILs are strong prognostic predictors in cancer[106]. This is extremely relevant for tumours with poor immune-cell infiltration, such as pancreatic cancer, which would depend on TOV-infection mediated lymphocyte infiltration for an enhanced response to immune checkpoint blockade. Zamarin et al[160] demonstrated constrained replication of an intratumoural-injected Newcastle disease virus in a B16 melanoma model. Lymphocytic infiltrates, however, were detected in both TOV-injected and non-TOV-injected tumours, and rendered the tumours sensitive to CTLA-4 blockade. The antitumour activity was dependent on CD8+ T cells, NK cells and type I and II IFNs[160]. Ipilimumab with or without talimogene laherparapvec, is in early clinical testing in patients with unresected melanoma (clinicaltrials.org: NCT01740297). Interestingly, an MV engineered to express CTLA-4 or PD-L1 antibodies delayed tumour progression and prolonged median OS in B16 melanoma models[161]. Finally, TOVs have demonstrated a tolerable toxicity profile, whereby flu-like symptoms are the most common adverse events, and in fact, most of the side effects seen so far in the combination regiment are related to the immune checkpoint blockade inhibitor[162]. Dias et al[163] suggested an oncolytic adenovirus expressing CTLA-4 locally might reduce systemic side effects normally induced with anti-CTLA-4 antibodies alone.
OVERCOMING OBSTACLES IN ONCOLYTIC VIRUS DELIVERY
The main issue with virotherapy is systemic delivery for targeting metastatic cancer cells. Intravenous administration is more practical, especially for treatment of a tumour in a hard-to-reach location such as the pancreas, and with the majority of patients presenting with advanced or metastatic disease. However, nonimmune human serum and existing anti-TOV antibodies may neutralize the TOV in the bloodstream. Furthermore, non-specific hepatic and splenic sequestration of the TOV and ineffective extravasation into the tumours are important issues[164]. Currently, studies in pre-clinical models aim to overcome these obstacles. These include chemical modification of viral coat proteins by conjugation of biocompatible polymers e.g. polyethylene glycosylation[165,166], using mesenchymal stem cell carrier systems to deliver the TOV to the tumour bed[167–169], and increasing vessel permeabilization[170,171].
In PDAC, however, the biggest hurdle may not be the host immune system, but the TME. The TME has played a significant role in not only acting as a physical barrier to deliver treatments, but it also in the development of resistance to conventional drugs. The TME remains a problem for successful TOV treatment. The TOV must be able to spread in the hypoxic and densely stromal-rich TME in order to attract enough attention to induce antitumour immunity[172]. Breaching the stromal barrier in PDAC is needed for TOVs to access the cancer cells[173]. Paradoxically, a recent study by Ilkow et al[174] demonstrated that the cross-talk between CAFs and cancer cells actually lead to increased permissibility of TOV-based therapeutics. Tumour cells producing TGF-α reprogrammed CAFs, dampening levels of anti-viral transcripts. This allowed the cells to be more sensitive to VV, vesicular stomatitis virus and maraba MG1 TOVs. The reprogrammed CAFs produced fibroblast growth factor (FGF)-2 which suppressed levels of retinoic acid-inducible gene I and increased the susceptibility of the tumour cells to virus[175]. This study also demonstrated that an FGF2-expressing TOV has improved therapeutic efficacy by sensitizing the tumour cells to virotherapy and is particularly relevant to pancreatic cancers, where CAFs are a major component of the tumour stroma[175]. It is important to note that not only the patient’s existing immune system may impede successful TOV therapy, but that the enhanced antitumour response by combinatory approaches (e.g., the inclusion of immune-checkpoint inhibitors) may also impede successful TOV infection, spread and engagement of the immune system. This stresses the importance of determining strategic combinations, dosing and timing schedules in future studies.
CONCLUSION
The poor prognosis of pancreatic cancer due in part to the limited efficacy of conventional and targeted therapies, appeals for a novel strategy to treat this disease. It has become very clear that the immune system has the greatest potential to selectively destroy tumours, and when it is strategically induced, a durable benefit can be achieved. Past and present studies have defined means for tumour escape from immune surveillance and have developed immunotherapies to counteract these mechanisms. However, with the various escape strategies leading to low immunogenicity and highly immunosuppressive tumour beds, a successful control of tumour growth by immunotherapy does not come without various obstacles and challenges. Future steps include the development of immune-monitoring strategies for the identification of biomarkers, to establishment guidelines to assess clinical end points of immunotherapy and finally to evaluate combination therapeutic strategies to maximize clinical benefit[176]. The ability of TOVs to stimulate inflammation, deliver genes and immunomodulatory agents as well as reduce tumour burden by direct cell lysis, allows them to be important therapeutic vectors for a highly immunosuppressed tumour such as PDAC. Immune checkpoint blockade agents can then reverse T cell anergy and further boost OV-induced responses. As this combinatory approach may exist as a double-edged sword, it is crucial to determine appropriate timing, dosing and sequence schedules of each agent.
SOURCE & REFERENCES
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