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
Curator: Larry H. Bernstein, MD, FCAP
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 ). 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.
2012pharmaceutical
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