Introduction

The idea of using viruses for the treatment of human cancer was suggested as early as 1912 by DePace, only 14 years after the first virus was discovered.¹ His curiosity aroused by a case of cervical tumor regression following vaccination against rabies virus, DePace² at that time undertook the first recorded clinical trial of virotherapy, inoculating eight more cancer patients with the vaccine. Nearly 100 years later, advances in molecular biology and virology have, for the first time, made it possible to harness these highly effective cellular parasites to destroy malignant cells. Many natural viruses have now been engineered or selected to create replicating oncolytic therapeutics that precisely target genetic defects arising during tumor development or unique features of the tumor microenvironment (reviewed in ref. 3). Administration of these viruses can safely induce tumor regression in a variety of models of human cancer through both direct oncolysis and stimulation of antitumor immune activity. By inserting molecular reporters into viral genomes, key aspects of virotherapy such as delivery and intratumoral replication are readily monitored in vivo, permitting tremendous advances in our understanding of the complex dynamics of this approach.^4,5,6,7 These promising advances have led to the hope that oncolytic viruses might be infused into the circulatory system to "seek and destroy" metastatic deposits in patients with advanced and otherwise incurable disease. However, the host immune system remains a critical obstacle to systemic administration of virotherapeutics.^{7,8,9,10,11,12,13,14}

The primary approach to systemic therapy thus far has been to inject naked purified virions into the bloodstream of tumor-bearing hosts. However, many oncolytic viruses that are effective when administered intratumorally are highly vulnerable to host defense mechanisms that survey the circulation for pathogens, including complement proteins, antibodies, and the reticuloendothelial system. It has been well documented that complement proteins compromise the oncolytic activity of herpes simplex virus vectors,^8,9 and also neutralize the infectivity of retroviral therapeutics.¹⁵ Pre-existing or therapy-induced neutralizing antibodies also severely compromise or ablate the systemic antitumor efficacy of adenovirus,^10,11 vesicular stomatitis virus,⁷ herpes simplex virus,⁸ measles virus,¹⁶ reovirus,¹³ and parvovirus¹⁴ platforms. In the case of adenovirus, adhesion to human erythrocytes appears to be another significant factor contributing to therapeutic inactivation.¹⁷ Extensive investigation of adenoviral therapeutics in murine models has also revealed that liver uptake is a major impediment to systemic delivery, where the majority of virus is rapidly removed from the circulation by resident Kupffer macrophages following intravenous infusion.^18,19 Macrophage–reticuloendothelial uptake appears to be a theme common to other oncolytic viruses, as we have also observed accumulation of most vesicular stomatitis virus virions within the liver and spleen following systemic administration (JC Bell and J Paterson, unpublished results).

As, thus far, the naked virion approach to systemic administration has failed to breach this multifaceted defense system, it seems clear that alternative delivery approaches must be developed before maximal efficacy can be achieved in the clinic. To this end, it has been hypothesized that the body's cells might be used as a "trojan horse" delivery vehicle, if first infected in vitro, injected systemically and then carried to tumor beds to release oncolytic virus. Indeed, cells are attractive as stealth carriers, as they are the natural hosts for virus, but are generally ignored by the immune system until the onset of antigen expression at the later stages of infection. A variety of cell types have now been studied as carriers to smuggle oncolytic viruses to tumors. As these cells exhibit different characteristics and many possess therapeutic activity in their own right, the type chosen for virus delivery will likely to have important repercussions on the efficacy of treatment. In the following, we discuss the lessons learned from work to date examining cells as virotherapeutic vehicles.

Primary T Lymphocytes

T lymphocytes normally use the circulatory system to travel between lymphatic organs and sites of foreign antigen expression, and thus tumor-targeted T cells would seem a logical carrier for systemic virus delivery. A variety of methods have been established that permit tumor-specific T cells to be isolated from patients or engineered to express transgenic T-cell receptors for specific tumor-associated antigens.²⁰ Cells generated in this way recognize tumor antigens presented in the context of major histocompatibility complex molecules and are therefore cytotoxic effectors that home to tumors and exhibit therapeutic activity in their own right.²¹ In a screen for potential oncolytic measles virus carrier cells, Ong et al.¹² examined freshly isolated human peripheral blood lymphocytes and found that only a minority (predominantly T cells) were susceptible to viral infection. In order to facilitate further study of this population as carriers, the proportion of T cells infected could be doubled from roughly 20 to 40% when the cells were first activated with interleukin-2 and phytohemagglutinin. Interestingly, however, the viral replication cycle appeared to be abortive even when T cells had been preactivated, as they expressed virally encoded GFP, but failed to develop characteristic cytopathic effects or release infectious virions. Despite their failure to produce free virions, infected T cells could, however, transfer measles virus infection to tumor cells via cell–cell fusion. This "heterofusion" process led to successful delivery and tumor infection when the infected T cells were administered to mice by intravenous injection. In a separate study, Cole et al.²² successfully employed T cells to achieve systemic delivery of tumor-targeted retroviral therapeutics, albeit through quite a different strategy. Murine CD8⁺ T cells proved refractory to infection with retroviral particles, although the latter could efficiently and reversibly adhere to the cellular surface until subsequent "hand-off" when T cells were cocultured with target cells. Release of virus was enhanced both by exposure to the heparanase-rich tumor cell surface, as well as upregulation of heparanase, upon activation of the carrier T cells, providing an additional level of tumor-specific targeting. In proof-of-principle experiments, the authors used CD8⁺ T cells specific for a particular tumor model to convincingly demonstrate that retroviral particles could "hitchhike" on the surface of tumor-homing effector cells before being handed off to malignant cells upon arrival in the tumor bed. Not surprisingly, intravenous administration of retrovirus-loaded effector T cells to mice with established metastases led to much greater efficacy than was achievable with either therapeutic alone. These findings indicate that the complementary properties of cellular and viral therapeutics may be combined for a synergistic, multipronged attack on tumors by arming tumor-lytic effector cells with a secondary, self-propagating weapon in the form of an oncolytic virus. This study also demonstrates that combined biotherapeutic strategies can dramatically enhance tumor specificity, as multiple targeting mechanisms can be built into both the therapeutic virus and the carrier cell.

Cytokine-induced Killer Cells

As an alternative to antitumor T cells, cytokine-induced killer (CIK) cells are another potential dual-purpose effector/carrier. CIK cells are obtained by in vitro treatment of human peripheral blood lymphocytes or murine splenocytes with interferon-, interleukin-2, and a T-cell receptor crosslinking antibody.^23,24 The resultant CD8⁺, natural killer-T effector cells mediate NKG2D-dependent, non-major histocompatibility complex-restricted lysis of a variety of transformed cell types²⁵ and traffic to tumors in vivo.²⁶ Without any further manipulation, Thorne et al.²⁷ have found that these cells support infection with an oncolytic strain of vaccinia virus. Importantly, CIK cells were able to produce high titers of virus, comparable to those generated by transformed cells, although viral release was delayed by several days. In theory, such replication kinetics could benefit viral delivery, allowing sufficient time for infected CIK cells to traffic to tumors before releasing their oncolytic payload. Indeed, systemically administered CIK cells have been shown to take up to 72 h to traffic to tumors,²⁶ roughly the same time frame at which vaccinia production was seen to peak in CIK cells. Using non-invasive imaging techniques, infected CIK cells were seen to deliver vaccinia to tumors following intravenous administration in mice and displayed powerful antitumor efficacy in several disease models. These findings demonstrate that like effector T cells, CIK cells can be loaded with virotherapeutics to achieve synergistic gains in antitumor activity. However, as CIK cell activity is not restricted to specific tumor antigens, it may be much easier to apply this type of biotherapeutic carrier to treat a wider range of patients and tumor types in the clinic.²⁵

Progenitor Cells as Virus Carriers

Mesenchymal progenitor cells are readily obtained from the bone marrow stroma, and can be cultured continuously under minimal growth conditions.²⁸ Their ability to engraft in tumors following intravenous injection²⁹ suggests that they may be suitable as systemic carriers for oncolytic virus. Studies to date have established that mesenchymal progenitor cells support the replication of oncolytic adenovirus and can transfer infectivity to tumors when injected directly,³⁰ although it is not yet clear whether these cells can mediate effective systemic delivery.

Circulating endothelial cells are thought to contribute to tumor neovasculature,³¹ and are therefore another cell type whose tumor-homing abilities might be exploited. Outgrowth endothelial cells may be amenable to use as therapeutic carriers because they are readily isolated from peripheral blood samples, grow rapidly in culture, and can be maintained for at least 30 population doublings.^32,33,34,35 Their potential as virotherapeutic carriers has been investigated and, notably, outgrowth endothelial cells supported infection with non-replicating retroviral and adenoviral vectors and were able to deliver retrovirus to tumors upon systemic administration.³⁶ If they prove susceptible to infection with replicating therapeutics, outgrowth endothelial cells might also be suitable vehicles for oncolytic viruses.

Immortalized Cell Lines

The ease with which transformed cells can be propagated and infected with oncolytic virus makes them an attractive vector with which to explore cell-based delivery. Early studies examining the administration of herpes simplex virus-infected teratocarcinoma cells were the first to show in vivo delivery to tumors.³⁷ Subsequently, delivery of adenovirus to lung metastases in human carcinoma cells provided the first true demonstration of systemic oncolytic virus delivery using carrier cells, albeit in immunocompromised mice.³⁸ A variety of transformed cell lineages have now been shown to mediate delivery of oncolytic parvovirus,³⁹ measles virus,¹⁶ and vesicular stomatitis virus⁷ in immune-competent as well as immune-deficient animals. Interestingly, non-invasive imaging studies have shown that cell carriers derived from a variety of solid tumor types accumulate entirely within the lungs of both tumor-bearing and tumor-free mice following intravenous administration (AT Power and JC Bell, unpublished results).⁷ These findings are consistent with previous reports showing that large-diameter solid tumor cells passively arrest within the first microcapillary bed encountered in the circulation⁴⁰ and therefore their potential as vehicles for systemic delivery may be somewhat limited. In contrast, both transformed and normal cells of hematopoietic lineages appear to show more disseminated distribution following intravenous injection and can deliver virus to other anatomical locations beside the lungs.^7,12,16,27 Given their natural residence within the circulatory system, it is perhaps not surprising that blood cells would exhibit size, deformability, and surface adhesion properties that facilitate passage through the circulatory system, making them ideal virus carriers for systemic delivery.

Perhaps the key theoretical advantage of using transformed cells for delivery is their ability to support high levels of viral replication and to release large quantities of virus within tumor beds. In a direct comparison, measles virus infection and in vivo delivery were indeed significantly more efficient when transformed human monocytes were used as carriers versus untransformed peripheral blood mononuclear cells or outgrowth endothelial cells.¹⁶

In order to use transformed cells as therapeutic carriers in human patients, it will be critical to ensure that uninfected cells cannot establish de novo metastatic growth following systemic administration. This could be accomplished by -irradiation of tumor cells before administration, which ablates tumorigenicity, but preserves metabolic activity. Indeed, it has been demonstrated in several clinical trials that modified tumor vaccines consisting of both autologous and allogeneic cells are able to maintain transgene expression, but do not give rise to tumors if first irradiated before intradermal injection into patients.^41,42,43,44 As -irradiation of cells does not appear to affect oncolytic virus production,^37,39 this may also be an effective way to ablate the tumorigenicity of systemically administered viral carriers. Alternatively, histoincompatible allogeneic or xenogeneic cells might be ideal carriers, because they can deliver oncolytic virus to tumor beds^7,39 before being cleared by the recipient's immune system, and have been well tolerated when given intratumorally to patients in clinical trials.^45,46 Genetically engineering carrier cells to express inducible suicide programs could be another potential way to ensure safety. Clinical precedence demonstrating the feasibility of this strategy has been established in studies where retroviral producer cells were safely administered and delivered the suicide gene thymidine kinase to brain tumors, suggesting that this approach would also be suitable for oncolytic virus delivery in human patients.⁴⁷ Given that the appropriate safeguards are taken, immortalized cell lines may provide a highly robust carrier platform with the ability to release a targeted burst of any given oncolytic virus upon delivery to tumor sites.

Immune Evasion with Cell-based Oncolytic Virus Delivery: the "Trojan Horse" Approach to Biotherapy

Although cellular delivery of virotherapies has been investigated for nearly a decade with the implicit notion of using this strategy for immune evasion, only very recently have data emerged concerning its efficacy in the context of host immunity. This is due in large part to the fact that many of the original oncolytic therapeutics were based on human viruses whose weak infectivity in murine tissues made it difficult to model immune responses in existing cancer models. Vesicular stomatitis virus is one oncolytic agent that induces a robust immune response upon administration to mice and therefore offers the opportunity to study virotherapy in the context of naturally evolving immunity. In this system, neutralizing antibody responses are elicited within the first week of therapy and completely ablate delivery of repeat systemic doses of naked virions.⁷ In contrast, carcinoma cells administered during the eclipse phase of infection were able to conceal viral antigen from circulating antibodies during delivery and subsequently release virus upon delivery to tumor beds. As a result, the efficacy of a systemic multiple-dose treatment regimen in an immune-competent tumor model was dramatically increased when virus was administered within carrier cells rather than as naked virions.⁷ Cells can also be used to evade anti-viral immune responses with other oncolytic viruses; Iankov et al.¹⁶ have shown that an immortalized monocyte cell line can deliver measles virus to tumors despite the presence of high-titer human antibodies passively transferred to mice. Although these results are promising, further work is now required to determine whether consecutive administrations of virus-laden cells elicit immunity and whether these repeated doses continue to achieve tumor delivery, as this will be an important goal of any multi-dose treatment regimen to be employed in a clinical setting. In order to predict the clinical potential of this and any other novel delivery strategy, it will be critical in future studies to expand this analysis using a quantitative approach. As demonstrated by Ong et al.,¹² one way this can be achieved is by using non-invasive molecular imaging technology to quantitate viral transgene expression in tumors of mice passively immunized with varying levels of neutralizing antibody. Applying this approach to examine measles virus delivery, they have demonstrated that the extent of tumor infection is dependent on the quantity of neutralizing antibody present, whether the therapeutic is administered as naked virions or within infected T cells.¹² However, their analysis also revealed quantitative differences between these two strategies, as cell-based delivery was effective over a range of antibody titers that mitigated infection with naked virions. Future studies employing and refining methods of quantitative in vivo assessment of viral and carrier-cell platforms will be critical in order to properly evaluate and compare their utility. Models describing relationships between key parameters such as antibody titers and tumor infection can then be constructed based on this experimental data, potentially providing mechanistic insight and clinically relevant predictions. Approached from a quantitative perspective, future studies within both animal models and human patients will undoubtedly reveal a great deal more about how the complex interactions between cell-delivered virotherapeutics and the host immune system influence tumor infection and growth dynamics.

Awakening the Immune System to Tumors: Cell–Virus Synergy?

In addition to eradicating pre-existing tumors, cancer biotherapies have the capacity to induce protective immunity against disease recurrence. Although administration of oncolytic viruses elicits anti-viral immunity that compromises efficacy, beneficial antitumor immunity can also be stimulated.^48,49,50,51 Similarly, irradiated, cytokine-expressing cancer cells or antigen-presenting immune cells can be used to vaccinate experimental animals against tumor challenge and administration to human patients have been investigated.^52,53,54 Combining these two approaches, by arming an already immunogenic cell-based therapeutic with an oncolytic virus, could therefore lead to synergistic enhancement of antitumor responses. Indeed, viral infection is known to activate a concerted cellular response involving the activation of hundreds of immunostimulatory genes, including those involved in chemotaxis, inflammation, T-cell regulation and antigen presentation,^6,55,56 which would likely boost their potency as vaccines. In support of this idea, administration of autologous tumor cells infected with Newcastle disease virus elicits a significant antitumor immune response in the B16.F10 murine melanoma model, whereas treatment with non-infected irradiated cells affords no therapeutic benefit.⁵⁷ Thus, oncolytic viruses concealed within cells for systemic delivery may, coincidentally, act as adjuvants to potentiate the immunostimulatory properties of the cellular carriers themselves.

Cell-virus Partnership: the Future of Cancer Biotherapy?

Nearly 100 years after the first virus was administered to a human patient in the effort to cure cancer, tremendous successes have been achieved in creating potent replicating virotherapeutics exquisitely designed to target malignant cells. The fusion of oncolytic virus and cell-based approaches into a single biotherapeutic modality has now opened the door to promising new areas of preclinical and clinical investigation. Having established the capacity of cells to systemically deliver virus to tumor deposits and evade circulating antibodies, murine models, and non-invasive imaging techniques now offer the opportunity to refine the targeting of cellular vehicles. As discussed above, early results suggest that all cell lineages are not equally capable of widespread dissemination to target more advanced metastatic disease. Therefore hematological cells that more readily navigate the circulation may provide the best platform for therapeutic delivery. Engineering cells to express surface molecules that bind the tumor cell surface or neovasculature, such as those previously used to retarget the tropism of virotherapeutics,^{58,59,60,61,62,63,64,65} could help to promote accumulation of infected carrier cells within tumor beds to further enhance the efficiency of delivery. Genetic manipulation could also be used to overcome the limitations of primary effector cells as viral carriers. Gene knockdown of the key upstream components of the innate anti-viral defense might enhance their ability to support viral replication and therefore the robustness of viral delivery. Engineering of immortalized leukocyte progenitors has been accomplished in order to generate myeloid cells continuously in vitro;⁶⁶ a similar approach might be adapted to generate a renewable source of antitumor effector cells and dispense with the laborious isolation and culture procedures required to obtain these cells for therapy. Alternatively, readily available tumor cell lines also offer advantages as oncolytic virus carriers; future exploration of their potential for systemic therapy in a clinical setting should be quite feasible provided appropriate measures are taken to first abrogate their proliferative capacity. Further preclinical study of the issues described here should pave the way for intelligently designed clinical trials investigating the safety and efficacy of this promising new partnership between cellular and viral biotherapeutics (Table 1).

Table 1 - Summary of cell lineages studied as carriers for systemic delivery of oncolytic viruses.

Full table

References

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