Problems with oncolytic viruses

Of note, the antibody question is complex, and in fact baseline neutralizing antibody titers have not prevented antitumor efficacy in humans [ 76 , 87 ]. The large amounts of virus that are produced by tumors into the bloodstream might simply overcome neutralizing antibodies producible into blood.

In wild type adenovirus infections, only small amounts of adenovirus enter the blood. Neutralizing antibodies are designed to block such virus, not the huge numbers produced by tumors infected with oncolytic virus. Nevertheless, in epidemiological analysis, lack of antibodies at baseline impacted survival statistically significantly [ 76 ], but not in a clinically meaningful manner, as responses and long survival could be seen regardless of baseline antibody titers.

Interestingly, sequential intravenous treatments by changing the virus or serotype might make a difference [ 88 ]. As expression of the Ad5 receptor CXADR appears limiting for efficacy in the context of advanced tumors, fully serotype 3-based oncolytic adenoviruses have been constructed [ 64 ]. This virus enters through non-CXADR-mediated mechanisms including desmoglein 2, which is highly expressed in advanced solid tumors [ 30 , 35 , 64 , 78 ].

Good safety and signs of efficacy were seen in patients treated with a fully serotype 3 adenovirus [ 64 ]. To achieve efficient dissemination of input virus and to minimize virus-related adverse events, adenoviruses have been modified to achieve increased tumor selectivity.

The strategies employed include transcriptional control of adenovirus early proteins such as the E1A or E1B. This blocks adenovirus DNA replication in quiescent normal tissues [ 61 , 66 ]. The fact that tumor cells contain several active oncogenes led to the realization that their resulting proteins could be harnessed to control transcription of adenovirus DNA.

For example, telomerase activity is a known feature of cancer cells, while activity in healthy cells is minimal [ 30 , 91 ]. Therefore, adenovirus replication has been successfully placed under the control of a human telomerase reverse transcriptase hTERT promoter showing antitumor efficacy in advanced cancers [ 64 , 68 ]. Similarly, p53 [ 69 ], carcinoembryonic antigen CEA [ 70 ] and prostate-specific antigen PSA [ 71 ] have been utilized to control expression of early adenovirus proteins.

The nature of viruses allows them to hijack the host cell to produce virus proteins. This allows therapeutic exploitation with the insertion of therapeutic transgenes into the adenovirus genome. Before the recognition of oncolytic adenoviruses as immunotherapy, one of the most common modifications was the insertion of the cytosine deaminase and herpes simplex-derived thymidine kinase [ 74 ]. More recently, the increased recognition of the immune system as an important component in the efficacy of oncolytic viruses led researchers to perceive oncolytic adenoviruses as potent vehicles for immune factors.

Adding a granulocyte macrophage colony stimulating factor GMCSF cytokine transgene into the adenoviral genome is a commonly used modification.

In this approach, virus replication is accompanied by GMCSF production, which results in the recruitment and maturation of dendritic cells DCs , and subsequent priming of T cells with tumor-associated antigens released by oncolysis [ 92 ]. Patient data confirms this notion, with reported increases in peripheral levels of T cells against tumor-associated antigens [ 66 ]. These finding suggest dendritic cell priming in humans as predicted by the established mechanism of action of GMCSF [ 93 ].

However, emerging human data suggests that GMCSF producing viruses might be safe and effective [ 76 , 77 ]. Beyond GMCSF, combined expression of IL and decorin in an oncolytic adenovirus allowed the recovery of antitumor immunity in a poorly immunogenic murine breast cancer model, via cytotoxic T cell infiltration and transforming growth factor beta TGFb reduction [ 82 ].

Coexpression of CD40L and BBL by an oncolytic adenovirus has also shown promising results, due to its ability to promote the destruction of pancreatic tumors, through repolarization of the tumor microenvironment. Such polarization enabled release of T cell attractants and immune stimulatory cytokines, allowing potent antitumor T cell responses [ 96 ].

Also, antibodies can be inserted as transgenes to enhance the efficacy of oncolytic virotherapy. For example, anti-CTLA4, a checkpoint inhibitor, has been successfully inserted in an oncolytic adenovirus platform. Its usage in murine models and ex vivo cultures of cancer patient peripheral blood mononuclear cells PBMCs resulted in increased antitumor activity of T cells [ 81 ]. More recently, dual targeted antibodies targeting T cells and cancer-specific cell surface antigens such as epidermal growth factor receptor EGFR [ 84 ], FR-a [ 85 ], familial adenomatous polyposis FAP [ 10 ] and CD44v6 [ 86 ], have demonstrated promising preclinical results [ 84 ].

Moreover, also other approaches have been studied. These include arming with fusogenic molecules, antibodies, T cell engagers, and ion channels capable of concentrating radioiodine. While in these cases, the transgenes are not necessarily immunologically active, and the oncolytic platform results in immunostimulation. It is important to note that clinical data suggests that oncolytic adenovirus single-agent efficacy has often been somewhat limited.

Several barriers that affect oncolytic adenovirus therapies have been suggested. These include antiviral interferons, which can be produced by the tumor stroma even if the cancer cells themselves lack such ability [ 50 ].

Other reasons include stromal barriers, hypoxia, hyperbaric, necrotic, and acidic areas [ 97 , 98 ]. However, some of these hurdles have been addressed in redesigned adenoviruses conditionally replicating in response to hypoxic factors or acidic tumor microenvironments [ 99 ]. Alternatively, oncolytic adenoviruses have been armed with hyaluronidase [ ], an enzyme that degrades hyaluronic acid which hampers virus dissemination.

Notably, treatment of a number of preclinical in vivo tumor models allowed increased antitumor efficacy. Neutralizing antibodies remain a concern for oncolytic immunotherapies. However, the use of bispecific adapters to retarget antiviral neutralizing antibodies can offer an attractive approach to increase the effectiveness of oncolytic adenovirus therapy [ ]. The coating of oncolytic adenoviruses with tumor derivatives has been reported to allow for successful delivery of particles into the tumor with potent antitumor responses [ ].

A long-term follow-up of these patients has been published [ 5 ]. Treatments were given in the context of an individualized treatment program under the EU Advanced Therapies directive [ 5 ].

While many objective responses were seen, no definite conclusions regarding overall survival benefit can be drawn as no reliable control group was available. However, some case-control analyses that were performed suggest survival benefit [ 88 ]. While taking into account the limitations of nonrandomized data, some interesting findings emerged [ 5 , 51 , 64 , 66 , 80 , 88 , 92 , , , ]. One of the most important observations was that all of the administered viruses appeared quite safe in patients with advanced cancer.

Good tolerability was seen across different serotype viruses, including various capsid modifications, and different immunological arming devices i. Concomitant low-dose cyclophosphamide and temozolomide were also well tolerated [ ]. The former was used to reduce regulatory T cells.

The latter aimed at increased induction of autophagy in infected cancer cells, as this appears to be an important mediator of oncolytic cell death. Moreover, virus replication could be increased by concomitant calcium channel blockage [ ]. No treatment-related patient deaths were observed [ 63 ]. Typical flu-like symptoms, such as fever and fatigue, were observed in most patients a few days after treatment.

These findings were confirmed in multiple subsequent clinical trials [ 61 , 94 , ]. Flu-like symptoms and fever could be effectively reduced with acetaminophen paracetamol. Biodistribution studies done with adenoviruses in rodents are unreliable as most animals lack entry receptors or their organ distribution is different from humans.

From ATAP patients, we have been able to collect important information about virus biodistribution in humans [ 63 ]. Many humans have neutralizing antibodies against different adenovirus serotypes, although often at low baseline titer [ 64 ]. However, as hundreds of billions of viruses are given in a typical treatment, pre-existing antibodies may be unable to completely block intravenous delivery.

In subsequent intravenous treatments with the same serotype, the situation is more unclear, which is one of the reasons intratumoral delivery is commonly used with oncolytic viruses. Of note, it has been proposed that antiviral immunity helps generate antitumor immunity [ 66 ]. It has been established in humans that adenovirus is able to travel through blood to metastases despite neutralizing antibodies [ 63 ].

For some viruses, the mechanism appears to relate to binding to blood cells [ ]. Interestingly, adenoviruses in blood qPCR data were most often found from blood clots, while some patients had significant amount of virus in the serum compartment [ 64 ].

Treatment responses or long survival are seen regardless of neutralizing antibody titers, although it should be noted that most patients were treated intratumorally [ 76 ]. Interestingly, we treated seven patients with the serotype 3 adenovirus using only intravenous administration.

This was seen also with patients who had pre-existing antibodies against the virus. Also, 5 of the 6 evaluable patients showed signs of possible benefit. This data indicates that viruses might be able to enter tumors also via the intravenous route [ 64 ]. This was later confirmed in an autopsy study where non-injected tumors were shown to have oncolytic adenovirus [ 63 ].

From a clinical standpoint, the use of viruses for cancer treatment in the modern era is in its infancy. Initially, wild type viruses were used, but this approach could result in adverse events caused by virus replication in normal tissues.

Nevertheless, Rigvir an ECHO-7 virus [ ], an oncolytic picornavirus with some innate tumor selectivity, was the first approved oncolytic virotherapy product for cancer approved in Latvia and later in a few other countries. The second oncolytic virus was rationally designed for tumor selectivity. Named H Oncorine , this adenovirus has been used in China since for the treatments of solid tumors [ ].

Of note, both of these viruses lack arming devices. The acknowledgement that repurposing the immune system to exert antitumor functions could provide a promising approach to treat cancer enabled scientists to employ the immunological capabilities of oncolytic viruses [ ]. This landmark approval in Western countries encouraged optimism in the medical community to continue developing and improving oncolytic viruses for cancer therapy, including adenoviruses. As expected, a high presence of cytotoxic T cell infiltration was observed in the tumors following treatment [ ].

Of note, and in contrast to combinations of checkpoint inhibitors [ ], adverse events were not compounded. This suggests that oncolytic viruses can be combined with checkpoint inhibition without a problematic decrease in safety. At the time of writing this review March , we did a search on clinicaltrials. Sixteen different oncolytic viruses were used in these completed or recruiting trials.

No active phase III clinical trials were found. Sixteen oncolytic adenoviruses used in phase I—II trials that have been completed or recruiting Mar clinicaltrials. It was designed based on human data from ATAP. Observations of hematological cancer regressions following virus infection were seen early last century [ 17 , 18 ]. Of note, response evaluation was possible for hematological malignancies, by microscopy and cell counting, while this was not true for most solid tumors at the time.

This might have caused overrepresentation of hematological cancer in early literature, due to observational bias. However, it cannot be denied that many reports suggested regression of hematological tumors after viral infections. As such, there is strong rationale to believe that oncolytic viruses could be used also in hematological malignancies. However, not all viruses are suitable for treatment of blood cell tumors.

For example, adenovirus does not appear to be able to lyse white blood cells [ ]. According to recent publications, growing interest towards oncolytic viruses is present also in the hematological field, as several viruses are being studied in preclinical settings [ ]. However, only a few trials have been published [ ]. A search from clinicaltrials. To conclude, to date, there have been few trials with oncolytic viruses in hematological cancers. Some noteworthy efforts include early phase trials with reovirus [ ], measles [ ], and vesicular stomatitis virus VSV in multiple myeloma [ ].

No hematological trials with oncolytic adenovirus were found. Arming with immunostimulatory cytokines has been one popular method to generate immunological synergy with the effects of oncolysis.

Clinical benefit of this approach was seen in the phase III OPTiM trial where 1 in 6 patients achieved complete responses with the oncolytic virus talimogene laherparepvec. Combining oncolytic viruses with T cell activating checkpoint inhibition can improve antitumor efficacy of oncolytic adenovirus therapy. Clinical proof-of-concept for the efficacy of combining oncolytic viruses with checkpoint inhibitors has been presented [ , ].

Furthermore, the safety profile of these treatments has been good and oncolytic viruses do not seem to increase the rate of serious adverse events. Although these combinations seem to yield increased potency and long-term benefits to some patients, not all benefit, and there is clearly a role for further improvement. Combining chemotherapy or radiation therapy in a rational way to improve treatment benefits, and even these conventional therapies seem to have an immunological component [ 27 , ].

However, clear clinical proof in support of this approach is currently limited. Combining other therapies such as adoptive cell therapy or targeted therapies might also result in better treatments. However, we are still lacking much information about the immune effects in individual tumors. This insufficiency of knowledge makes it hard to understand which patients would benefit most of what kind of treatment combinations.

This could be the greatest challenge in the field at the moment. Classic trial design is not well suited for understanding mechanisms on an individual tumor and patient level. An ideal cancer treatment should be so good that most patients would clearly benefit while side effects should be tolerable. Our own contribution to this quest is a novel oncolytic adenovirus, designed specifically with T cells in mind.

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