Oncolytic virotherapy in turns of times and its place in cancer treatment nowadays

Oncolytic virotherapy in turns of times and its place in cancer treatment nowadays

Regardless of the huge progress in treatment of certain tumours (mainly in children), the war against cancer, announced by the U.S. President Richard Nixon in 1971, almost a half century later has not, alas, brought to the expected results. People across the globe still suffer and die from the cancer. The positive contribution has managed to merely extend the survival yet not to achieve complete recovery therefore one can understand a willingness to search for new opportunities that would be efficient, safe, convenient, available to patients and not create an additional burden of side effects.

History

The oncology stirred up interest about application of viruses already in the middle of XIX century, influenced by the observations when a malignant tumour in hopeless cancer patients went into a temporary regression after an infectious disease of patients. Such cases were mostly observed in young people suffering from leukaemia and lymphomas[1], [2]. Even though the observed remissions were short-lived, — one, two months — and full recovery from the cancer was not documented, the very fact was sufficiently intriguing to start further studies. Back then the humanity did not know that viruses exist, because they could not been spotted in the conventional optical microscope.

In 1884 Charles Chamberland invented a non-glazed porcelain filter that completely removed all bacteria or other cells measuring 100-1000 nm of size. It was followed by next discoveries — in 1886 Nikolai Gamaleia proved that the cattle plague is caused by the substances penetrating through the Chamberland’s filters; in 1892 Dmitri Ivanovsky concluded that tobacco mosaic disease is caused by filtrating toxins and only in 1901 it turned out that yellow fever in humans is caused also by substances penetrating Chamberland’s filters.

In the beginning of XX century the first official reports on spontaneous tumour regressions after Pasteur vaccination (weakened rabies virus) appeared[3]. At the same time Paul Ehrlich discovered that diseases, including oncological illnesses, can be treated with chemical substances, and Japanese pathologists Yamagiwa Katsusaburō and Koichi Ishikawa proved that cancer can be induced with chemical substances in lab animals thus laying a basis for chemical cancerogenesis. It opened up the gates for avalanche of studies in these areas, pushing the cancer virology aside.

In 1922 a Romanian physician, cytologist and immunologist from the Pasteur Institute, Constantin Levaditi (1874-1953) with his colleagues[4], noticed that tumours are more susceptible to viruses (oncotropism) and are able to kill them (oncolysis). It encouraged a massive study of oncotropic and oncolytic properties of various other viruses in the 40s of XX century and it led to first human studies[5],[6],[7].

In the middle of XX century it became possible to replicate viruses outside the body in human cell lines. It opened new horizons for research. Nevertheless further interest in virotherapy varied between fervent enthusiasm in 50s and 60s and almost complete denial in 70s and 80s, because the viral activity mechanisms were not clear, pathogenicity issue was unsolved and chemotherapy continued its walk of fame, and interest in other socially important viruses such as HIV.

In the beginning of XXI century, due to gene engineering possibilities, interest in virotherapy was reinstated. Defects could be turned into effects — to lessen or even fully prevent pathogenicity, to improve oncotropic and oncolytic properties. Viruses prior to genetic modification were adapted for replication in certain tissues by performing repeated passages in relevant cultures[8],[9]. A possibility to genetically modify viruses outlined the modern transition to the oncolytic virotherapy, but it did not exclude application of natural viruses. Currently there are 3 registered oncolytic viruses – Rigvir® (year of 2004, completely natural, genetically unmodified enterovirus), Oncorine® (year of 2005, genetically modified adenovirus) and Imlygec® (year of 2015, genetically modified herpes virus), and registration of another forms of both natural and genetically modified viruses is pending.

Therefore the oncolytic virotherapy is neither an alternative nor untraditional treatment method but rather a rapidly developing way of treatment.

The story of Latvia

Latvia was one of the first Soviet Republics to start administering polio vaccines in 1957 by injecting a vaccine containing an inactivated poliovirus (Jonas Salk vaccine) for high-risk population groups. The vaccination was later massively continued with Albert Sabin’s peroral vaccine that already contained weakened polio virus strains.

In the early 60s the scientists of August Kirchenstein Institute of Microbiology and Virology came to an idea to research preschool children intestinal microflora before and after receiving polio vaccine by mouth. It turned out that this vaccine did not significantly affect the children microbioma, yet the large amount of enteroviruses residing there attracted the scientists’ attention. Due to a lucky coincidence Albert Sabin had recently visited the Soviet Union and also Latvia and had presented several intestinal viruses from his collection. In 1965 the Cancer Virotherapy Laboratory was set up, led by the professor Aina Muceniece, where study of oncotropic and oncolytic properties of different enteroviruses took place, the study line being globally topical at that time.

The most convincing oncotropic and oncolytic properties among all the researched viruses were observed in several viral strains of ECHO group (ECHO6, ECHO7, ECHO11 and others). When researching potential usefulness for oncolytic virotherapy the professor A. Muceniece discovered[10] that almost 70% of human enteroviruses demonstrate oncotropic and oncolytic properties in heterotransplantants of human angiosarcoma and hondrosarcoma in cheek pouches of Golden hamsters. Such properties were demonstrated by the viruses obtained both from Latvian and Estonian children and Sabin’s collection. Experiments in vitro confirmed that the majority of human tumours adsorb human enteroviruses. After intramuscular injection the typical cytopathic effects of viral antigens and enteroviruses were established in approximately 50% of cases.

The spectrum of enteroviruses that human tumours adsorbed depended on tumour type as it was convincingly proved in a doctoral thesis in 1968 by Rita Garklāva[11].

Since there were no effective remedies for treating melanoma at that time, ECHO-7 virus was started to be adapted for melanoma tissues, bringing positive result and lying a basis for Rigvir® (in favour of the city where it was researched) strain registration in 2002. It was a happenstance of favourable coincident series and wisdom of the researchers that back in the 60s Latvian scientists obtained viruses about which it was written 50 years later that “enteroviruses are a hope giving instrument in the cancer therapy[12].

Oncotropism and oncolysis

Certain viruses are capable of penetrating the cancer cell on a selective basis and to replicate there. Even though oncolytic viruses are equally good at penetrating both in cancer and healthy cells, the pathologically altered transduction of signals of the cancer cells, response to stress and homeostasis make them selectively most appropriate for virus replication. It is possible that normal antiviral activity of cells to identify them and to get rid of them is somehow altered in the cancer cells thus additionally supporting the targeted replication of viruses exactly in that environment. Today we know that, for example, reoviruses gladly “occupy” cancer with a mutated RAS antigen on its surface[13]. It rationally supports that reoviruses might be suitable for tumours with RAS mutation[14]. But it turns out that the choosiness of the viruses regarding selection of cells where to replicate is much more complicated and depends on a subtle interaction among the virus and the tumour[15] and the condition of the immunity. It can also be influenced by cell surface receptors, potential of viral replication and antiviral response elements of the cells. The potential to destroy oncolytic viruses (lytic potential) is also dependent on the very virus, its dose, natural or inducted tropism of the virus and susceptibility of tumour cell to different types of cell death (apoptosis, necrosis, pyroptosis and autophagy).

Cell surface receptors that are selectively identified by different viruses may differ among the tumours. For example, CD155 through which polioviruses bond can be found basically on highly differentiated glioma cells[16]. Meanwhile vesicular stomatitis virus (VSV) is almost pantropic, because it bonds to ubiquitous LDL receptor[17]. Nevertheless the viral tropism depends on the “hospitality” or certain tumour. VSV belongs to interferon responsive viruses and it mainly infects cells with reduced IFN reactivity[18]. Mutations in BRAF or Cycline A genes increase a potential to infect VSV and parvoviruses[19]. Another way to encourage viral replication only in tumour cells is to modify E1A and E1B genes. Thus the virus will replicate selectively only in cells that have defective p53 and Rb tumour suppression pathogenesis paths, as observed in approximately 50% of human tumours[20].

In the course of evolution the very viruses have adapted to changing conditions of human body. Therefore it is less likely that we will be able to ever find a “miracle virus” that will heal all tumours with equal efficiency. It is more credible that viruses with a different “cell occupation tactics” will have to be applied to the “weak areas” of cells of certain location tumours. Besides, one has to consider that cancer tissues are heterogeneous and can consists of different viral responsive and viral non-responsive factions.

Manipulations with viral genome may boost destruction of tumour cells by oncolytic viruses[21],[22]. By arming the oncolytic viruses with proaptotic genes, tumour suppression genes or immunity stimulating genes that attack the tumour, it is possible to increase the oncolytic capacity of these already genetically modified viruses.

Oncolytic viruses in the cancer cells may induce also autophagy — essentially important catabolic process that provides cell homeostasis[23]. Oncolytic viruses destroy the complex machinery of cell autophagy in order to promote replication of themselves[24],[25]. And finally, some oncolytic viruses are able to destroy tumours also indirectly by blocking tumour’s vascularisation[26].

Impact of oncolytic viruses on immunity

The studies on the impact of oncolytic viruses on the immunity started in the 60s of last century[27]. Recent studies have shown that the immunogenic cancer cell death is possible[28].

Anti-cancer immune response induced by oncolytic viruses after an active viral replication is currently considered to be the main condition of a successful therapy[29]. Patients whose immune response improves from oncolytic virotherapy are considered “elite respondents”. They are also expected to have the longest disease regression period. Therefore in area of oncolytic virotherapy it is important to analyse and understand the cases that have turned into “elite respondents”. Phenotypic differentiation of these patients may be crucial to discover some indicators of immunity or genetics that could serve as markers of prognostically efficient virotherapy such as HLA profiles, cytokine expression levels, suppressor cell activity and the like.

Regardless of the mechanisms through which oncolytic viruses trigger cancer cell death, the oncolysis releases various tumour-associated antigens (TAA), inflammatory cytokines and chemokines and other “danger” signals that “wake up” the immunity by recruiting and activating immune competent cells. As the dendritic cells (DC) and others antigen-presenting cells (APC) activate and mature, they more efficiently deliver this information to T cells thus initiating anti-cancer and anti-viral immune response[30]. In order to intensify this property, different cytokines, immunomodulators and tumour-associated antigens can be encrypted in oncolytic viruses by means of modification[31]. The oncolytic viruses expressing cytokines such as IL-12 and IL8 had convincingly better therapeutic effect[32]. But one of so far most efficient cytokines of all the tested seems to be granulocyte-macrophage colony-stimulating factor (GM-CSF) which promotes maturing of dendritic cells and induces specific cytotoxic T cells[33],[34].

Administration routes of oncolytic viruses

Since in the course of replication the viruses literally tear apart the cell and move to next “areas of residence”, several routes of administration are possible. In the first human studies viral preparations were administered perorally, intravascularly, intramuscularly, intraperitoneally, rectally, by scraping into skin, injecting in the very tumour or the surrounding tissues, inhaling it and even soaking the bread pieces with virus containing supernatant and then giving the patient to hold them in mouth until dissolved. If the goal is to provide a systemic anti-cancer immune response, it is not necessary to infect each individual tumour cell.

One of the newest possible routes of administration of the virotherapy is infecting the patient’s immune competent cells ex vivo with the oncolytic virus and re-administering of it into the body, namely so-called Troyan horse tactics[35].

Human studies confirm the conclusions obtained in animal studies, that are: 1) oncolytic viruses can be systematically carried to metastases by intravenous injections;
2) barriers of intravenous administration of the virus can be reduced by gradual increased doses;
3) direct destruction of cancer cells is not the single goal of the therapy; 4) immune competent cells can restrict and promote virus spread at one and the same time[36].

Preclinic and clinic studies have shown that the oncolytic viruses infect the tumours rather unevenly and incompletely, depending on the dose and administration route. Therefore the viral spread can be inhibited by tumour size[37], thick intratumoral connective tissue layers[38], interstitial fluid pressure[39], poor blood vessel network[40] and necrosis and calcification[41]. Due to said factors the oncolytic virotherapy might not be capable of fully destroying the tumour mass.

Side effects, tolerability and safety of use

Very important observation shows that in the course of more than twenty years of application of oncolytic virotherapy within the framework of clinical studies in thousands of patients no severe side effects have been established, yet the proportion of clinically significant side effects was very low in comparison to other standard therapy methods[42].

Summary of 40 years of experience of Latvian scientists about more than thousand cancer patients also indicate at clinically and epidemiologically completely safe parenteral administration of ECHO-7 virus[43].

Efficiency assessment

Efficiency of the conventional chemotherapy with its direct cytotoxic influence is often measured against the decrease in tumour mass as compared to pre-therapy level and evaluating it after a certain period of time. Depending on changes of the obtained tumour mass, they are referred to remission grade and survival. Efforts to standardize tumour response to therapy were observed in the 60s of last century, until in 1979 WHO published RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Tumour response on chemotherapy is assessed according to criteria elaborated by WHO so that different studies could be compared among each other and against the historical data[44]. Later on the joint efforts of the task group resulted in elaborated RECIST criteria[45] that were revised as current updated version 1.1 coming in effect as of January 2009[46]. According to these evaluation criteria the growth of a tumour or emerging new foci means disease progression (DP) which was automatically adjusted to term “drugs don’t work” and therapy with this remedy in DP case should be discontinued.

Evaluation criteria of oncolytic virotherapy in visual diagnostics also have not yet been precisely defined and the early studies were at some level compromised by “pseudoprogressive” finding, which was, possibly, brought about by infection related inflammation and oedema[47]. Similar picture appears also in PET/CT examinations with 18FDG, where accumulation intensity in the beginning of the therapy increases, but then, in case of a successful therapy, decreases[48].

Immunoncological remedies considerably differ from the cytotoxic remedies in that they stimulate body’s immunity responses to tumour’s presence. Currently there are several immunity modulating remedies used in oncology and each of them suppress tumour progression in some way.

  • vaccinations, that encourage the immunity to counteract the presence of a tumour;
  • monoclonal antibodies, that address certain cancer cells to block signal transmission routes, which provide tumour growth, as well as trigger cytotoxic response of the immunity;
  • checkpoint inhibitors that reduce avoidance of tumour cells from natural immune supervision by blocking certain receptors (CTLA-4 and PD-1), located on the tumour cell surface thus alleviating the work of T cells;
  • cytokines, which stimulate different immune response mechanisms (IL-2 and IFα);
  • oncolytic viruses, which have not only cytotoxic (oncolytic) properties, but which can also stimulate natural and adaptive immunity. Besides the medicines of this group affect tumour cells selectively (oncotropism) and in some sense are the best tolerable remedies.

As new immuno-oncological preparations appear in use, Dzhed Volchok with colleagues offered their evaluation criteria in 2009[49]. When analysing irRC (immune-related Response Criteria) it turns out that if one evaluates only against RECIST criteria, the positive effect of therapy can be underestimated[50]. It is clearly shown by the case reports on long-term effect in patients suffering from tumours of different location and having received ECHO-7 virus[51]. Meanwhile other study showed that total survival rate reliably and considerably differed in melanoma patients who were only observed and who received ECHO-7 virus[52].

A good quality survival instead of proportion of patients that react on therapy, which not always correlated to significant life extension, is what matters the most for a patient and his or her relatives. Here we can see the clash of interests between those who prefer indicators that can be evaluated as soon as possible and those who evaluate long-term effects.

Monotherapy with oncolytic viruses

Currently viral studies show that almost every virus can initiate and almost all types of tumours can have malignant death cell initiated. The first human studies took place in late 40s of last century when Alice Moore managed to prove for the first time that the viruses have oncolytic properties when they are administered also to humans suffering from malignant tumours of various localisation[53]. The scope of viruses researched lately has expanded considerably. In majority of cases the goal of the study was to find out the safety of virus administration, its impact on efficiency and survival. Rather recent studies analyse also immunity indicators that were researched in Latvia in more distant 70s and 80s. In the end of 2015 many and various viruses[54] applied in monotherapy were mentioned in I/II phase clinic study set.

  • adenoviruses intratumourally, subcutaneously and intravascularly in patients with spread solid tumours, colorectal and bladder cancer;
  • coxsackie viruses intratumourally in melanoma patients;
  • reovirusesi intratumourally in patients suffering from colorectal cancer, spread solid tumours, melanoma and glioma recurrences or metastatic brain cancers;
  • herpes simplex viruses intratumourally in patients suffering from melanoma, metastatic glioblastoma, cranial and neck tumours and intrapleurally in patients suffering from mesothelioma;
  • vaccine viruses intratumourally in patients suffering from hepatocellular carcinoma and many more.

Monotherapy consisting of oncolytic viruses has achieved different success[55],[56],[57]. Perhaps it is related to host body adaptation to viral spread and promotion of faster elimination of it. It can also be the case that after some time, taking into consideration tumour heterogeneity, a resistance may develop[58]. In order to overcome it, the oncology often combines diverse methods with different activity mechanism. It has been observed that a synergistic combination of oncolytic viruses and other medicines potentiate the destructive activity of tumours[59],[60].

Oncolytic virotherapy combined with other methods

According to several reports in ESMO congress 2016, viral therapy is one of directions that are seen as the next wave in development of new anti-cancer remedies. It was reiterated in the congress that there is a huge anti-cancer therapy potential in bacteria (let us remember William Cowley toxin!). The goal is not to create a universal virus for all cancer types, but to develop a certain type of a virus for certain tumour[61]. When combining chemotherapy with oncolytic viruses the oncolytic effect of the latter increases[62]. It has been established that several cytotoxic remedies may induce immunogenic cell death (ICD)[63].

Chemotherapy remedies combined with oncolytic viruses not only potentiate cytotoxic effect[64], but can also remove obstacles to successful activity of oncolytic viruses. Different combination of reoviruses with chemotherapeutic remedies has been studied in the prostate cancer cell lines in vitro. Meanwhile when combining reovirus with docetaxel in vivo the tumour mass reduced but the survival rate increased[65]. It was also supported by I and II phase clinical studies on reovirus combination with carboplatin/paclitaxel scheme in patients suffering from spread cancers and a separate group with metastatic head and neck tumours[66]. Not only such combination was well tolerated, but also showed convincing survival boost — total survival rate in viral combination group was 7.1 month while in control group it was 3.4-4.5 months.

Antibodies to cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1/programmed death-ligand-1   (PD-1/PD-L1) are already used with good success in different tumour therapy, including melanoma[67],[68],[69]. More and more new reports show that oncolytic viruses regulate PD-1/PD-L1 expression on tumour cell surface therefore it would be purposefully to combine these medicines.[70] Recently a study was published showing hopeful results where T-VEC is combined with anti-CTLA-4 antibodies[71] followed by III phase study on adding T-VEC to anti-PD-1 antibodies. The studies have been also launched with unmodified coxsackie virus preparation CAVATAC in combination with different checkpoint inhibitors of the receptors.

At the same time pathogenetic mechanisms used by oncolytic viruses to promote their replication actually are very similar to those that increase tumour cell malignancy potential, for example IFN route defect, apoptic resistance, immunosuppression. Thus by affecting one or another pathogenetic route with chemotherapeutic remedies we can at once adversely influence the potential of oncolytic viruses. In such a way, for example, in order to boost the replication intensity the viruses need cells in the phase of active cell splitting, while the largest part of anti-cancer remedies have cytotoxic or cytostatic properties with cell death or reduction of proliferation potential[72]. We also know that some oncolytic viruses stimulate angiogenesis in order to improve vascular permeability of tumours[73]. Thus at the same time ordination of inhibitors of angiogenesis we can adversely affect the activity of the oncolytic virus. And finally, modulation of body’s immune response with chemopreparations may contradict the therapeutic effect of the oncolytic virus.

Since the chemotherapeutic remedies are still very crucial in treating tumours, it is understandable why there are efforts to combine them with different viruses[74].

                  Conclusion

Oncolytic viruses are currently considered as a sword that cuts on both sides, namely, they destroy cancer cells directly and has immunomodulatory potential[75]. Due to tolerability and selective activity the oncolytic virotherapy has become a serious weapon in the armoury of future cancer medicines.

 

Footnotes

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