The effect of oncolytic viruses on the immune system
Scientists began studying the impact of oncolytic viruses on the immune system in the 1960s. An oncolytic virus-induced immune response against tumours after active viral replication is now considered to be the main requirement for a successful treatment. Patients who experience an improved immune system response as a result of oncolytic virotherapy are considered to be elite responders. They can also expect the longest periods of disease regression. Therefore, in the field of oncolytic virotherapy it’s important to analyse and understand the cases in which patients have become elite responders. The detection of these patients could be significant in the discovery of immune system or genetic indicators that could serve as predictable and effective virotherapy markers.
Regardless of the mechanisms by which oncolytic viruses initiate the death of cancer cells, the oncolysis frees a variety of tumour-related antigens and other distress signals that provoke the immune system to mobilise, recruit and activate immunocompetent cells. As dendritic cells as well as other antigen-presenting cells begin to activate and mature they can more effectively transmit information to T cells thus initiating an immune response against the tumour and the virus. Moreover, this capability can be enhanced in oncolytic viruses via genetic modification by encoding them with a variety of cytokines, immunomodulators and tumour-related antigens.
Entry pathways for oncolytic viruses
As they replicate, viruses literally tear apart cells and then spread to the next host, which is why a number of different entry pathways are available to them. During the first clinical studies on humans, viruses were administered orally, via the blood vessels, intramuscularly, intraperitoneally (in the abdominal cavity), rectally (rectum), scratched into the skin, injected directly into the tumour itself or in surrounding tissues, via the airways (inhaled) and even by instructing patients to suck on small pieces of bread which had been saturated with a specific virus. If the objective is to induce a systemic immune system response to the tumour, then it’s not necessary to infect every single cancer cell. The virus’s children will seek out the next live cancer cell to occupy once it has destroyed the first cell.
One of the latest possible avenues of administering virotherapy is by infecting the patient’s own immunocompetent cells ex vivo (outside the living organism) with the oncolytic virus and then reintroducing the cells into the body, which is also known as a Trojan Horse tactic.
Human trials have only confirmed the results of laboratory studies on animals, which are as follows: 1) oncolytic viruses can be systemically administered to metastases by injecting them intravenously; 2) intravenous viral entry barriers can be reduced by gradually increasing the dosage; 3) the destruction of tumour cells isn’t the only objective of this treatment; 4) immunocompetent cells can simultaneously help and hinder the spread of the virus.
Preclinical and clinical studies have shown that oncolytic viruses infect tumours in a relatively inconsistent and incomplete manner regardless of the dosage and entry pathway. Obstacles to the effective spread of the virus can include the size of the tumour, thick intratumoral connective tissue layers, interstitial pressure and a weak vascular network as well as necroses and calcification in the tumour mass. For these reasons, oncolytic viruses may not be able to completely destroy a tumour mass.
Side effects, tolerability and safety
One significant observation that has been made as the result of 20 years of clinical studies on thousands of patients is that severe side effects have not been documented and clinically significant side effects have only been documented in rare cases, which pale in comparison to other standard treatments.
In addition, 40 years of experience by Latvian researchers on several hundred cancer patients also indicates that the parenteral use of the ECHO-7 (Rigvir®) is clinically and epidemiologically safe. Mild and temporary reactions were observed – a small increase in temperature, drowsiness, minor flu-like aches and pains and troubles swallowing. ECHO-7 viral therapy has never been suspended as a result of side effects.
Evaluation of its efficacy
The efficacy of conventional chemotherapy and its direct cytotoxic effect is usually measured by how much the size of the tumour mass has decreased compared to its pre-treatment level and to make this evaluation after a specific period of time. Depending on the changes to the tumour mass, a determination is made as to the degree of remission and potential life expectancy. Attempts to standardise tumour responses to therapy began in the 1960s, but the first such list was only published in 1979 when the WHO released its RECIST (Response Evaluation Criteria in Solid Tumours) criteria. Tumour responses to chemotherapy were evaluated according to criteria laid out by the WHO, so a variety of studies could be compared to one another as well as to historical data. The collective efforts of these work groups later resulted in the creation of the RECIST criteria, which has been re-evaluated over time including the current 1.1 version, which has been valid since January of 2009. According to these evaluation criteria, tumour growth or the appearance of new tumours indicates a progression of the disease (PD), which automatically means that the chosen drugs are not effective and should be discontinued.
Efficacy criteria for evaluating oncolytic virotherapy have yet to be precisely defined and early research was somewhat compromised by so-called pseudoprogression, which is common in this method of treatment. This was possibly caused by inflammation and swelling related to the viral infection as well as lymphocyte infiltration in and around the tumour. This has also been observed in PET/CT scans that use FDG (fludeoxyglucose F 18), where the intensity of accumulation increases at the beginning of treatment, but later decreases as a result of successful therapy.
Immuno-oncology drugs differ significantly from cytotoxic drugs as they stimulate the body’s immune system response to the presence of the tumour. Currently, a number of immunomodulating drugs are available, each hindering the progression of the tumour in its own way (for more detailed information see the chapter regarding the types of immunotherapy):
- vaccines, which encourage the immune system to attack the tumour cells present in the body;
- monoclonal antibodies, which target specific cancer cells to block signal pathways that ensure the growth of the tumour and also promote the immune system’s cytotoxic response;
- checkpoint inhibitors, which reduce the ability of the tumour cells to avoid the natural supervision of the immune system by blocking specific receptors (CTLA-4 and PD-1) that can be found on the surface of tumour cells;
- cytokines that stimulate various immune response mechanisms (IL-2 and IFα);
- oncolytic viruses, which not only possess cytotoxic (oncolytic) capabilities, but also the ability to stimulate the natural function of the immune system and its ability to adapt. In addition, this group of drugs selectively target cancer cells (oncotropism) and are in many ways the best tolerated drugs available.
As new immuno-oncological drugs came on the market in 2009, Jedd D. Wolchok and his colleagues offered their own evaluation criteria. By analysing immune-related response criteria
(irRC) it turns out that many positive effects of treatment are undervalued by evaluating results solely on the basis of the RECIST criteria. This is clearly visible when looking at the long-term effect on patients who had been treated with the ECHO-7 virus for a variety of different tumours. Another study showed that overall life expectancy noticeably and significantly differed for patients who had only been observed from those who had been treated with the ECHO-7 virus.
Good quality of life, rather than the proportion of patients who respond to treatment, which doesn’t always correlate with a significant extension of life, is what’s most important to patients and their relatives. This is also where the interests of those who prefer evaluations as quick as possible collide with those of people who evaluate long-term efficacy.
Drugs are often publicly criticised for not having enough empirical evidence supporting their efficacy. I have to agree, because the higher the toxicity of a drug or the likelihood of side effects, the more rigorous the clinical trials need to be to justify its use.