A strain of the common cold virus has been found to potentially target, infect and destroy cancer cells in patients with bladder cancer, a new study in the medical journal Clinical Cancer Research reports.
No trace of the cancer was found in one patient following treatment with the virus.
Researchers from the University of Surrey and Royal Surrey County Hospital investigated the safety and tolerability of exposure to the oncolytic (‘cancer-killing’) virus coxsackievirus (CVA21), a naturally occurring strain of the common cold, in fifteen patients with non-muscle invasive bladder cancer (NMIBC).
NMIBC is found in the tissue of the inner surface of the bladder and is the tenth most common cancer in the UK with approximately 10,000 people each year diagnosed with the illness.
Current treatments for this cancer are problematic.
Transurethral resection, an invasive procedure that removes all visible lesions, has a high tumour recurrence rate ranging from 50 per cent to 70 per cent as well as a high tumour progression rate between 10 per cent and 20 per cent over a period of two to five years.
Another common course of treatment, immunotherapy with Bacille Calmette-Guerin, a live bacterium used to treat bladder cancer, has been found to have serious side effects in one third of NMIBC patients while one third do not respond to the treatment at all.
During this pioneering study fifteen NMIBC patients, one week prior to pre scheduled surgery to remove their tumours, received CVA21 via a catheter in the bladder.
Examination of tissue samples post-surgery discovered that the virus was highly selective, targeting only cancerous cells in the organ and leaving all other cells intact.
The virus was found to have infected cancerous cells and replicated itself causing the cells to rupture and die.
Urine samples taken from patients on alternate days detected ‘shedding’ from the virus indicating that once virally infected cancer cells had died, the newly replicated virus continued to attack more cancerous cells in the organ.
Typically tumours in the bladder do not have immune cells, preventing a patient’s own immune system from eliminating the cancer as it grows.
Evidence suggests treatment with CVA21 inflames the tumour causing immune cells to rush into the cancer environment, targeting and killing the cancer cells.
These tumours devoid of immune cells are known as ‘cold’ areas immunologically; however, treatment with the virus causes inflammation and immune cell stimulation to create ‘immunological ‘heat’.
‘Hot’ tumours in this way are more likely to be rejected by the immune system.
Following treatment with the virus cell death was identified in the majority of the patients’ tumours.
In one patient no trace of the cancer was found during surgery.
Hardev Pandha, Principal Investigator of the study and Professor of Medical Oncology at the University of Surrey, said: “Non-muscle invasive bladder cancer is a highly prevalent illness that requires an intrusive and often lengthy treatment plan. Current treatment is ineffective and toxic in a proportion of patients and there is an urgent need for new therapies.
“Coxsackievirus could help revolutionise treatment for this type of cancer.
Reduction of tumour burden and increased cancer cell death was observed in all patients and removed all trace of the disease in one patient following just one week of treatment, showing its potential effectiveness.
Notably, no significant side effects were observed in any patient.”
Dr. Nicola Annels, Research Fellow at the University of Surrey, said: “Traditionally viruses have been associated with illness however in the right situation they can improve our overall health and wellbeing by destroying cancerous cells.
Oncolytic viruses such as the coxsackievirus could transform the way we treat cancer and could signal a move away from more established treatments such as chemotherapy.”
Cancer immunotherapy and the emergence of immune checkpoint inhibitors have markedly changed the treatment paradigm for many cancers.
They function to disrupt cancer cell evasion of the immune response and activate sustained anti-tumor immunity.
Oncolytic viruses have also emerged as an additional therapeutic agent for cancer treatment.
These viruses are designed to target and kill tumor cells while leaving the normal cells unharmed. As part of this process, oncolytic virus infection stimulates anti-cancer immune responses that augment the efficacy of checkpoint inhibition.
These viruses have the capability of transforming a “cold” tumor microenvironment with few immune effector cells into a “hot” environment with increased immune cell and cytokine infiltration.
For this reason, there are multiple ongoing clinical trials that combine oncolytic virotherapy and immune checkpoint inhibitors.
This review will detail the key oncolytic viruses in preclinical and clinical studies and highlight the results of their testing with checkpoint inhibitors.
As the worldwide cancer incidence continues to rise,1 the need for novel treatment strategies has become increasingly important.
Targeting cancers at the molecular level is an attractive option, as demonstrated by the recent successes of systemically delivered immunotherapeutics (Figure 1).
The field of immunotherapy seeks to develop treatments that effectively augment the body’s own immune response to cancer in an effort to achieve local and systemic anti-tumor immunity.
Unfortunately, certain cancers (e.g., pancreatic cancer) have a unique tumor microenvironment that has a relative paucity of circulating immune effector cells.2
This scenario creates a “cold” tumor microenvironment and results in the tumor’s being less responsive to immunotherapies.
Conversely, “hot” tumor microenvironments are known to be immunogenic and have a much higher response rate to immunotherapy.3
Therefore, strategies to transform cold tumor microenvironments to hot ones are especially attractive, as they will help to increase the effectiveness of immune checkpoint inhibitors (ICIs).4
OVs are able to target and kill cancer cells while minimizing toxicities to surrounding normal tissues.5
After infection with these viruses, the local tumor microenvironment is altered with an increase in activated T cells, natural killer (NK) cells, and cytokines.6
This review will explore the combination of ICIs with OVs for cancer therapy and will highlight key preclinical data, along with notable clinical trials.
Immune checkpoints are inhibitory pathways in the immune system that modulate the amplitude and duration of immune responses.
In some instances, tumors manipulate these immune-checkpoint pathways, resulting in a resistance to the body’s native immune system.
ICIs work by disrupting the cancer cells’ signals, thereby exposing the tumors’ T lymphocytes to attack (Figure 2).
T lymphocytes have been the major focus of efforts to therapeutically manipulate endogenous antitumor immunity because of their functions in (1) selective peptide recognition, (2) direct cytotoxicity to certain antigen-expressing cells (by CD8+ effector T cells), and (3) their ability to orchestrate diverse immune responses (by CD4+ helper T cells), which involves both adaptive and innate effector mechanisms. T cell-mediated immunity includes multiple sequential steps involving the clonal selection of antigen-specific cells, their activation and proliferation in lymphoid tissues, their translocation (trafficking) to sites where the antigen is presented, the execution of direct effector function, and the provision of help (through cytokines and membrane ligands) for a multitude of effector immune cells.
Each of these steps is regulated by counterbalancing stimulatory and inhibitory signals that fine-tune the immune response.
Specificity is conferred to the response via antigen-independent second signals that modify the initial signal, which was provided by the interaction of antigenic peptides with T cell receptors.7
The inhibitory signals in the immune response are triggered through membrane receptors, such as those for B7, programmed death receptor ligand-1 (PD-L1), and high-mobility group protein box1 (HMGB-1), and are overexpressed on tumor cells, and hence the interactions of these inhibitory receptor with their ligands (both membrane bound and soluble), such as cytotoxic T lymphocyte-associated antigen-4-B7 (CTLA4-B7), programmed death receptor-1 (PD-1)-PD-L1, and T cell immunoglobulin and mucin domain 3 (TIM3)-HMGB1, limit T cell activation (Figure 3).8, 9, 10, 11
These aforementioned interactions are the targets for currently used ICIs and are explained in more detail in the following sections.
Its mechanism functions to halt the initial stage of naive T cell activation in the lymph nodes and results in decreased T cell responses.14Anti-CTLA-4 antibodies are designed to block CTLA-4 binding and prevent the inhibition of T cell function.
A notable example is ipilimumab, which was approved by the U.S. Food and Drug Administration (FDA) in 2010 for the treatment of advanced melanoma.8
PD-1 has emerged as a promising target that is capable of inducing antitumor immune responses. In contrast to CTLA-4, it is more broadly expressed and functions to limit the activity of T cells in peripheral tissues at the time of an inflammatory response to minimize potential autoimmunity.15, 16, 17
PD-1 is highly expressed on regulatory T (Treg) cells;18 therefore, blockade of the PD-1 pathway may enhance antitumor immune responses by diminishing the number and/or suppressive activity of intratumoral Treg cells.19
PD-L1 and -L2 are the main ligands for PD-1.
High expression levels of PD-L1 are reported in most melanoma, ovarian, and lung cancer samples.9
Additionally, PD-L1 is commonly expressed on myeloid cells in the tumor microenvironment,20 suggesting that PD-L1 is adaptively induced as a consequence of immune responses within the tumor microenvironment.
Multiple anti-PD-1 and anti-PD-L1 agents have been developed in recent years. For instance, pembrolizumab was the first PD-1 inhibitor approved by the FDA in 2014 for the treatment of melanoma.21
It was later approved in combination with nivolumab for the treatment of metastatic non-small-cell lung cancer and head and neck squamous cell carcinoma.22
Also, atezolizumab is a fully humanized IgG1 antibody against PD-L1 that was FDA approved in 2016 for the treatment of urothelial carcinoma and non-small-cell lung cancer. Furthermore, avelumab and durvalumab are fully humanized IgG1 antibodies that are FDA approved to treat Merkel cell carcinoma, urothelial carcinoma, and non-small-cell lung cancer (H.C. Chung et al., 2016, Am. Soc. Clin. Oncol., abstract).23
Other Immune Checkpoint Targets
Lymphocyte activation gene-3 (Lag-3) is another immune checkpoint receptor, and it is upregulated on activated CD4+/CD8+ T cells and NK cells and has a high affinity for major histocompatibility complex (MHC) class II molecules.24
Clinical trials are ongoing wherein the antibody against LAG-3 is being tested as a monotherapy or in combination with other checkpoint inhibitors.25
For instance, a soluble LAG-3Ig fusion protein was tested in patients with advanced renal cell carcinoma and was well tolerated and led to stabilization of disease in those who received higher doses of the drug in a dose-escalation study.26
TIM-3, is a member of the TIM gene family that plays a critical role in regulating immune response and is expressed on Th1 (T helper), Th17, and CD8+ T cells (Figure 3).
Interactions between TIM-3 and its ligands result in suppression of Th1 and Th17 responses and induce immune tolerance, supporting an inhibitory role of TIM-3 in T cell-mediated immune responses.10
Four relevant ligands have been shown to interact with TIM-3 including galectin-9 (Gal-9), HMGB1, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM 1), and phosphatidylserine (PS).24
In cancer patients, administration of TIM-3 antibodies increases proliferation and cytokine production by tumor-antigen-specific T cells.27
Preclinical studies with TIM-3 show that it is expressed along with PD-1 on tumor-infiltrating lymphocytes, and combination therapy targeting these two domains may augment anti-tumor responses.28
OVs are native or recombinant viruses that target cancer cells.
The viruses cause the cancerous cells to die at the end of its replication cycles through lysis or by the activation of an antitumor immune response, thus minimizing damage to normal tissues (Figure 4).29, 30
Historically, virologists have been concerned that the immune system may hamper the success of oncolytic virotherapy because of immune-mediated viral clearance, and toxicities have been noted in immune-compromised patients receiving non-engineered viruses.31, 32, 33
Although immune clearance of virus is still a concern, OVs are now recognized as efficient immune-stimulatory agents capable of activating and redirecting innate and adaptive immune responses against the tumor (Figure 5).34, 35
It is these interactions between immune cells and signaling factors (i.e., cytokines and chemokines) that are critical to the induction of antitumor immunity and thus successful immunotherapy.
Recent understanding of the mechanism of OV infection and of the resulting changes in the surrounding tumor immune microenvironment further characterizes this unique class of cancer therapeutics and underscores the importance of the field of oncolytic immunotherapy.36
The activity of an OV is a reflection of the biology of the virus from which it was derived and its host-virus interactions.
Typically, OVs fall into two classes.
The first class includes naturally replicating viruses that replicate only in cancer cells and are non-pathogenic in humans because of their sensitivity to innate antiviral immunity.
These include the parvoviruses, myxoma virus (MYXV), Reovirus, Newcastle disease virus (NDV), and Seneca Valley virus (SVV).
The second class includes those that are genetically manipulated for use as vaccines or vectors, such as poliovirus (PV), measles virus (MV), vaccinia virus (VACV), adenovirus, herpes simplex virus (HSV), and vesicular stomatitis virus (VSV).5, 37
These viruses target the tumor cells directly or indirectly, replicate and express proteins that are deemed cytotoxic to the cell’s survival,38 and/or induce anti-tumor response upon expressing key tumor epitopes.39
The specific targeting mechanism is different for different OVs and is based on the viral engineering performed,40, 41 and replication mechanisms can be controlled by using gene promoters that are activated only in tumor cells. 42
ournal information: Clinical Cancer Research
Provided by University of Surrey