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This paper explores the gene-mediated cytotoxic immunotherapy as an adjuvant to standard cancer care. It describes the mechanism for treating cancerous tissues with immunotherapy strategies. We examine its effects on the immune system of a patient. We investigate previous animal and clinical tests using the data to analyze the efficacy of the therapy. The paper focuses on prostate cancer indicating survival statistics of patients under standard cancer care and how immunotherapy will increase the chances to survive. The paper presents the gene-mediated cytotoxic immunotherapy as a successful application in combating recurrence cancer, which increases metastatic prostate cancer survival rates. We also mention Advantagenes ProstAtakTM therapy as the recent brand of immunotherapy that combats recurrent prostate cancer. The immunotherapy and standard care procedures are the core of the research on the innate and adaptive immune systems and the role of T cells in cancer treatment.

Gene-mediated cytotoxic immunotherapy

Nowadays, the most commonly available options of cancer treatment include surgery, chemotherapy, and radiation. Other treatment options are hormone therapy, stem cell transplant, and precision medicine. Most of these treatment options have adverse side effects due to their ability to affect normal healthy cells in the body. Thus, patients can still have cancer recurrence after a therapy. Moreover, treatment options also result in significant changes in genetic structures of the organism. Emerging treatment options, such as gene-mediated cytotoxic immunotherapy (GMCI), offer a targeted approach to cancer treatment with minimum damage to normal healthy cells. GMCI provides systemic protection against cancer and reduces the chances of its recurrence. Gene-mediated cytotoxic immunotherapy clinical trials are proving the therapy increases survival rates and it might become the part of standard cancer care.

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Prostate Cancer Survival and Recurrence

Cancerous tumors can occur in any organ of the body. Prostate cancer is the most common type of cancer in men. It mostly occurs in the prostate gland or nearby organs. The number of cancer survivals differs depending on the type of disease and detection stages. The survival rates for five and ten years are 98% and 95% respectively (Strauss, & Madan, 2016). Recent advancements in medicine have improved the latest statistics of cancer survival to about 100%.

Cancer recurrence rates vary due to the type of treatment, patients age, detection stage, genetics, and other external factors (Predina et al., 2011). Unfortunately, the majority of cancer survivors fear cancer recurrence because it is common for malignant cells to become resistant to treatment and to grow faster than before. Treatment options, including surgery, chemotherapy, hormone therapy, and radiotherapy, cannot guarantee future without cancer recurrence. For example, the percentage of patients who have or had the distant stage of prostate and live for five is 28%. This shows that despite the medical progress, another type of treatment is required to increase the chances of survival.

Standard Prostate Cancer Treatment

Cancer surgery involves removing the cancerous region and healthy tissue surrounding it to reduce the chance of recurrence. Radiotherapy, on the other hand, includes exposing of the cancerous regions to high doses of radiation to destroy cancerous cells or to shrink tumors. The radiation slowly kills the exposed cells or reduces their growth. It is mainly used together with other treatment options, for example, to decrease tumor size before surgery. During surgery, it affects only the intended region while after surgery, radiotherapy destroys remaining cancerous cells.

Chemotherapy involves the usage of drugs to kill cancerous cells or to slow their growth. The administered drugs travel via the bloodstream to the cancerous region where they influence the cancerous cells (Mataraza, & Gotwals, 2016). This therapy offers systemic protection against cancerous cells. However, chemotherapy affects normal healthy cells in the body reducing their growth and leading to various side effects, such as hair loss.

Immunotherapy is a treatment type that aims at assisting the immune system in fighting prostate cancer. It is a form of biological treatment mainly involving monoclonal antibodies, T cells, and cytokines (Garnett-Benson, Hodge, & Gameiro, 2015). Gene- mediated cytotoxic immunotherapy is a type of immunotherapy that uses an adenoviral vector to deliver foreign antigens. The vector resembles a vehicle delivering a foreign antigen that triggers the normal body immune response and flooding the area with disease-fighting cells and substances.

Attenuated Viruses

Viruses have been used to treat cancer since the discovery of Bacillus CalmetteGu?rin (BCG). It was primarily applied as a vaccine against tuberculosis which can also be used against bladder cancer. BCG, an attenuated bacterial vaccine, created the possibility to use attenuated organism in the treatment of cancer. Viruses that destroy cancer cells are known as oncolytic viruses. Human viruses, such as herpes simplex (HSV), have been genetically modified to provide tumor selectivity (Mataraza, & Gotwals, 2016). Therefore, an attenuated HSV attached to an adenovirus enhanced the adenovirus-mediated herpes simplex virus-thymidine gene therapy.

Cytotoxic Immunotherapy

Cytotoxic Immunotherapy involves injecting cells with a cytotoxic that makes tumor die in an unnatural way (necrosis) triggering an immune response that would not have been caused by normal death (apoptosis) (Strauss, & Madan, 2016). Necrosis of the cells provokes an immune response that is normally characterized by the immediate activation of T cells. T cells proliferation and cytokine secretion follow in the affected region.

The treatment also stimulates the creation of antigen-specific disease-fighting cells. Consequently, it boosts the immunity from any other cancerous cells in other parts of the body. It provides a vaccination against cancer development and is, therefore, useful in cancer recurrence prevention.

Therapy Procedure

The adenovirus used as a delivery vehicle is administered directly into the tumor via injection. A volume of the drug-containing adenovirus-mediated herpes simplex virus thymidine kinase (AdV-tk) is directed using imaging techniques, including ultrasound, to various locations in the tumor where it will have the maximum effect. The prodrug administration follows the AdV-tk injection. The prodrug can be administered either orally or intravenously. The consequences of AdV-tk/prodrug are still unknown requiring more tests on its impact on DNA damage and repair activities that allow maximum viral transduction.

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Animal Testing

Several tests were conducted on animals to ascertain the efficiency of GMCI. In most case, GMCI was effective among immunocompetent individuals. The models used in the study were immunocompetent mice (Strauss, & Madan, 2016). They were injected with tumor cell lines which simulated human cancer. Standard care treatment that includes surgery, radiation and chemotherapy was followed. However, available options demonstrated limited efficacy. AdV-tk/prodrug treatment was introduced as an additional way to combat cancer. The scientists focused on ganciclovir (GCV) and valacyclovir for prodrug therapy.

Results demonstrated that neoadjuvant AdV-tk/prodrug decreased post-operative cancer recurrences and increased intratumoral trafficking of CD8 T cells. GMCI treatment boosted direct cytotoxic effects and provoked flooding of CD8 T cells in the local cancerous site (Strauss, & Madan, 2016). In fact, GCMI proved to be the most successful treatment for small tumors with minimal toxicity. Besides, it can bring positive results in the cooperation with the existing treatments.

Experiments of animals had several drawbacks. The animals had slow results production, and it was challenging to induce certain cancer types. Some of them developed longer than expected. Moreover, poor access to surgical expertise and expensive housing/breeding for the animal models hindered the research process. As a result, it was challenging to monitor tumor development and to experiment with treatment.

Mechanism of Action of Cytotoxic Immunotherapy

Natural Immune System Suppresses Cancer Growth

The natural body systems destroy defective cells. However, in the cases of cancerous or non-cancerous tumor growth, the body is usually rendered unable to reduce the defective cells. The role of the immune system is visible in immunocompromised patients whose cancer grows faster comparing with immunocompetent individuals. Research indicates that tumor cells are less receptive to immune cells and produce secretions that inhibit the immune system (Strauss, & Madan, 2015). Cytotoxic immune therapy, therefore, aims at stimulating the normal immune system.

Innate Immune Response and Adaptive Immunity

The innate immunity responds immediately to the tumor, but it is not antigen-specific. The antigen-specific attack is created by the adaptive immunity that offers systematic protection (Strauss, & Madan, 2015). Antigen-specific immune cells (T cells) are stimulated with antigen presenting cells (APC), such as dendritic cells (DC) and monocytes. APCs are activated by activities associated with innate immunity response. Once T cells are stimulated, they spread making anti-tumor effects through secretions of cytokines and direct attack by cytotoxic T lymphocytes (CTL). The immune system might face the influence of several factors: Interleukin 10 (IL-10), a human cytokine synthesis inhibitory factor (CSIF), and Transforming growth factor beta (TGF-?).

Immune Cell Responses Process

During GMCI treatment, immunogenic cell death that activates the innate immune system is vital. In GMCI, the cell death or necrosis releases tumor antigens that activate the immune system response. Dendritic cells (DC) migrate and activate at the tumor area where they mature. DC maturation stimulates co-stimulatory agents and activates antigen presenting cells (APC). Normal cells death (apoptosis) does not activate the immune system as a mechanism of preventing autoimmune responses.

Dying tumor cells release antigens taken up by APCs. The antigens are present on the MHC class I and MHC class II molecules. The MHC class I molecules are responsible for the activation of the CTL stimulation in the innate system while the MHC class II molecules relate to the adaptive immunity (Aguilar et al., 2015). Antigen-specific receptors on the T cells respond to the presented antigens when co-stimulatory molecules, such as CD80, lead to T cell activation. After, T cells spread on the tumor regions. Without the co-stimulatory molecules, the immune system would not react to the tumor leading to T cells energy. Thus, cell necrosis is an essential stage of cell response process.

Activated CD4+ helps T cells produce cytokines that activate two different pathways. The first one stimulates CTL activation and secretion of cytokines, such as IL-2 and IFN?. The second path expresses IL-2 and IL-4 and stimulates B cell maturation to plasma cells that secrete antigen-specific antibodies. CD8+ CTL produced during the process increase anti-tumor immunity as the tumor antigen-specific CTL kills malignant cells in the body (Garnett-Benson, Hodge, & Gameiro, 2015). The amount of CD8+ CTL in the peripheral blood correlates with antitumor and clinical responses to the vaccines in prostate and pancreatic cancer studies.

Immunotherapy stimulates regulatory T cells (Treg) that hinder activation and functioning of other cells. Overcoming inhibitory factors related to Treg is critical in maintain immunity. In cancer patients, inhibitory factors, such as myeloid-derived suppressor cells (MDSC) and impair DC function, increase during aggravated clinical stages. It is vital for immunotherapy techniques to trigger danger signals that activate T cells through necrosis. GMCI must effectively stimulate the innate and adaptive immunity.

Cytotoxic Immunotherapy Strategies

Gene-mediated Cytotoxic Immunotherapy (GMCI) functioning

Cytotoxicity is necessary for immunotherapy to trigger the required immune system reaction that releases tumor-associated antigens (TAA) (Aguilar, Guzik, & Aguilar-Cordova, 2011). The GMCI approach consists of an adenoviral vector that contains herpes virus thymidine kinase gene delivered to the tumor and followed by systemic administration of an anti-herpetic prodrug.

AdV-tk injected directly into the tumor site causes the local expression of the herpes simplex virus (HSV) thymidine kinase (HSV-tk). Besides, the administered prodrugs are substrates of HSV-tk. The prodrugs become toxic to DNA-repairing dividing cells after the reaction with HSV-tk and cellular kinases (Aguilar, Guzik, & Aguilar-Cordova, 2011). DNA-damaging substances (chemotherapy agents or radiation) increase DNA repair activity making those cells more susceptible to the AdV-tk/prodrug reaction. The tumoricidal effect includes the surrounding cells as the activated prodrug spreads through apoptotic vesicles or GAP junctions. This effect is known as the local bystander effect.

Effects on the Immunity

The treatment is a systematic bystander effect that protects against recurrence and the spread of metastases. Immunocompromised models showed no systemic effect linking systemic anti-tumor protection to the human natural immune system (Predina et al., 2011). The animal models treated with AdV-tk and saline did not have any immune system activation. The research leads to the conclusion that AdV-tk/prodrug-induced cell death is necessary to initiate innate and adaptive immune responses.

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Stimulation of the Innate Immune System

The danger signals after the AdV-tk/prodrug treatment was important in stimulating antigen presenting cells and TLR ligands (Co-stimulatory agent), cytokines, heat shock proteins, and adhesion molecules. Drug experiments proved that the immunogenicity of the HSV-tk expressing cells relates to the predominant types of cells death (apoptosis or necrosis) after the prodrug treatment (Aguilar, Guzik, & Aguilar-Cordova, 2011). Cells that underwent necrosis were highly immunogenic while cells that underwent apoptosis were poorly immunogenic. The immunogenic tissue had higher macrophages, DC, and T cell infiltration. The HSV-tk/prodrug-treated tumors had higher infiltration rates due to the expression of adhesion molecules that mediated leukocytes adhesion and chemotaxis. The tumors expressed co-stimulatory molecules CD80 and CD86 on the APCs vital for T cell activation.

Importance of T cells in Immunotherapy

T cells are important in GMCI. Tumors from animal and human models treated with HSV-tk/ prodrug combination had higher infiltration levels of CD4+ and CD8+ T cells. The individuals showed higher levels of IL-2, IFN and GM-CSF and no inhibitory molecules, such as cytokines IL4 and IL-10 (Huang, Chen, Teh, & Butler, 2015). The research discovered that CD8+ T cells play an important role in local and systemic tumoricidal effects (Mataraza, & Gotwals, 2016). The immunotherapy was ineffective in immunocompromised patients with low level of T cells.

Adenoviral Vectors as a Delivery Vehicle

Adenovirus was the preferred choice of delivery vector because it can transduce dividing or non-dividing cells. Experiments done using retroviruses failed because of poor transduction (Huang, Chen, Teh, & Butler, 2015). Despite pre-existing immunity to adenoviruses that exist in most of the population, intratumoral delivery allows transduction to occur before immune clearance. This leads to repeated administration without added toxicity because the immune system clears the adenovirus. Animal models demonstrated improved survival rates after an average of three-course treatments of the AdV-tk/ prodrug.

Combination with Standard Cancer Treatment

GCMI brings more advantages in conjunction with other standard cancer treatments. Immunotherapy kills metastatic or residual cancer cells left after radiation, surgery, or chemotherapy (Huang, Chen, Teh, & Butler, 2015). In fact, it increases DNA repair processes that enhance AdV-tk/prodrug action after cell damage by radiotherapy or chemotherapy. Finally, it changes the bystander effect resulted from cell damage and inflammation caused by radiation or chemotherapy.

Successful Clinical Trials

Phase 1 and Phase 2 Clinical Trials

GMCI has been tested for various cancer types. Moreover, it has become a viable treatment option. Professionals resorted to this therapy to treat malignant gliomas, prostate, esophageal, pancreatic, and ovarian cancer (Wheeler et al., 2016). Results usually showed promising advantages, increased survival rates, and reduced recurrence rates in phase 1.

Phase 2 was conducted to test the safety and efficacy of AdV-tk/prodrug GMCI in combination with standard care treatment (SOC). Patients with malignant glioma received SOC + GMCI treatment while others had only SOC treatment (Wheeler et al. 2016). The AdV-tk/prodrug treatment followed the radiation treatment. During the process, the results were recorded. The prodrug comprised valacyclovir, an orally administer prodrug.

Consequently, the overall survival period of patients under the SOC +GMCI was 17.1 months while patients who had only SOC lived 13.5 months. Survival rates for one, two, and three years of SOC+ GMCI were 90%, 53%, and 32%. SOC rates were 67%, 28% and 6% respectively (Wheeler et al., 2016). Patients under GMCI treatment showed no dose-limiting toxicity. Common side effects were headaches, fever, and fatigue. The results of the trial showed that AdV-tk/prodrug immunotherapy allowed the patients with malignant gliomas to survive and to experience radiotherapy with no adverse reactions.

Phase 3 Clinical Trials

In 2011, phase 3 featuring Advantagenes ProstAtakTM was launched. ProstAtak is a branded gene-mediated cytotoxic immunotherapy designed to prevent prostate cancer recurrence (Cordes, Gulley, & Madan, 2016). It relates to the replication-defective adenoviral vector with a herpes thymidine kinase gene (AdV-tk). The therapy is designed to help patients after radiation treatment for localized prostate cancer.

The treatment induces cytotoxicity after the Adv-tk/prodrug administration. The cytotoxicity triggers cell death that occurs through necrosis and apoptosis in the tumor (Cordes, Gulley, & Madan, 2016). It also decreases vascularity and loss of glandular architecture. During the therapy, the tumor is shrinking.

The treatment has 40-50% failure risk in late stage prostate cancer, 25-35% failure risk in intermediate stage cancer, and 10% risk of early stage cancer. This means that the therapy is more effective in the early stages of prostate cancer. As a result, the average percentage of reduced recurrence rates is 10-30% (Cordes, Gulley, & Madan, 2016). It is important to note that no significant adverse effects resulting from the ProstAtak were recorded comparing with the expected influence of radiotherapy.

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The treatment protects against recurrent or metastatic cancer. The therapy triggers the innate and adaptive immune responses creating antigen-specific immune cells that enter the peripheral blood supply and circulate in the body (Cordes, Gulley, & Madan, 2016). The local bystander effect prevents the recurrence of cancer cells that survived radiotherapy. Systemic bystander effect offers whole body protection against cancer.

The treatment is administered through direct injections. The procedure requires the usage of Transrectal ultrasound (TRUS) to four strategic sites at each apical and basal points of prostate lobes (Cordes, Gulley, & Madan, 2016). The 20-22G biopsy needle delivers 0.5ml of the agent to each site. After, the prodrug (Valacyclovir) is administered orally stimulating good bio-availability.

Advantages of GMCI

GMCI improves the natural immune system. Eventually, immunity can fight and destroy cancerous cells through triggering danger signals from the local tumor sites. The therapy kills the prostate cancer cells and stimulates the spread of T cell (Aguilar, Guzik, & Aguilar-Cordova, 2011). The stimulation of both the innate and adaptive immune systems leads to the development of local and systemic immunity. The treatment can be offered with no dose-limiting toxic accumulation due to the natural immunity that clears the adenovirus from the system. Once the adenovirus has gone, the prodrug has no activating agent and leaves the system. Repeated dosages can be prescribed after immune clearance.

The treatment is localized so that the damaging effects of the cytotoxins are limited to the tumor areas. The neighboring cells near the injection sites are also affected. However, it prevents tumor recurrence. Activation of the T cells by co-stimulatory agents after the presentation of tumor-associated antigens ensures that T cells develop antigen-specific fighting characteristics. The activated T cells circulate in the system attacking tumors cells.

Gene-mediated cytotoxic immunotherapy improves survival rates through combating cancer recurrence and metastasises. GMCI increases CD8+ T cells proliferation into local tumor sites and boosts systemic immunity. The immunotherapy is more effective with the standard cancer treatments. GMCI has no adverse side effects being the best option for fighting residual cancer after standard treatments. Therefore, GMCI is the key to improving post-operative survival rates due to its local influence. However, the treatment is viable in immunocompetent individuals. It means that further research is required.

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