Adenovirus vectors:

Introduction

Adenovirus vectors have been widely used for gene transfer applications in vitro, in vivo, and in clinical trials due to their ability to infect a broad range of mammalian cell types. These vectors are based on adenoviruses, which are non-enveloped viruses with a protein capsid and a double-stranded DNA genome. Adenoviruses enter cells through attachment to the cellular receptor CAR and subsequent internalization through clathrin-mediated endocytosis.ref.21.28 ref.21.29 ref.21.29 They have a large DNA insertion capacity and can efficiently transfer genes into both dividing and non-dividing cells.ref.21.28 ref.21.29 ref.2.1

Most adenoviral vectors used are derived from serotypes 2 or 5, which are endemic in humans and cause upper respiratory tract infections. These vectors have been extensively studied and used in gene therapy, demonstrating safety and efficacy in clinical trials. However, there are limitations to using adenovirus vectors for oncolytic therapy, as they can trigger strong immune responses in humans, limit delivery and expression of exogenous genes, and cause undesired immune responses.ref.11.14 ref.11.14 ref.11.14 Further research and optimization of treatment schedules, dosages, and immunological analysis are needed to fully harness the potential of oncolytic adenoviruses.ref.11.14 ref.11.14 ref.11.14

Non-Human Adenovirus Vectors for Gene Delivery

Advancements have been made in the development of novel non-human adenovirus (NHAdV) vectors for gene delivery in humans. These vectors have shown potential as effective gene therapy vehicles due to their immunogenicity, tropism, and broad host range. NHAdV vectors have been derived from various species, including chimpanzees, bonobos, gorillas, and other animals.ref.2.1 ref.12.21 ref.12.21 They can be altered by using alternative serotypes, providing flexibility in their design.ref.2.1 ref.2.1 ref.12.21

NHAdV vectors have advantages over first-generation adenoviral vectors in terms of safety and stability of transgene expression. Unlike first-generation adenoviral vectors, NHAdV vectors do not integrate into the host genome, making them safe vectors for transient gene expression. Additionally, NHAdV vectors have shown improved stability and reduced immunogenicity compared to first-generation vectors.ref.2.34 ref.60.75 ref.63.75

However, the production of NHAdV vectors is more challenging compared to first-generation adenoviral vectors. The differences in species and serotypes require specialized techniques for vector production. Despite these challenges, NHAdV vectors are being explored for their potential use in clinical trials, and further research is needed to optimize their production and enhance their therapeutic efficacy.ref.2.34 ref.2.34 ref.2.34

Advantages of Adenovirus Vectors for Oncolytic Therapy

Adenovirus vectors offer several advantages for oncolytic therapy. They can infect and replicate in both dividing and non-dividing cells, allowing for efficient targeting of cancer cells. Adenoviral vectors also have a large insertion capacity for therapeutic transgenes, enabling the delivery of multiple therapeutic agents simultaneously.ref.11.14 ref.27.0 ref.11.14

In addition, adenovirus vectors have a lytic replication cycle, which can lead to oncolysis. This replication cycle involves the destruction of infected cells, which can be beneficial in cancer treatment. Furthermore, adenoviral vectors are easy to manipulate genetically, allowing for easy modification and production of high titers.ref.27.0 ref.11.14 ref.27.0 These advantages make adenovirus vectors an attractive option for oncolytic therapy.ref.27.0 ref.11.14 ref.11.14

Limitations of Adenovirus Vectors for Oncolytic Therapy

Despite their advantages, there are limitations to using adenovirus vectors for oncolytic therapy. Adenoviruses can trigger strong immune responses in humans, which can limit their delivery and expression of exogenous genes and cause undesired immune responses. The immunogenicity of adenoviruses can also result in immune clearance of the virus and limit their therapeutic efficacy.ref.11.14 ref.11.14 ref.11.26

Additionally, the efficacy of oncolytic adenoviruses as a single agent is modest, and their efficacy can be improved when combined with other modalities. Further research and optimization of treatment schedules, dosages, and immunological analysis are needed to fully harness the potential of oncolytic adenoviruses. By addressing these limitations, the therapeutic efficacy of adenovirus vectors for oncolytic therapy can be enhanced.ref.27.0 ref.27.0 ref.27.0

Strategies to Enhance Specificity and Efficacy of Adenovirus Vectors in Targeting Cancer Cells

Adenovirus vectors can be modified and engineered to enhance their specificity and efficacy in targeting cancer cells. One approach is to modify the viral fiber protein, such as through knob modifications or the insertion of the Ad3 fiber into Ad5. These modifications improve the affinity and binding of the virus to cancer cells, increasing the specificity of the vector.ref.24.4 ref.24.4 ref.24.4

Another strategy is to use antibody fusion constructs, where two antibodies are used to target both adenovirus capsid proteins and specific membrane receptors on tumor cells. This results in improved selectivity and higher affinity of the virus to tumor cells. Complementation deletions can also be employed, where mutations are introduced in viral genes that are vital for replication in normal cells but are complemented by altered cell cycle regulation in tumor cells.ref.29.17 ref.29.16 ref.29.16 This allows for selective replication of the virus in cancer cells.ref.29.16 ref.29.17 ref.29.16

Directed evolution techniques can also be used to screen adenoviruses with improved selectivity for tumor cells and oncolytic activity. By subjecting the viral vectors to iterative rounds of mutation and selection, adenoviruses with enhanced tumor cell specificity and oncolytic activity can be obtained.ref.27.0 ref.27.0 ref.27.0

Furthermore, viral vectors can be engineered to deliver and encode transgenes that act as "suicide-genetic switches" for controlled lysis of target cancer cells or to enhance or direct antitumor immune responses. These modifications and strategies aim to improve the specificity and efficacy of adenovirus vectors in targeting and killing cancer cells, making them more effective as oncolytic therapy agents.ref.11.14 ref.11.14 ref.11.14

Conclusion

Adenovirus vectors have been widely used for gene transfer applications and have shown promise in oncolytic therapy. The development of novel non-human adenovirus vectors has expanded the options for gene delivery in humans, with potential advantages in terms of safety and stability of transgene expression. However, the immunogenicity of adenoviruses and their modest efficacy as single agents in oncolytic therapy present challenges that need to be addressed.ref.11.14 ref.11.14 ref.11.14

Modifying adenovirus vectors to enhance their specificity and efficacy in targeting cancer cells offers potential solutions to these challenges. Strategies such as modifying the viral fiber protein, using antibody fusion constructs, employing complementation deletions, and utilizing directed evolution techniques can improve the selectivity and oncolytic activity of adenovirus vectors. Additionally, engineering viral vectors to deliver transgenes that enhance or direct antitumor immune responses can further enhance the therapeutic efficacy of adenovirus vectors in oncolytic therapy.ref.11.26 ref.11.26 ref.11.26

Further research and optimization of these strategies, as well as additional studies on treatment schedules, dosages, and immunological analysis, will contribute to the advancement of adenovirus vectors as effective oncolytic therapy agents. With continued efforts and improvements, adenovirus vectors have the potential to play a significant role in the treatment of cancer.ref.27.0 ref.27.0 ref.27.0

Oncolytic therapy:

Introduction to Oncolytic Therapy

Oncolytic therapy is a type of cancer treatment that utilizes oncolytic viruses to selectively infect and kill cancer cells while sparing normal cells. These viruses are genetically modified to enhance tumor targeting and replication in tumor cells. Oncolytic therapy differs from other cancer treatments, such as chemotherapy and radiation therapy, in several ways.ref.27.1 ref.27.1 ref.27.1

Targeted Approach of Oncolytic Therapy

Firstly, oncolytic therapy specifically targets cancer cells, whereas chemotherapy and radiation therapy can also affect healthy cells. This targeted approach aims to minimize off-target toxicity and reduce side effects. By selectively infecting and killing cancer cells, oncolytic therapy can minimize damage to healthy tissues.ref.38.31 ref.38.31 ref.38.31

Immune Response Induction

Secondly, oncolytic therapy has the potential to induce an immune response against the tumor. The replication of oncolytic viruses in cancer cells can lead to the release of tumor-specific antigens, which can stimulate an immune response and potentially enhance the body's ability to fight the cancer. This immune response can have a systemic effect and may help to prevent the recurrence of cancer cells.ref.19.30 ref.19.28 ref.11.25

Combination Therapy

Thirdly, oncolytic therapy can be combined with other cancer treatments, such as chemotherapy, radiotherapy, and immunotherapy. These combinations aim to enhance the overall effectiveness of the treatment and potentially overcome resistance to conventional therapies. By combining different treatment modalities, oncolytic therapy can target cancer cells through multiple mechanisms, increasing the chances of success.ref.35.2 ref.16.2 ref.35.18

Ongoing Clinical Trials

It is important to note that oncolytic therapy is still an emerging field, and clinical trials are ongoing to evaluate its safety and efficacy in different cancer types. These trials are crucial in determining the optimal use of oncolytic therapy and identifying any potential limitations or challenges. Further research and development are needed to optimize the delivery and effectiveness of oncolytic therapy.ref.28.140 ref.63.140 ref.60.140

Mechanisms of Selective Targeting and Killing of Cancer Cells

The mechanisms by which oncolytic viruses selectively target and kill cancer cells involve their target specificity and cytolytic capacity. Oncolytic viruses are defined by their ability to specifically kill tumor cells while leaving normal tissues unharmed. They exhibit features such as high reproductive capacity in vivo, the ability to infect both dividing and nondividing cells, and stability in vivo.ref.29.3 ref.29.3 ref.29.3

Viral entry into cells is a crucial step in the infection process and is dependent on the specific interaction between viral attachment proteins and cellular receptors. Some viruses have a natural preference for replication in tumor cells, while others require modification of their tropism to specifically enter and replicate in tumor cells. Various strategies can be employed to achieve this specific targeting, including transductional targeting strategies.ref.23.17 ref.11.6 ref.16.7 These strategies involve incorporating new targeting specificity into viral surface proteins, incorporating a scaffold into viral surface proteins to allow the attachment of targeting moieties, or using bispecific adapters to mediate targeting of a virus to a specified moiety on a tumor cell.ref.16.7 ref.16.7 ref.11.6

Challenges Associated with Oncolytic Therapy

The challenges associated with oncolytic therapy include the availability of suitable target receptors on tumor cells, the unspecific uptake of the virus by certain organs or tissues, and the need for improved safety and efficacy. The potential side effects of oncolytic therapy can include dose limiting toxicity, off-target effects, and acquired resistance due to incomplete tumor mitigation.ref.11.26 ref.63.140 ref.60.140

Additionally, the efficacy of systemic administration is limited by the presence of circulating antibodies and the difficulty of achieving infiltration of dense tumor extracellular matrices. The heterogeneity of tumor gene mutations also poses a challenge for direct targeting. Furthermore, the engineering of viruses for oncolytic therapy is complex and requires significant investment in biosafety measures and equipment.ref.11.26 ref.77.79 ref.77.79

Future Prospects of Oncolytic Therapy

Despite these challenges, oncolytic viruses show promise as drug delivery modalities and may find utility in gene modification oncotherapeutic delivery. Ongoing technological advances and the potential for further development in the next decade offer hope for the future of oncolytic therapy. Continued research and innovation are crucial in overcoming the challenges associated with oncolytic therapy and realizing its full potential.ref.11.26 ref.11.26 ref.11.26

Recent Advancements and Future Prospects in Clinical Settings

In recent years, onco-virotherapy has been studied extensively in clinical settings, with a focus on evaluating clinical outcomes and immunological responses. Clinical outcomes studied after onco-virotherapy include overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), dose-limiting toxicity (DLT), and maximum tolerated dose (MTD). These outcomes provide valuable information on the effectiveness of oncolytic therapy in improving patient outcomes.ref.74.21 ref.74.21 ref.74.21

Immunological outcomes studied in onco-virotherapy include immune response, T-cell activation, cytokine production, and tumor-infiltrating lymphocytes. Understanding the immunological responses induced by oncolytic therapy is crucial in determining its mechanism of action and potential for enhancing the body's immune system in fighting cancer.ref.19.30 ref.19.28 ref.19.26

Control groups commonly assessed in comparison to onco-virotherapy include standard of care, placebo, and other treatment modalities. Comparing the outcomes of onco-virotherapy to these control groups helps to evaluate its effectiveness and determine its role in the current treatment landscape.ref.74.21 ref.74.21 ref.74.21

Onco-virotherapy has shown significant improvement in clinical outcomes compared to respective control groups. These improvements include improved overall survival, progression-free survival, and objective response rate. The success of onco-virotherapy in improving patient outcomes highlights its potential as a valuable addition to cancer treatment options.ref.74.21 ref.74.21 ref.74.21

To date, over 2,000 cancer patients have been recruited and treated with onco-virotherapy. Phase I/II trials have mostly been conducted in a relatively small group of patients, while phase III trials have involved more than 200 patients per group. Onco-virotherapy has been administered as a monotherapy and occasionally in combination with chemotherapy, radiotherapy, or targeted therapy.ref.74.21 ref.74.21 ref.74.21 The use of combination therapies aims to maximize the therapeutic effect and overcome potential resistance to treatment.ref.74.3 ref.74.21 ref.74.21

To improve safety and efficacy, genetic modifications have been performed on viral vectors used in onco-virotherapy. Adenoviruses, herpes viruses, vaccinia viruses, and reoviruses have been engineered to enhance tumor-specific replication and improve tumor specificity. Combination therapies with immunotherapeutics, such as checkpoint inhibitors, have also been explored to harness the immune system's potential in fighting cancer.ref.11.14 ref.11.26 ref.11.14

However, oncolytic therapy still faces challenges that need to be addressed. These challenges include limited systemic delivery capacity, acquired resistance due to incomplete tumor mitigation, patient-specific tumor gene mutations, limited applicability of broadly applicable targets, high costs of combination therapies, cumbersome engineering of viruses, and limited reporting of negative trial results. Overcoming these challenges will be crucial in advancing oncolytic therapy and realizing its full potential.ref.77.79 ref.28.140 ref.11.26

In conclusion, oncolytic therapy is a promising approach to cancer treatment that selectively targets and kills cancer cells while sparing normal cells. It has the potential to induce an immune response against the tumor and can be combined with other treatment modalities to enhance effectiveness. Ongoing clinical trials are evaluating the safety and efficacy of oncolytic therapy in different cancer types.ref.19.30 ref.19.30 ref.19.30 Despite challenges, recent advancements and future prospects in oncolytic therapy offer hope for improving patient outcomes. Continued research and development are needed to optimize the delivery and effectiveness of oncolytic therapy and overcome the challenges associated with its implementation.ref.19.30 ref.19.30 ref.19.30

Adenovirus vector delivery systems:

Methods of delivering adenovirus vectors to tumor sites

Adenovirus vectors have been widely used for in vivo gene therapy and have shown promise as a method for delivering therapeutic genes to tumor sites. There are several methods of delivering adenovirus vectors to tumor sites, including intratumoral injection and systemic administration.ref.11.14 ref.11.14 ref.61.11

One method of delivering adenovirus vectors to tumor sites is through intratumoral injection, where the adenovirus vector is directly injected into the tumor site. This method allows for direct delivery of the vector to the tumor cells, bypassing the need for systemic circulation. Adenovirus vectors have the advantage of being able to transduce both dividing and non-dividing cells, making them an effective choice for intratumoral injection.ref.11.14 ref.11.14 ref.11.14 This method has been used in human cancer treatment, particularly for cancer gene therapy strategies based on intratumoral injection.ref.11.14 ref.11.14 ref.11.14

Another method of delivering adenovirus vectors to tumor sites is through systemic administration, where the adenovirus vector is delivered to the tumor site through the bloodstream. This method allows for wider distribution of the vector throughout the body, potentially targeting metastatic tumors as well. Adenovirus vectors can be modified to improve their targeting ability and restrict viral replication to tumor cells, enhancing their tumor selectivity and oncolytic activity.ref.11.14 ref.11.14 ref.11.14 Additionally, adenovirus vectors can be armed with cancer-specific apoptosis genes to induce tumor cell death. Systemic administration of adenovirus vectors has shown promising outcomes in clinical trials for the treatment of various types of cancer.ref.11.14 ref.11.14 ref.11.14

Strategies to improve the delivery efficiency and tumor specificity of adenovirus vectors

While adenovirus vectors offer a versatile and effective method for delivering therapeutic genes to tumor sites, there are strategies that can be employed to improve their delivery efficiency and tumor specificity.ref.11.14 ref.62.0 ref.62.0

One approach to improve the delivery efficiency and tumor specificity of adenovirus vectors is to modify the surface epitopes of the virus capsid or mask the virus with synthetic polymers. By doing so, the vectors can bypass the body's immune defenses and reduce the risk of immune responses against the vector. This can improve the vector's ability to reach the tumor site and deliver the therapeutic genes effectively.ref.45.14 ref.45.14 ref.45.14

Another strategy to improve the delivery efficiency and tumor specificity of adenovirus vectors is to use helper-dependent adenoviral vectors (HDAdVs). HDAdVs lack all viral coding sequences, resulting in reduced toxicity and immunogenicity. This can enhance the safety profile of the vectors and reduce the risk of immune responses against the vector.ref.2.34 ref.2.34 ref.2.34 HDAdVs have shown promise in preclinical studies and are being explored for their potential in clinical applications.ref.2.34 ref.2.34 ref.2.34

Directed evolution techniques have been implemented to screen adenoviruses with improved selectivity for tumor cells. By subjecting adenovirus libraries to selection pressures that favor tumor cell binding and transduction, researchers can identify adenoviruses with enhanced tumor specificity. These selected adenoviruses can then be further engineered and optimized for their therapeutic potential.ref.29.17 ref.77.14 ref.29.17

Adenoviral vectors can be engineered to deliver and encode transgenes that act as "suicide-genetic switches" for controlled lysis of target cancer cells. These transgenes can be designed to induce cell death specifically in tumor cells, while sparing normal cells. This approach allows for targeted destruction of tumor cells, improving the specificity and efficacy of adenoviral vector-based therapies.ref.62.0 ref.11.14 ref.11.23

Viral vectors can be modified to enhance or direct antitumor immune responses by incorporating genes that enhance immune responses or encode tumor-specific antigens. By doing so, the vectors can stimulate the immune system to recognize and attack tumor cells, leading to a more robust and targeted antitumor response. This approach has the potential to enhance the overall efficacy of adenoviral vector-based therapies.ref.11.14 ref.11.14 ref.69.4

Challenges and potential solutions for overcoming immune responses to adenovirus vectors

While adenovirus vectors have shown promise as a method for delivering therapeutic genes to tumor sites, there are challenges associated with immune responses against the vectors that need to be addressed.ref.11.14 ref.68.34 ref.11.14

A high intravenous dose of the vector can overwhelm the innate immune mediators, leading to a systemic cytokine shock. This has been observed in a clinical gene therapy trial where a patient died as a result. One potential solution is to explore alternative routes or ex vivo transgene delivery methods to avoid systemic administration.ref.42.0 ref.17.9 ref.42.0 However, certain applications may still require systemic delivery. Additionally, genetic changes in the vector design, such as retaining genes located in the E3 region, have shown prolonged transgene expression and immune evasion capabilities. Further research is needed to optimize the delivery methods and vector design to minimize innate immunity-associated toxicity.ref.42.0 ref.45.15 ref.21.36

Constraints in genetic design have also contributed to immune responses against adenovirus vectors. In order to make the vectors biologically safer and accommodate larger foreign DNA inserts, certain immune-evasive countermeasures encoded by proteins transcribed from the viral E1, E3, and E4 regions have been crippled. However, studies have shown that vectors expressing genes located in the E3 region can escape immune eradication and demonstrate prolonged transgene expression.ref.21.29 ref.21.29 ref.21.29 This suggests that careful consideration of the genetic design of adenovirus vectors can help overcome immune responses.ref.21.29 ref.21.29 ref.21.29

The injection of adenovirus can activate both innate and adaptive immune responses against the virus itself. This immunogenicity is considered one of the major limitations for the in vivo use of adenoviral vectors. The innate immune response involves the activation of Toll-like receptors and the production of type I interferons and inflammatory cytokines.ref.2.4 ref.17.9 ref.59.6 Natural killer cells are also activated, and complement opsonization contributes to viral clearance. Pre-existing antibodies against adenovirus can further contribute to inflammation and immune responses. Strategies to mitigate immunogenicity include using low seroprevalent adenovirus serotypes, detargeting the vectors from professional antigen-presenting cells, and designing miRNA binding sites to silence transgene expression.ref.2.4 ref.59.6 ref.17.9 These approaches aim to reduce the immune response against adenoviral vectors and improve their safety and efficacy in gene therapy and vaccine applications.ref.2.4 ref.17.9 ref.2.4

Current status of clinical trials involving adenovirus vectors for oncolytic therapy

Adenovirus vectors have been extensively studied for gene therapy and as anticancer agents, and they have shown promising outcomes in clinical trials. Adenovirus vectors have been used in clinical trials for the treatment of various types of cancer, including melanoma, prostate cancer, non-small-cell lung cancer, bladder cancer, ovarian cancer, head and neck cancer, hepatocellular carcinoma, colon cancer liver metastases, and more. The use of adenoviral vectors in clinical trials has demonstrated safety and efficacy, and they have been shown to be highly efficient at in vivo gene delivery.ref.11.14 ref.11.14 ref.11.14 Adenovirus vectors have been used in combination with other modalities, such as immune checkpoint inhibitors, to improve their efficacy. The development and optimization of treatment schedules, dosages, and immunological analysis are ongoing challenges in the field of oncolytic adenoviruses. Overall, oncolytic adenoviruses have entered clinical use and have shown promise as a therapeutic approach for cancer treatment.ref.27.0 ref.11.14 ref.11.14

In conclusion, adenovirus vectors offer a versatile and effective method for delivering therapeutic genes to tumor sites. Intratumoral injection and systemic administration are two methods of delivering adenovirus vectors to tumor sites. Strategies to improve the delivery efficiency and tumor specificity of adenovirus vectors include modifying the virus surface, using helper-dependent adenoviral vectors, directed evolution techniques, engineering adenoviral vectors as "suicide-genetic switches," and modifying viral vectors to enhance or direct antitumor immune responses.ref.11.14 ref.11.14 ref.11.14 Challenges associated with immune responses to adenovirus vectors include innate immunity-associated toxicity, constraints in genetic design, and immunogenicity. Potential solutions for overcoming these challenges include exploring alternative routes or ex vivo transgene delivery methods, retaining genes located in the E3 region, and mitigating immunogenicity through the use of low seroprevalent serotypes and detargeting strategies. Adenovirus vectors have shown promise in clinical trials for oncolytic therapy and have been used in combination with other modalities to improve their efficacy.ref.11.14 ref.11.14 ref.11.14 Further research and development are needed to optimize the use of adenovirus vectors in gene therapy and vaccine applications.ref.11.14 ref.11.14 ref.11.14

Safety and efficacy of adenovirus vectors in clinical applications:

Safety Concerns with Adenovirus Vectors in Humans

Adenovirus vectors have shown promise in gene therapy applications due to their ability to efficiently deliver therapeutic genes to target cells. However, their use in humans raises several safety concerns that need to be carefully evaluated before proceeding to clinical trials.ref.68.34 ref.68.34 ref.68.34

One of the main safety concerns is the potential for infection with the same adenoviruses as monkeys. Adenoviruses are common pathogens in monkeys, and there is a possibility of zoonotic transmission to humans. Therefore, it is crucial to thoroughly evaluate newer adenovirus vectors for patient safety in human-like animal models before advancing to clinical trials.ref.28.136 ref.21.29 ref.63.79

Another safety concern is the pre-existing humoral and cellular immunity in humans that may limit gene transfer efficiency and result in immune responses against the vector and transgene product. Many individuals have been exposed to adenoviruses in the environment, leading to the development of immunity. This pre-existing immunity can neutralize the vector before it reaches the target cells, reducing the efficacy of gene transfer and potentially triggering immune responses against the vector and transgene product.ref.68.34 ref.21.29 ref.21.29

Severe immune responses can have serious consequences in humans, including systemic inflammation, organ damage, and even death. Therefore, it is essential to carefully monitor and evaluate the immune responses induced by adenovirus vectors in clinical trials to ensure patient safety.ref.45.15 ref.17.9 ref.45.16

Additionally, the potential for homologous recombination between wildtype adenoviruses and recombinant adenoviruses is a concern. This recombination could lead to the generation of new wildtype adenoviruses with expanded tissue tropism, potentially increasing the risk of unintended effects and altering the safety profile of the vectors.ref.60.79 ref.28.79 ref.63.79

Furthermore, shedding of adenoviruses from injection sites and patient excretions has been observed in several clinical trials. This shedding can pose a risk to individuals in close contact with the patients, such as healthcare providers and family members. Therefore, it is crucial to implement appropriate safety measures to minimize the risk of viral transmission during clinical trials.ref.28.79 ref.60.79 ref.63.79

In summary, the safety concerns associated with adenovirus vectors in humans include the possibility of infection with monkey adenoviruses, pre-existing humoral and cellular immunity, severe immune responses, potential for homologous recombination, and viral shedding. Thorough evaluation in human-like animal models and careful monitoring of immune responses and viral shedding in clinical trials are essential to ensure patient safety.ref.28.79 ref.60.79 ref.60.79

Clinical Trials of Adenovirus Vectors for Oncolytic Therapy

Adenovirus vectors have been extensively tested in clinical trials for oncolytic therapy, with promising results. These trials aim to evaluate the therapeutic efficacy and outcomes of adenovirus vectors in treating various types and stages of cancer.ref.27.0 ref.27.0 ref.27.0

The efficacy of oncolytic adenoviruses can be improved through vector design, delivery techniques, and ancillary treatment. Adenovirus vectors have been shown to be safe, with no serious adverse effects reported even at high doses. However, their efficacy as a single agent has been modest.ref.27.0 ref.27.0 ref.27.0 To enhance their anti-tumor effects, adenovirus vectors are often combined with other modalities, such as chemotherapy, radiation therapy, or immunotherapy. These combination approaches have shown improved efficacy in preclinical and clinical studies.ref.27.0 ref.27.0 ref.27.0

Clinical trials of adenovirus vectors for oncolytic therapy have successfully recruited patients of different ages, sexes, and tumor types and stages. The vectors have been modified to improve tumor specificity and introduce therapeutic transgenes, such as cytokines or immune checkpoint inhibitors. Different routes of administration, including intratumoral, intravenous, subcutaneous, and intramuscular, have been tested to achieve better biodistribution and target distant metastatic sites.ref.61.11 ref.45.14 ref.45.14

Multiple virus injections have been preferred in clinical trials, and the number of injections varies from daily to monthly intervals. This repeated dosing strategy aims to maintain therapeutic virus levels in the tumor, overcome immune clearance, and allow for the oncolytic activity to effectively eradicate cancer cells.ref.60.141 ref.28.141 ref.63.141

The clinical outcomes related to safety and efficacy are evaluated through various measures, including overall survival, tumor size change, and assessment of clinical responses. Overall survival is a crucial endpoint in determining the long-term efficacy of oncolytic adenovirus therapy. Tumor size change is often measured through imaging techniques, such as computed tomography (CT) or magnetic resonance imaging (MRI).ref.14.16 ref.14.16 ref.14.16 Clinical responses, such as the reduction in cancer-related symptoms or improvement in quality of life, are also important indicators of therapeutic efficacy.ref.14.16 ref.14.16 ref.14.16

The success of oncolytic adenoviruses in clinical trials has led to their approval for the treatment of certain cancers. For example, talimogene laherparepvec (T-VEC), an oncolytic adenovirus, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced melanoma.ref.27.0 ref.27.0 ref.27.0

The field of oncolytic adenoviruses is rapidly advancing, and future clinical trials are expected to feature these vectors. Ongoing research focuses on further optimizing vector design, delivery strategies, and combination approaches to enhance the safety and efficacy of adenovirus vectors in oncolytic therapy.ref.27.0 ref.27.0 ref.27.0

Strategies to Enhance the Safety Profile of Adenovirus Vectors

To address the safety concerns associated with adenovirus vectors, several strategies have been developed to enhance their safety profile in clinical applications.ref.21.29 ref.60.125 ref.63.125

One strategy is the development of conditionally replicative adenoviruses (CRAds). CRAds are designed to exhibit tumor-specific amplification, resulting in the selective lysis of cancer cells. This tumor-specific replication can minimize the off-target effects and reduce the potential for viral dissemination to healthy tissues.ref.60.76 ref.28.76 ref.63.76 By restricting viral replication to tumor cells, CRAds aim to improve the safety profile of adenovirus vectors.ref.60.76 ref.28.76 ref.63.76

Conditionally replicative adenoviruses (CRAds) achieve tumor-specific replication through various mechanisms and genetic modifications. One approach is the deletion of the E1B sequence, specifically the E1B-55K protein, which allows viral genome replication in cancer cells lacking p53, leading to cancer cell killing and reducing the number of administrations needed for effective treatment. Another approach is the use of cancer or tissue-specific promoters to limit the expression of essential early HAdV genes to specific cells and/or tissues.ref.28.76 ref.60.76 ref.63.76 Additionally, modifications to the viral coat, such as incorporating a partial peptide sequence from fibronectin containing an RGD-4C motif, enhance the affinity and therapeutic effects of CRAds in CAR-negative cancer cells. Chimeric viruses, created by inserting the fiber from one adenovirus serotype into another, have also been used to broaden the transduction range of host cells. Furthermore, retargeting strategies have been employed to permit CAR-independent infection and circumvent existing humoral immunity for HAdV-5.ref.28.76 ref.60.76 ref.63.76

However, there are potential challenges and limitations associated with the use of CRAds. Off-target toxicity, particularly transduction of the liver, is a serious concern even when CRAds are blinded for CAR. This can be attributed to blood factors opsonization of CRAd virions for Kupffer cell uptake, which can be counteracted by ablating the fiber region that interacts with these blood factors or by reducing liver sequestration through hexon mutations or complete exchange of hexons.ref.28.76 ref.60.76 ref.63.76 Other strategies to enhance safety include PEGylation or polymer/dendrimer coating of CRAd virions, as well as cell-based or magnetic/liposomal nanoparticle delivery techniques. Additionally, the low expression of CAR in tumor cells can limit the efficacy of CRAds, leading to the exploration of retargeting strategies and the use of alternative receptors such as CD46 and CD80/CD86.ref.28.76 ref.60.76 ref.63.76

Another strategy is to minimize the viral gene content in adenovirus vectors. This reduction in viral gene content decreases the immunogenicity of the vectors, reducing the potential for immune responses against the vector and transgene product. By minimizing the viral gene content, the focus can be shifted towards expressing therapeutic transgenes that target cancer cells or modulate the tumor microenvironment.ref.11.14 ref.11.14 ref.62.0

Retargeting the tropism of adenovirus vectors is another approach to enhance their safety profile. This can be achieved through modifications to the surface epitopes of the virus capsid or masking the virus with synthetic polymers. These modifications aim to bypass immune defenses and redirect the vector towards specific receptors on cancer cells, improving the specificity and reducing the potential for off-target effects.ref.45.14 ref.45.14 ref.45.14

In summary, strategies to enhance the safety profile of adenovirus vectors include the development of CRAds, minimizing the viral gene content, retargeting the vector tropism, and masking the virus with synthetic polymers. These strategies aim to improve the safety and efficacy of adenovirus vectors in clinical applications, particularly in oncolytic therapy.ref.21.29 ref.28.77 ref.60.77

In conclusion, the safety concerns associated with adenovirus vectors in humans necessitate thorough evaluation in human-like animal models and careful monitoring in clinical trials. Despite these concerns, adenovirus vectors have shown promise in oncolytic therapy, and their efficacy can be further improved through vector design, delivery techniques, and combination approaches. Strategies to enhance the safety profile of adenovirus vectors, such as the development of CRAds and retargeting the vector tropism, are being explored.ref.60.136 ref.63.136 ref.28.136 With further advancements and optimization, adenovirus vectors hold great potential for the treatment of various cancers.ref.27.0 ref.60.136 ref.63.136

Works Cited