Authors: Ava DeSanti, Josephine Grouette, Jordana Rosenberg, and Thelma Salinas
Mentor: Fiona Hartley. Fiona is currently a doctoral student in the Department of Oncology at the University of Oxford.
Abstract
Gene therapy involves the manipulation of genetic material to rectify abnormal cellular processes, providing a selective and direct approach to targeting cancer cells. There are several types of gene therapy which aim to reduce cancer progression. Tumor suppressor gene therapy focuses on reinstating the function of genes which naturally suppress tumor development. The inhibition of oncogenes, genes which foster uncontrolled cell growth, can impede cancer progression. Furthermore, inhibition of angiogenesis disrupts formation of blood vessels that sustain tumors. Oncolytic viruses individually infect and destroy cancer cells while CAR-T cell therapies focus on enhancing patients' immune systems to specifically target and eliminate cancer cells.
The significance of gene therapy lies in its potential to revolutionize cancer treatment and drive personalized therapies. CAR-T cell therapy leverages the immune system for precise targeting, inhibiting oncogenes halts cancer at its genetic roots, tumor suppressor gene therapy reinforces the body’s natural defenses, and oncolytic viruses offer innovative strategies to eliminate tumors. Collectively, these methods hold promise for more effective and successful targeted therapeutic interventions to be. Gene therapies directly target cancer cells, sparing healthy tissue, and therefore reduce common adverse side effects to cancer therapies such as nausea, hair loss, and damage to the immune system. This offers a more targeted and tolerable approach to cancer treatment. Ongoing research aims to integrate gene therapies with traditional cancer treatments for prevention and early intervention, leading to improved patient outcomes. This review aims to evaluate the current state of research in the field of gene therapy for cancer.
Introduction
Cancer is currently the second leading cause of death globally, accounting for 1 in 6 deaths around the world (National Cancer Institute, 2020). It is a complex disease characterized by the uncontrolled division and growth of abnormal cells within the body. Cancer involves a myriad of genetic alterations and mutations which collectively contribute to the dysregulation of normal cellular processes, resulting in the formation of malignant tumors. Cancer's ability to adapt and resist traditional treatment methods pose challenges in the development of effective therapeutic interventions, but the number of people it continues to impact presents a significant reason as to why more research should be dedicated to exploring innovative therapeutic approaches.
Today conventional cancer therapies include surgery, chemotherapy, and radiotherapy, which have been the cancer treatment cornerstone for decades. These methods have shown efficacy in many cases, but their limitations appear increasingly apparent. For example, surgery is constrained by the location, accessibility, size of the tumors, along with the necessary invasiveness, posing great challenges for a variety of patients. Chemotherapy, due to its systemic approach, leads to tremendous and severe side effects caused by its impact on rapidly dividing normal cells. Furthermore, radiotherapy, though effective to individually target tumors, can cause collateral damage to the surrounding healthy tissues. As the shortcomings of these conventional therapies become more evident, the exploration of gene therapy offers a promising avenue for overcoming the complexities of cancer and enhancing treatment outcomes.
Gene therapy involves introducing genetic material or genetically modifying a patient’s cells to treat or alleviate a disease. This can be achieved by delivering genetic material using a carrier called a vector. These genes, gene segments, or oligonucleotides can be delivered using two main approaches: in vivo and ex vivo. In the in vivo approach, the cells are modified inside the body. The vector may be delivered intravenously, injected directly into a metastatic nodule, or using intravesical therapy for superficial bladder cancer (Amer, 2014). In the ex vivo approach, blood is removed from the patient, where immune cells are extracted to then genetically modified to directly target and attack specific cancerous cells.
As the goal of gene therapy is to correct the underlying cause of a disease at the genetic level, gene delivery therapy for cancer focuses on manipulating the activity of tumor suppressor genes or inhibiting oncogenes within tumors. Tumor suppressor genes act as barriers against abnormal cell growth preventing the formation of tumors and the progression of cancer. In gene therapy, the aim is to replace the natural function of tumor suppressor genes which has been lost through cancer causing mutations, thus enhancing the cell’s ability to regulate and control cell division and inhibiting the progression of cancerous cells (Cesur-Ergün & Demi-Dora, 2023). Conversely, oncogenes are mutated genes that carry the potential to cause cancer by initiating the cell to divide and multiply (proliferate) uncontrollably allowing cell growth to go unchecked. The objective of gene delivery therapy is to inhibit the activity of these oncogenes through delivery of inhibitory genetic material to halt their cancer-promoting effects (Cesur-Ergün & Demi-Dora, 2023).
Cancer gene therapy also encompasses oncolytic viruses, viruses which specifically infect and destroy cancer cells. Additionally, cells from a patient’s own immune system can be modified and enhanced through gene therapy to recognize and destroy cancer cells within their body (Cesur-Ergün & Demi-Dora, 2023).
In this review, we will evaluate the current state of research and advancement in the field of gene therapy for cancer. The scope of the review encompasses analyzing the different approaches and techniques used in gene therapy, assessing the safety and efficacy of gene therapy treatments, and discussing the potential challenges and prospects of this therapeutic approach. The review aims to provide a comprehensive understanding of the current landscape of gene therapy and its potential impact on medical treatments.
Figure 1: A comprehensive overview of the diverse gene therapy strategies in cancer treatment. This figure displays the versatility of gene therapy technologies in cancer treatment, highlights suicide gene therapy, tumor suppressor gene activation, immunotherapy using CAR-T cells, and inhibition of both oncogenes and angiogenesis. Figure reproduced from Cesur-Ergün & Demi-Dora (2023).
Literature Review
Vectors Used in Gene Therapy
Gene therapy for cancer utilizes various vectors, each with unique characteristics. Viral vectors, such as retroviruses, lentiviruses, and adenoviruses, are frequently used because they infect cells and deliver genetic material (Bezeljak, 2022). Both retroviruses and lentiviruses integrate their genetic material into the host's genome, providing long-term and stable expression of therapeutic genes (Bezeljak, 2022). Both have gained considerable attention in ex vivo gene therapy applications for cancer such as the modification of T cells to create chimeric antigen receptor T cells (CAR-T cells). Retroviruses and lentiviruses are utilized as vectors to deliver therapeutic genes into the T cells, providing them with targeting capabilities against cancer cells (Bezeljak, 2022). The success of CAR-T cell therapy is seen through the stable integration of genetic material into the host cell allowing for effective and sustained expression of the modified genes. On the other hand, other vectors such as adenoviruses have been engineered to deliver genes to specific cells, but they do not integrate into the host genome, so gene expression is transient (Bezeljak, 2022). Non-viral vectors are considered safer alternatives to viruses but display a lower efficiency towards gene delivery; examples include liposomes and nanoparticles (Dalal et al., 2018). Ultimately, selecting a vector depends on the target cell characteristics and overall therapeutic goals, necessitating a balance between safety and efficiency (Dalal et al., 2018).
In gene therapy, viruses are engineered to transport therapeutic genes to specific target cells. In order to enter the host cell, viruses use their natural mechanisms which involve binding specific receptors on the cell surface and subsequent internationalization (Chaney & Helmer, 2023). The viral genetic material is released inside the cell, either integrating into the host's genome or remaining episomal allowing for either stable or transient therapeutic gene expression (Chaney & Helmer, 2023). Ultimately, the choice of which viral vector is used depends on several factors, including the duration of gene expression required, the type of target cells, and safety considerations.
Gene Delivery of Tumor Suppressor Genes
Tumor suppressor genes, such as the p53 protein, help regulate cell division by keeping cells from proliferating uncontrollably, therefore helping prevent the formation of tumors (Cross & Burmester, 2006). When these genes are dysfunctional or mutated, gene therapy strives to institute normal, functional copies of the genes to restore the tumor suppressor function. Tumor suppressor genes also prevent tumor formation by repairing DNA damage and promoting apoptosis. Apoptosis is the death of cells that should be occurring naturally, also known as programmed cell death. However, in cancer patients, apoptosis does not function properly due to mutations in tumor suppressor genes which cause them to be deactivated.
Gendicine is an example of a gene therapy product that delivers a tumor suppressor gene to cancer cells. It was approved for the treatment of head and neck squamous cell carcinoma by the Chinese Food and Drug Administration in 2003 and is a recombinant adenovirus engineered to express the tumor suppressor gene p53 (Zhang, 2018). p53 is a master regulator and can prevent cell division or induce apoptosis in cells. A Gendicine trial showed complete regression in 64% of tumors and partial regression in 29% of tumors when patients had 8 weekly intratumoral injections combined with radiation therapy (Peng, 2004). No serious side effects have been reported yet, except for transient fever which occurred in 50–60% of individuals (Zhang, 2018).
Suicide Gene Therapy
Suicide gene therapy is a therapeutic strategy in which cell suicide influencing transgenes are introduced into cells. One method introduces a suicide gene into the specific target cell (e.g., a tumor cell or an HIV-1 infected cell), then, expression of enzymes, proapoptotic proteins, and toxins triggers the target cell to ultimately “commit suicide” (Saeb et al., 2021). Another method introduces a gene which enables them to convert a pro-drug, which is not toxic, into the active form of the drug.
Figure 2: Suicide gene therapy involves delivering a gene to cancer cells which allows them to convert a non-toxic pro-drug into the active form. Alternatively, it can involve delivering a gene which encodes a toxin. Both of these lead to apoptosis of the cancer cell. Figure from Saeb et al. (2022).
Rexin-G, or DeltaRex-G, is approved in the Philippines (Gordan & Hall, 2010) and delivers a dominant negative variant of human cyclin G1 to cancer cells which blocks the cell cycle from continuing and is cytotoxic (i.e., forces them to commit suicide) (Gordan et al., 2019). Analysis of long-term data showed that Rexin-G was able to cause sustained remission in patients presenting with advanced cancer (10 year survival rate of 5%) (Gordan et al., 2019). Rexin-G is delivered intravenously and is able to seek out tumors due to its specific targeting mechanism of the cancerous cells. It displays a SIG-targeting peptide on the surface of the virus which enables it to bind to abnormal collagenous (SIG) proteins found in the tumor microenvironment (TME) (Chawla et al., 2019).
The cytosine deaminase gene of Escherichia coli converts the nontoxic compound 5-fluorocytosine into 5-fluorouracil (5-FU), a widely used chemotherapy drug. Gene therapy can be used to deliver this cytosine deaminase gene into cancer cells. This means that a patient can be administered with non-toxic 5-fluorocytosine and it will be converted into the toxic 5-FU inside the engineered cancer cells. This allows a common chemotherapy drug to be used with fewer side effects as healthy cells do not express the cytosine deaminase gene and therefore are not exposed to 5-FU. In an early demonstration of this concept, Pierrefite-Carle et al. (1999) conducted a study in which colon cancer cells, which were modified to express cytosine deaminase, were engrafted in the liver of rats to mimic formation of a metastatic tumor. They then analyzed the effect of 5-fluorocytosine treatment in vivo and found that 7/11 drug-treated animals were tumor free after 30 days. These animals were also resistant to challenge with wild-type tumor cells, with 0/7 treated animals developing tumors, whereas 4/4 control animals developed tumors (Pierrefite- Carle et al., 1999). This study was an early example demonstrating the potential use of suicide gene-modified tumor cells as therapeutic vaccines.
Studies have documented the potential promise of herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) suicide gene therapy in working to kill off tumors (Zarogoulidis et al., 2013). HSV-TK is an enzyme that transforms ganciclovir into a toxic substance, and when this compound is integrated into the cells, it hinders its ability to multiply (Moriuchi et al., 1998). Researchers utilized this suicide gene therapy on 12 patients with recurrent glioblastoma (Oraee-Yazdani et al., 2023). They used adipose derived stem cells to carry the gene HSV-TK safely. Patients were followed up for about 16 months, showing the gene therapy to be safe without causing too many problems. Unfortunately, during the study, 11/12 patients showed tumor growth, resulting in nine of their deaths. The average span of time from the beginning of the treatment until death was only about 16 months, and the tumor showed to only show suppression for about 11 of those months.
Gene Delivery for the Inhibition of Oncogenes
A pro-oncogene gene regulates cell growth, division, and survival. An oncogene is a mutated pro-oncogene that has the potential to form and progress cancer through uncontrolled cell proliferation, allowing the division and multiplication of cells to go unchecked. Inhibiting oncogenes is a promising strategy to reduce tumor growth and disrupt the signals driving abnormal cell division, potentially slowing down and halting cancerous cell progression. The goal of oncogene inhibition therapy is to deliver genetic material that will impact, interfere with, and influence the oncogene's activity, halting cell proliferation.
Angiogenesis is the process by which new blood vessels are formed from existing ones. In many cancers, angiogenesis is crucial to supply tumors with the nutrients and oxygen required for cell growth. Therefore, inhibition of angiogenesis can starve tumors of their necessary blood supply, halting cell growth and expansion. A key strategy in cancer treatment is targeting factors that promote blood vessel formation, such as vascular endothelial growth factor (VEGF) (National Cancer Institute, 2018).
RNA Interference (RNAi)
Gene therapy, through RNA interference (RNAi), is an ongoing approach being taken to inhibit oncogenes within cancers. Small inferring RNA molecules (siRNA) can be programmed to individually target and bind to the messenger RNA (mRNA) of a specific oncogene, prohibiting its translation into a functional protein. This disrupts the gene’s activity and hinders the pro-growth signaling the oncogene is involved in transmitting. The siRNA molecules induce the formation of silencing complexes (RNA induced silencing complex - RISC) which act as molecular scissors, binding to the disease mRNAs and orchestrating their destruction (Alnylam Pharmaceuticals, 2023). The RISC binds mRNA molecules which have complementary sequences to the siRNA, meaning specific mRNAs can be targeted by modifying the sequence of siRNA. This enables siRNAs to be engineered to target and degrade the mRNA of oncogenes, thereby inhibiting oncogenic processes. This modular RNAi therapeutic strategy has the potential to target any gene inside the genome, including those deemed “undruggable” by antibodies and small molecules. Present examples of RNAi gene therapies to inhibit oncogenes and angiogenesis consist of Atu027, which inhibits angiogenesis through targeting VEGF receptor 2, and siG12D-LODER, which aims to target KRAS, an oncogene frequently mutated in various cancers (Alnylam Pharmaceuticals, 2023).
Figure 3: The RNAi process within the cell. This clearly showcases siRNA targeting the mRNA of a specific oncogene and inhibiting its translation into a functional protein by its degradation. Picture taken from Alnylam Pharmaceuticals (2023).
This therapeutic strategy is not only focused on cancer treatment, but also on managing diverse medical disorders such as human papillomavirus, hepatitis B virus, liver cirrhosis, and hypercholesterolemia (Amer, 2014). While direct therapeutic administration into tumors is possible, delivering siRNA systemically faces many challenges based on the vulnerability of naked siRNA molecules towards host cellular phagocytosis, renal filtration, and enzyme degradation (Amer, 2014). Through clinical trials, researchers have aimed to develop various systems to protect siRNA from enzymatic degradation and enhance its effectiveness in silencing specific genes. Examples of systemic delivery clinical trials consist of ALN-VSPOI for liver cancer and solid tumors and CALAA-01 for malignant melanoma (Amer, 2014).
CALAA-01
CALAA-01, developed by Calando Pharmaceuticals, has undergone a phase 1 clinical trial where 24 patients with different cancers were treated to compare the results to the data collected from the multi-species animal studies (Zuckerman et al., 2014). This clinical trial was the first example of systematic administration of siRNA, using a cationic polymer as part of the nanoparticle delivery system, to demonstrate gene inhibition by RNAi. During the study, 19 (79%) patients had post treatment scans that were considered evaluable for tumor response, but these concluded with limited objective tumor response observed (Zuckerman et al., 2014). Other challenges emerged in this trial such as its relatively high liver and kidney toxicity along with its low delivery efficiency (Zuckerman et al., 2014). This clinical trial is an example of the further research required in RNAi gene therapy cancer treatments. All RNAi gene therapies represent innovative advancements in cancer treatment, providing the potential to target gene abnormalities during tumor growth, though ultimately require deeper investigations into effective delivery systems.
Oncolytic Viruses
Oncolytic virotherapy is an emerging form of cancer treatment that has the potential to be the future of cancer therapy. An oncolytic virus is a virus that has been genetically engineered to attack cancer cells directly and indirectly. The virus is modified through gene deletion and transgene addition so that it does not cause disease within the host and avoids infecting healthy cells. For instance, T-VEC, an oncolytic HSV-1, does not cause the host to develop herpes (Shalhout et al., 2023). An oncolytic virus directly kills cancer cells when it injects its DNA into the host cell, uses the host cell to grow and replicate, and then causes the cell to lyse. Since the oncolytic virus targets tumor cells, it directly fights the cancer. The cancer cell’s trait of excessive replication aids the oncolytic virus by allowing it to replicate faster and spread more (Terrível et al., 2020). Since the cancer cell replicates faster than usual, the virus is also able to replicate with it at the same pace. The body’s adaptive immune response to the tumor-derived antigens released by the cell lysis enables oncolytic viruses to indirectly kill cancer cells. When a cancer cell lyses, it releases many chemicals, such as ATP and tumor-derived antigens. This release sends a warning signal throughout the body. The immune system recognizes the tumor-derived antigen as dangerous, generating an immune response in the body which targets cells with the tumor-derived antigen (Terrível et al., 2020). This is a form of immunogenic cell death (Shalhout et al., 2023). Although the body’s antitumoral adaptive immune response is much slower than its innate immune response, the adaptive immune response is more potent, specific, and long-lasting (Terrível et al., 2020). Oncolytic viruses may be armed with immunostimulatory agents to modulate the immunosuppressive phenotype of the TME (Zheng et al., 2019). Its potency is maximized by combining oncolytic virotherapy with other forms of classic treatment such as immunotherapy and chemotherapy (Santos Apolonio, 2021). For example, oncolytic virotherapy could be paired with immune checkpoint inhibitor (ICI) therapies. ICI therapies aim to boost anti-tumor immune responses. As oncolytic virotherapy modulates the TME towards a less immunosuppressive phenotype, it can be paired with ICI therapies to aid patients in overcoming resistance to ICI therapies (Ylösmäki & Cerullo, 2020). The virus works best when administered in the intratumor environment (Zheng et al., 2019).
Figure 4: Schematic of oncolytic virus function. Picture taken from Yaghchi et al. (2015).
Viruses Used in Oncolytic Virotherapy: Benefits and Drawbacks
There are many types of viruses that can be used for oncolytic virotherapy. Only a few are currently approved, but many are under evaluation. The most challenging part of oncolytic virotherapy is identifying which virus and delivery system suits the patient’s system. Due to the heterogeneity and complexity of cancer cells and tissues, a single oncolytic virus is not enough; additionally, the patient can be immune to some viruses already (Mondal et al., 2020). The Cancer Research Institute lists many viruses that are being tested: adenovirus, herpes simplex virus, vaccinia, Maraba, measles, Newcastle disease virus, picornavirus, reovirus, and vesicular stomatitis (Bell, 2023). Different oncolytic viruses work on different types of cancer, meaning that each virus has its benefits and drawbacks (Mondal et al., 2020). The three most-studied viruses include HSV, adenovirus, and vaccinia. All three of these viruses have a wide host-cell range and large genome capacity, meaning that they can infect various cell types and have a greater transgene capacity. Adenovirus has numerous disadvantages: initial antiviral immunity, toxicity, and hepatic absorption (Aurelian, 2013). Vaccinia’s disadvantage is that there are difficulties regarding systemic delivery, but its additional advantage is its substantial vaccine potential: it can be engineered to express tumor associated antigens, which results in the body developing an adaptive immune response against this tumor associated antigen. This primes the immune system to detect and destroy the cancer in the same way a traditional vaccine primes the body to recognize a pathogen. HSV also has individual pros, including neurotropism and the capability to resist initial antiviral immunity and antiviral medications (Aurelian, 2013). Like adenovirus, HSV’s disadvantage is hepatic absorption. Other oncolytic virus candidates such as reovirus, Seneca Valley virus, myxoma virus, Newcastle disease virus and vesicular stomatitis virus are weaker due to their deficient tumor penetration, stimulation of an innate antiviral immune response, and difficulty infecting cancer stem cells (Aurelian, 2013). However, reovirus, Seneca Valley virus, myxoma virus are advantageous because they do not cause disease in humans and Newcastle disease virus and vesicular stomatitis virus are advantageous because they are selective towards tumor cells with insufficient interferon responses (Aurelian, 2013).
Approved Oncolytic Viruses and Examples of Clinical Trials
There are four approved oncolytic therapies for use in patients across the world:
Oncorine, T-VEC, Rigvir, and DELYTACT (Rahman & McFadden, 2021).
Oncorine (H101) is an adenovirus serotype 5 that was approved in 2005 in China (Lawler et al., 2017). It is approved to treat head and neck cancer. Oncorine is engineered with deletions for viral E1B-55K and four deletions in viral E3. Oncorine also proves to be successful: patients being treated with Oncorine and chemotherapy have a 78.8% response rate compared to a 39.6% response rate to chemotherapy individually (Russell & Peng, 2018). The main side effect is fever, which can be controlled with medication (Zhang et al., 2021). Gastric carcinoma is globally the third most common cause of cancer. China accounts for 44% of worldwide gastric carcinoma cases and 49% of worldwide gastric carcinoma deaths and the available targeted drugs show lack of efficacy, showing the need for new forms of treatment. Oncorine, or H101, underwent a clinical trial in 2012-2018, approved by the Ethics Committee of Qingdao Municipal Hospital (Zhang et al., 2021). The patients were 18-80 years of age, did not initially undergo surgical treatment, and could be injected intratumorally. There was a total of 95 patients split into groups A, B, and C: Group A contained 30 patients treated with H101, Group B contained 33 patients treated with chemotherapy, and Group C contained 32 patients treated with H101 and chemotherapy in conjunction. Group C’s disease control rate and overall response rate (81.3% and 50.0%) were substantially higher than groups A (63.3% and 30.0%) and B (66.7% and 33.3%), implying that H101 works best in conjunction with chemotherapy. Additionally, Group C had much greater 1- and 2- year survival rates (Zhang et al., 2021).
T-VEC (Imlygic) is an HSV-1 that was approved in 2015 in the United States by the US Food and Drug Administration (FDA) and in Europe by the European Medicines Agency (EMA). It is approved to treat metastatic melanoma. It is engineered with ICP34.5 and ICP47 deleted and encodes two copies of human GM-CSF; GM-CSF is a cytokine that plays an important role in immune reactions (Egea et al., 2010). In a phase II trial published by Senzer at al. (2009), the survival rates were 58% at one year and 52% at two years. However, mild flu-like symptoms were reported. Overall, T-VEC’s clinical trials show promising results (Zhang et al., 2023). This treatment is the only FDA approved oncolytic therapy. There were three major T-VEC clinical studies before it was approved by the FDA. Its phase I clinical trial was published by Hu et al. in 2006 and administered an intratumoral T-VEC injection in patients with different tumor types: refractory breast, head and neck, and gastrointestinal cancers and malignant melanoma. 30 patients were part of a single-dose group, and 26 were evaluated. Of the 26, 19 patients had residual tumors with 14 displaying substantial amounts of necrosis and apoptosis. The phase II clinical trial was published by Senzer at al. in 2009 with T-VEC administered in 50 patients with stage IIIc unresectable metastatic melanomas. The overall response rate was 26%, the complete response rate was 16%, and the partial response rate was 10% with 92% of responses lasting for at least three years (Zhang et al., 2023).
Adenovirus, HSV, and vaccinia viruses have the most history with clinical trials. Hundreds of clinical trials have been conducted in various countries, with most being combination trials (Yun et al., 2022). Unlike adenovirus and HSV, no vaccinia virus has passed the clinical trial stage yet. An example of a vaccinia virus clinical trial is Pexa-Vec. Pexa-Vec’s safety was determined in a phase I trial in which 14 patients received an intratumoral injection; in this trial, a second wave of viremia was found in patients, implying that Pexa-Vec replicated successfully. In other studies, antitumor immunity was detected and measured (Cripe et al., 2015). However, phase III of the Pexa-Vec clinical trial was terminated early due to uninspiring results (Forster, 2019). As there have only been a few oncolytic viruses that have made it past phase III clinical trials, this is an example of what happens most commonly.
Figure 5: Oncolytic virus clinical trials. Figure taken from Yun et al. (2022).
Rigvir (ECHO-7) is a picornavirus that was approved in 2004 in Latvia. It is unmodified and approved to treat melanoma. Rigvir has displayed success, as melanoma patients' 3- and 5- year survival was 54–57% and 42–56% without Rigvir and 78–84% and 66–81% with Rigvir (Alberts et al., 2018). Side effects of Rigvir from previous clinical studies include subfebrile temperature (37.5°C for a couple of days), pain in the tumor area, sleepiness, and diarrhea (Doniņa et al., 2015).
Lastly, DELYTACT (teserpaturev/G47Δ) is another HSV-1 that was approved in 2021 in Japan. It is approved to treat malignant glioma or any main brain cancer. It is engineered with a triple mutation composed of the deletions of ICP34.5, ICP6, and a47 genes. In study GD01, the one-year survival rate was 95% (Maruyama et al., 2023).
CAR-T Therapy
CAR-T cell therapy is a type of immunotherapy which utilizes chimeric antigen receptor T cells (CAR-T cells) to fight cancer. The CAR-T cells are engineered to recognize and target specific proteins in cancer cells. CAR-T cell therapy has shown promising results in treating certain types of blood cancer, like leukemia and lymphoma, and some CAR-T therapies have been approved by the FDA (Cesur-Ergün & Demi-Dora, 2023). CAR-T cells are made by extracting T cells from a patient's blood, then genetically modifying them ex vivo to express chimeric antigen receptors (CARs) that recognize cancer cells (Cesur-Ergün & Demi-Dora, 2023). These modified T cells are expanded and infused back into the patient, where they can target and kill cancer cells. The manufacturing process involves several steps and can be done manually or through automated systems (Cesur-Ergün & Demi-Dora, 2023).
Figure 6: In CAR-T cell treatment, medical professionals extract blood from the patient and isolate T cells. These T cells are then altered at a genetic level to transform them into CAR-T cells. Following this, the CAR-T cells are cultured outside of the body to expand their numbers. Once quality control is completed, the CAR-T cells are administered to patients. Figure reproduced from Cesur-Ergün & Demi-Dora (2023).
The Structure of the CAR
The CAR has several domains, each of which is important for CAR-T cell function (Vucinic et al., 2021). The figure below displays the extracellular antigen-binding domain, the hinge region, the transmembrane domain and the intracellular signaling domain.
Figure 7: Domains of the chimeric antigen receptor. Figure reproduced from Elahi et al. (2018).
The antigen-binding domain is the part of the CAR that specifically recognizes the antigen on the cancer cell. It is typically derived from monoclonal antibodies connected to form a single-chain variable fragment (scFv). The scFv’s interaction and position affect the CARs affinity and specificity for the target. Affinity is important for CAR function, but it needs to be balanced to avoid activation-induced death and toxicities. Other factors like where the antigen is located, how much of it is present, and avoiding unwanted signaling also play a role in optimizing CAR-T cells (Cesur-Ergün & Demi-Dora, 2023).
The hinge region is an important part of the CAR structure. It extends the binding units from the transmembrane domain and provides flexibility to overcome obstacles. The length and composition of the hinge region can affect flexibility, expression, signaling, and epitope recognition. The optimal spacer length depends on the target epitope. Different hinge lengths have been used in CARs, such as short hinges for membrane-distal epitopes and long hinges for membrane-proximal epitopes. Commonly used hinge regions are derived from CD8, CD28, or lgG4, but lgG-derived spacers can cause CAR-T cell depletion (Cesur-Ergün & Demi-Dora, 2023).
The transmembrane domain of CARs anchors them to the T cell membrane and affects their function. Different domains like CD4, CD8a, or CD28 have different effects on CAR expression, stability, signaling, and dimerization. CD3ζ, enhances T cell activation but decreases CAR stability compared to CD28. The choice of domain also influences cytokine production and cell death in CAR-T cells (Cesur-Ergün & Demi-Dora, 2023).
The intracellular signaling domain also plays an important role in CAR-T cell function. First-generation CARs used CD3ζ or FcRγ signaling domains, but they showed limited efficacy (Cesur-Ergün & Demi-Dora, 2023). Second-generation CARs with a costimulatory domain, like CD28 or 4-1BB, along with the CD3ζ signaling domain, have shown improved responses and high patient response rates (Cesur-Ergün & Demi-Dora, 2023). These costimulatory domains have different functional and metabolic profiles. CARs with CD28 differentiate into effector memory T cells, while CARs with 4-1BB differentiate into central memory T cells. Second-generation CAR-T cells have shown strong therapeutic responses in hematological conditions.
Approved CAR-T Cell Therapies
Breyanzi (lisocabtagene maraleucel) is a CD19-directed CAR-T cell therapy approved by the FDA for treating adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy (U.S. Food and Drug Administration, 2021). It demonstrated a 73% overall response rate and 54% complete response rate in the TRANSCEND NHL 001 trial (Bristol-Myers Squibb Company, 2021). Breyanzi has a 4-1BB costimulatory domain and is administered as a single dose containing 50 to 110 x 106 CAR-positive viable T cells (Bristol-Myers Squibb Company, 2021).
Kymriah (tisagenlecleucel) is a CD19-targeted CAR-T cell therapy approved by the FDA and EMA for treating certain types of blood cancer (Plieth, 2021). It has been approved for relapsed or refractory B-cell acute lymphoblastic leukemia in adults and children, and for diffuse large B-cell lymphoma in adults who have failed at least two previous treatments. Kymriah has shown a control crossover rate of 51% (Plieth, 2021). However, it can also cause severe side effects, such as cytokine release syndrome and neurological events, and its use is associated with a boxed warning (Plieth, 2021). As a result, Kymriah is only available at certified treatment centers and requires careful monitoring and management of adverse events.
Challenges in CAR-T Cell Therapy
Despite successes in using CAR-T cell therapy, there are still challenges to overcome. These include: antigen escape, on-target off-tumor effects, CAR-T cell trafficking and tumor infiltration, the immunosuppressive microenvironment, and CAR-T cell-associated toxicities (Büşra C. &, Devrim D, 2023).
One of the challenges of CAR-T cell therapy is tumor resistance due to antigen escape. Some malignancies can downregulate or completely lose the target antigen, making the CAR-T cells less effective. Clinical trials using dual-targeted CAR-T cells have shown promising results in reducing relapse rates (Cesur-Ergün & Demi-Dora, 2023).
CAR-T cell therapy is also challenged by the potential for "on-target off-tumor" effects. This means that the antigens targeted by CAR-T cells can also be present on normal tissues, leading to unintended toxicity. To address this, there are a variety of experiments that undertake different strategies, such as targeting tumor-specific post-translational modifications like truncated O-glycans (Cesur-Ergün & Demi-Dora, 2023). Although there have been some challenges, ongoing research is focused on developing new versions of CAR-T cells with modifications to improve their effectiveness while minimizing toxicity concerns.
When it comes to CAR-T cell therapy for solid tumors, one of the challenges is the ability of CAR-T cells to reach and infiltrate the tumors. The tumor microenvironment and physical barriers in solid tumors can make it difficult for CAR-T cells to penetrate and move around. To overcome this, different delivery routes are being explored. For example, local administration can eliminate the need for CAR-T cells to travel to the tumor site and reduce unintended toxicity. Some approaches include intraventricular injection for breast cancer brain metastases and glioblastoma, as well as intrapleural injection for malignant pleural mesothelioma (Sterner & Sterner 2021). Intraventricular injection of CAR-T cells involves delivering genetically modified T cells directly into the ventricles of the brain. Additionally, there is ongoing research on modifying CAR-T cells to express chemokine receptors that respond to tumor-derived chemokines, which can enhance their trafficking to the tumor site (Foeng et al., 2022).
In TME, different types of cells can suppress the immune response, like myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. They produce certain substances that promote tumor growth and can decrease the effectiveness of CAR-T cell therapy. That is why combining CAR-T cell therapy with checkpoint blockade, like PD-1/PD-L1 blockade, is being explored as a potential immunotherapy approach (Wang et al., 2019). By blocking these inhibitory pathways, it can help CAR-T cells persist and function better.
CAR-T cells may produce toxicities. These toxicities can be influenced by factors like the design of the CAR, the specific target, and the type of tumor. One of the most extensively studied toxicities is cytokine-release syndrome, which happens when there is an excessive production of cytokines and a massive expansion of T cells in the body (Cesur-Ergün & Demi-Dora, 2023). It can lead to symptoms like fever, low blood pressure, and organ dysfunction. Other toxicities include hemo-phagocytic lymphohistiocytosis and/or macrophage activation syndrome and immune effector cell-associated neurotoxicity syndrome (Cesur-Ergün & Demi-Dora, 2023).
Discussion
This review discussed and evaluated gene delivery, gene delivery of tumor suppressor or suicide genes, gene delivery for inhibition of oncogenes and angiogenesis, oncolytic viruses, and CAR-T therapy. Tumor suppressor genes may be delivered into cancer cells to restore their lost function using gene therapy. Suicide gene therapy covers both the introduction of cytotoxic genes into the cell, or the introduction of viral or bacterial genes into tumor cells which in turn convert a non-toxic pro-drug to a toxic one. There are two systems that have been extensively investigated: the cytosine deaminase gene which converts the pro-drug 5-fluorocytosine to 5-FU, and the HSV thymidine kinase gene which phosphorylates ganciclovir resulting in its conversion to a toxic substance. By suppressing the abnormal cell growth signals (oncogenes) and restricting the formation of new blood vessels (angiogenesis) that nourish tumors, this strategy aims to disrupt essential pathways for cancer development, offering a promising avenue for more effective and targeted therapeutic interventions. Oncolytic viruses are packaged with immunostimulatory agents and modifications that allow them to directly and indirectly kill cancer cells. Although not many oncolytic viruses have been approved yet, there are many clinical studies currently being performed. Lastly, CAR-T cells are a type of immunotherapy that involves genetically modifying a patient’s own T cells to recognize and attack cancer cells, with the goal of enhancing their ability to target and eliminate cancer cells while minimizing harm to healthy cells. CAR-T cell therapy has shown promising results in treating certain types of blood cancer and research is ongoing to expand its application to other cancer types. With more research ahead, these new forms of gene therapy may be the future of cancer treatment.
Limitations of Cancer Gene Therapies
Though there have been successes in using gene therapy to treat cancer, there are limitations associated with these strategies. These are discussed in detail below.
Expense and Accessibility
The expense and accessibility of cancer gene therapy poses a limit on its potential. For example, one round of CAR-T therapy costs $400,000 (Thorn, 2023). For most patients, this price is not a realistic option. However, charity-based programs are working to bring this cost down to $50,000. If gene therapy were to be the future for cancer treatment, it needs to be as accessible as chemotherapy and other mainstream treatments (Thorne, 2023).
Triggering an Unwanted Immune Response
Oncolytic virotherapy faces limitations due to the body’s pre-existing immunity to viruses. Oncolytic virotherapy works if the virus is able to inject itself into the tumor and replicate substantial amounts. With the body’s pre-existing immunity to viruses, the oncolytic virus must be disguised so that the body does not recognize it immediately. The immune system has the ability to destroy the gene therapy virus before it can reach the tumor cells, especially with the challenges it faces to reach the tumor cells. For instance, innate immunity towards adenoviruses weakens their potential as a gene therapy virus (Bezeljak, 2022). The most commonly used adenovirus serotype, Ad5, has 50% seroprevalence in North America and over 90% in Côte d’Ivoire. Patients who had already been exposed to the virus would be initially prepared to expel the adenovirus, hindering its ability to replicate in tumor cells and cause cell lysis (Bezeljak, 2022).
Difficulty Getting the Vector into Solid Tumors
Solid tumors are difficult to work with for forms of gene therapy due to the characteristics of the surrounding of the tumor cells. There is an array of challenges that solid tumors impose on the virus, and the virus must get through these obstacles in order to function. Physical barriers are the major challenge. The virus must surpass the endothelial layer to reach the tumor cells. Interstitial hypertension caused by the atypical lymphatic networks, vascular hyperpermeability, and dense extracellular matrix hinders viral infiltration (Zheng et al., 2019). Another challenge is that the blood supply of the tumor is typically impaired which prevents effective delivery of the therapeutic virus. The characteristics and abnormalities of the TME make it difficult for the viruses used in gene therapy to infect cancer cells within the tumor, thus hindering their function (Zheng et al., 2019).
Gene therapy may face challenges in administration for cancers where the tumors cannot be directly injected. As the process of reaching solid tumor cells is difficult, gene therapy works best when the injection site is in the intratumoral environment. If it is not, then the form of gene therapy has to overcome the many challenges to reach the tumor while persisting with sufficient presence in the body.
The Immunosuppressive Tumor Microenvironment
The immunosuppressive TME is another limitation that the gene delivery cancer therapies face. The TME has an immunosuppressive phenotype because it contains different types of cells that can suppress the immune response. As stated earlier, myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T-cells contribute to the immunosuppressive trait. These cells produce substances that nurture tumor growth, giving the tumor an environment in which it thrives (Lemos de Matos et al., 2020). This characteristic of the TME may affect the efficacy of oncolytic viruses and CAR-T cell therapy. Pairing CAR-T therapy with ICI could help increase its effectiveness by helping the CAR-T cells persist and function better in the TME by blocking these inhibitory pathways. (Ylösmäki & Cerullo, 2020). Oncolytic viruses could also be armed with immunostimulatory agents to modulate the TME and change its phenotype. When the TME is modulated by oncolytic viruses, the dendritic cells and T-cells are activated by type I interferon (Lemos de Matos et al., 2020). Therefore, although the TME poses a major challenge, there are strategies that can be utilized to overcome this obstacle.
Targeting Tumor Cells
The ability to target tumor cells is a strength that oncolytic viruses have over chemical drugs, as viruses can be engineered to target proteins found on the surface of cancer cells (Terrível et al., 2020). However, “off-target” effects, where the virus infects some healthy cells, are unavoidable. Non-specific uptake of the viruses can happen in the liver and spleen, resulting in unwanted side effects and loss of efficacy. This “off-target” effect is due to the Kupffer cells in the liver, which uptake viral vectors such as adenoviruses without specificity (Das et al., 2015). However, this may be avoided by completing pretreatment with warfarin sequenced by multiple doses of replication-defective adenoviruses (Das et al., 2015).
Side Effects
The most common side effects of gene therapy include flu-like symptoms (Baldo, 2014). After initially receiving a type of gene therapy, a patient's immune system may react to the foreign vector, causing symptoms such as fever, severe chills, drop in blood pressure, nausea, vomiting, and headache. Gene therapy that involves the immune system may cause excess immune reactivity to healthy cells that resemble the disease cells, potentially causing damage to healthy cells (Belete, 2021).
Lack of Long-Term Data
Gene therapy lacks long-term data because it is relatively new, and not many medications have been approved yet. The earliest approved gene therapy treatment for cancer was approved in 2003 but did not reach the market until 2004, and the majority of treatment candidates are in the process of being reviewed and approved. It is important to note that the first approved treatment was only in China (Pearson et al., 2004). Clinical use of gene therapies is rapidly increasing, and it is estimated that by 2025, the FDA will be approving between 10 and 20 gene therapies each year (Gottlieb, 2019). This fast pace of approvals must be matched by the development of new clinical frameworks for adequately assessing and managing the potential delayed effects of these new therapies. Safety concerns associated with gene therapy are not new and have been highly publicized. The tragic death of Jesse Gelsinger in late 1999, during an early safety trial of a gene therapy for ornithine transcarbamylase deficiency, led to the near abandonment of the approach (Sibbald, 2001). To add to this concern, delayed adverse events associated with gene therapy have been reported before, such as in clinical trials for X-linked severe combined immunodeficiency. Recent long-term studies of animals suggesting that insertional mutagenesis could take years to become apparent have raised more red flags. For full understanding and mitigation of the risk of a delayed adverse event, participants in gene therapy trials will need to be monitored for an extended period of time, commonly referred to as the ‘long-term follow-up’ period of a clinical study (Nature Medicine, 2021).
How Many People Have Been Treated?
Over 3000 genes are associated with disease-causing mutations and, as of November 2017, more than 2597 gene therapy clinical trials had been carried out (Belete, 2021). Over 65% of these gene therapy trials aimed to treat cancer (Belete, 2021). By August 2019, 22 gene therapy medicines had been approved by the drug regulatory agencies from various countries (Belete, 2021). Gene therapy has gradually been accepted by the government and the public since the 1980s and has become an important alternative to the existing treatments in the past few years (Ma et al., 2020).
Future Directions
All forms of gene therapy warrant further investigation in clinical trials. As these forms of therapy are still relatively new, there is a great amount of research to be done to confirm the safety and efficacy of the treatments. While combination trials evaluate the efficacy of the drug, isolated treatment trials evaluate the safety of the drug. Even if a new form of treatment is effective at selectively attacking cancer cells, it must be safe for the rest of the body, meaning that its side effects cannot be dangerous.
Conclusion
This review explores emerging cancer treatments while evaluating their function, efficacy, benefits, and limitations. CAR-T therapy, gene delivery of tumor suppressor or suicide genes, gene delivery for inhibition of oncogenes and angiogenesis, and oncolytic viruses are all new forms of cancer gene therapy under investigation. These cutting-edge technologies often deploy the host’s own immune system in the fight against cancer: oncolytic viruses deploy and stimulate the natural immune system while CAR-T therapy engineers the patient’s own blood cells to recognize the cancer. Although these treatments are not yet widespread, they have the potential to be the future of cancer therapy. Despite advancements in chemotherapy, radiotherapy, and surgery, cancer remains a devastating disease. Combining gene therapies with the classic forms of cancer treatment provides hope for a new realm of successful treatment. Gene therapy cancer treatments are increasingly entering clinical trials and being approved, renovating the landscape of modern medicine.
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