Talimogene Laherparepvec - Indication, Dosage, Precautions, Side Effects, and Pharmacological Aspects

Introduction

Talimogene Laherparepvec (T-Vec) comes under a medication group called oncolytic viruses. Oncolytic viruses (OV) use naturally occurring or genetically altered viruses to treat cancer and has been introduced recently to anti-cancer drug therapy. It is a first-in-class oncolytic immunotherapy based on the genetically modified herpes simplex virus type 1 that has been approved for treating cutaneous and subcutaneous lesions that cannot be operated on and also for nodal lesions in patients with melanoma that has returned after initial surgery or for the melanoma where treatment is not possible.

How Does the Talimogene Laherparepvec or IMLYGIC Work?

The active ingredient in IMLYGIC, talimogene laherparepvec, is an oncolytic virus which is a type of gene therapy. It came from a weaker strain of herpes simplex virus type 1 (the cold sore virus). This virus has been altered to cause infection and grow within melanoma cells. The drug multiplies by using the melanoma cells' mechanisms, eventually overwhelming them and killing them. Even though IMLYGIC can enter healthy cells, it is not intended to multiply there. The genetically modified drug expresses the human cytokine GM-CSF (granulocyte-macrophage colony-stimulating factor), which has antitumor and immune-stimulating properties. The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) encourages dendritic cell differentiation and survival, as well as myeloid cell growth and maturation. It encourages the body's natural defense mechanism and the patient's immune system to recognize and eliminate melanoma cells.

Information for Patients:

What Is Melanoma?

Melanoma is a tumor that develops from melanocytes that undergo malignant transformation. Melanocytes, which are skin cells, are the source of melanoma. Melanomas typically occur on the skin because of melanocytes. The neural crest cells are the source of these melanocytes. However, it can develop in other organs where neural crest cells migrate, such as the gastrointestinal tract and brain. Melanin, a dark pigment that gives skin its color, is produced by these cells. However, some melanomas are pink, red, purple, or skin-colored. Melanomas are typically black or brown in color. Patients with stage 0 melanoma have a 97 % five-year relative survival rate, compared to 10 % for those with stage IV disease. Although there is no known cause for all melanomas, exposure to ultraviolet (UV) radiation from sunlight, tanning beds, or tanning lamps increases the risk of getting the disease. By reducing UV radiation exposure, the risk of melanoma can be reduced.

What Are the Clinical Indications For Melanoma?

• Melanomas can appear on any part of the body; however, they are often seen on the parts that are exposed to the sun, such as the legs, face, and back.

• It can also occur in the body parts that are not much exposed to the sun, like the soles and palms.

• The first signs that are present are a modification to an existing mole and the appearance of a new, pigmented growth or other uncharacteristic feature on the skin.

• The "ABCDE" memory aid from the American Academy of Dermatology can help to remember the indicators that a spot on the skin might be melanoma:

  • Asymmetry- The two halves do not match each other.

  • Border- No smooth edges.

  • Color- It has a mottled, uneven color with brown, black, gray, red, or white undertones.

  • Diameter- New growth should be present in the moles which are bigger than 0.6 millimeters.

  • Evolving- The mole spot may show changes in color, shape, and size. Additionally, moles can change over time to manifest new signs and symptoms like new itchiness or bleeding.

What Is Talimogene Laherparepvec and How It Is Used?

Talimogene Laherparepvec is used in the treatment of melanoma (a type of skin cancer) tumors that cannot be surgically removed or that recur even after surgical removal. The drug belongs to the class of oncolytic viruses. It is a weakened and altered variety of the HSV-1 cold sore virus, which aids in the destruction of cancer cells.

Talimogene Laherparepvec injection is administered by a physician or nurse in a hospital or clinic It comes as a suspension (liquid). The medication is injected by the doctor directly into the tumors present on the skin, underneath the skin, or in the lymph nodes. After the first dose of treatment, the second dose is administered three weeks later. The subsequent dosage is administered after every two weeks. The treatment duration depends entirely on the tumor's response to the treatment. All the tumors may not be injected with the medicine at the same time, and the decision entirely lies with the doctor. When a patient starts treatment with talimogene laherparepvec, and after each injection, the doctor or pharmacist will give the patient a manufacturer's patient information sheet (medication guide).

What Should the Patient Inform the Doctor Before Taking Talimogene Laherparepvec?

Before taking Talimogene Laherparepvec, the patient must inform the doctor about the below things:

• If the patient is allergic to Talimogene Laherparepvec or its ingredients. The patient must consult the doctor to know about the ingredients of the Talimogene Laherparepvec injection before taking it. They must also inform about allergy reactions to other medicines.

• If the patient is on any medicines, that can result in the weakening of the immunity and the body’s immune system. A few of the drugs include Azathioprine, Anti-Thymocyte Globulin, Belatacept, Cortisone, Cyclosporine, Dexamethasone, Methotrexate, Prednisone, and Methylprednisolone. Apart from these medicines, there are other medicines that can disrupt the immunity of the body and hence should be informed to the doctor. It is easy for the doctors to decide the course of treatment if the patient conveys the correct information regarding their medication chart.

• If the patient is taking any prescribed or over-the-counter medications, vitamins, and herbal supplements. The doctor might change the dosage of medications or monitor the patient carefully for any side effects.

• If the patient is on antiviral medications like Acyclovir, Famciclovir, Ganciclovir, Valacyclovir, and other antiviral drugs. The antiviral drugs might have an impact on the efficacy of how well the medicine Talimogene Laherparepvec works.

• If the patient is pregnant or thinking of conceiving a child or breastfeeding a child. During the course of the treatment, women should practice birth control methods and not conceive. In case the patient gets pregnant, inform the doctor at the earliest as the Talimogene Laherparepvec injection can cause harm to the fetus.

• If the patient has or had leukemia (blood cancer), lymphoma (cancer of the lymphatic system of the body), human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), or any other illness that compromises and weakens the immune system. The doctor might take the decision not to administer the Talimogene Laherparepvec injection.

• If the patient had radiation therapy for melanoma tumors, multiple myeloma (a bone marrow cancer), an autoimmune disease (when the immune system of our body attacks healthy tissue and causes pain, swelling, and damage), or if in close contact with a pregnant woman or someone with a compromised immune system.

What Are the Necessary Precautions That the Patient Needs to Follow Post-injection?

• Patients must be informed that the Talimogene Laherparepvec injection contains a virus that might spread and infect other people. So the injection site should be covered and packed with airtight and water-tight bandages. It should be covered for a longer time period if the injection site is oozing. Replace the bandages as soon as possible if they become loose or come off. One should wear rubber or latex gloves while bandaging the injection sites. Make sure to place all bandages, gloves, and cleaning supplies used for the injection sites in a sealed plastic bag before discarding them in the trash.

• The injection sites or bandages should not be touched or scratched as it can cause the virus present in the Talimogene Laherparepvec medication to spread to other areas of the body. People close to the patient on medication should take extra care to avoid touching their bandages, injection sites, or bodily fluids. If anyone nearby experiences any of the following symptoms of a herpes infection, check with the doctor immediately. The symptoms present may be pain, burning, or tingling in the blister near the mouth, genitals, fingers, or ears; eye pain, redness, or tears; blurry vision; sensitivity to light; weakness in the arms or legs; extreme sleepiness; or mental confusion.

What Are the Side Effects of Talimogene Laherparepvec Injection?

There are many side effects of the Talimogene Laherparepvec injection. Doctors should be notified immediately if any of these symptoms appear and remain for a longer period of time.

• Fatigue.

• Nausea and vomiting.

• Pain in the stomach along with diarrhea and constipation.

• Muscle and joint pain.

• Delayed healing of the injection site.

• Headache.

• Loss in weight.

• Skin that is flaky, dry, itchy, or burning.

• Pain in the upper and lower limbs.

The serious side effects of the Talimogene Laherparepvec injections, which should be notified immediately to the doctors, are mentioned below.

• Breathing issues or shortness of breath.

• Swelling present on the face, hands, feet, or stomach.

• Skin that is warm, red, swollen, or hurts around the injection site

• Fever, chills, sore throat, or other symptoms of infection.

• On the injected tumors, there is dead tissue or open sores.

• Open sores and dead tissue on the injected tumors.

• Urine that is pink, cola-colored, or foamy.

Information for Doctors:

Description of Talimogene Laherparepvec:

A sterile suspension called Talimogene Laherparepvec is intended for intralesional injection. The HSV-1 (Herpes Simplex Virus) strain Talimogene Laherparepvec has been genetically altered to express huGM-CSF and is alive and attenuated. The primary isolate that served as the parental virus for Talimogene Laherparepvec was subsequently modified by recombinant means to introduce and delete genes.

Clinical Pharmacology:

Mechanism of Action:

The exact mechanism of action is unknown. The injections are the live, attenuated herpes simplex virus that has been genetically modified to replicate inside tumors and produce the immune-stimulating protein GM-CSF. It causes the lysis of tumors, which is followed by the release of tumor-derived antigens, which, along with GM-CSF (granulocyte-macrophage colony-stimulating factor) derived from a virus, may promote an immune response that is antitumor.

Pharmacokinetics:

A quantitative polymerase chain reaction (qPCR) assay was used to determine the levels of Talimogene Laherparepvec viral DNA in different tissues and secretions. Viral infectivity assays were used to quantify the test results for infectious Talimogene Laherparepvec at the site of injections.

Clinical Study:

Samples of Talimogene Laherparepvec DNA were collected from 60 patients who were treated with intralesional injection of Talimogene Laherparepvecv. Samples were collected from the patient’s blood, urine, injection site, medical dressings, mucosa of the oral cavity, anogenital area, and suspected herpetic lesions. Samples of occlusive dressings were taken during therapy. Up to 30 days after the conclusion of treatment, blood, and urine samples were taken. Throughout the course of treatment and for up to 60 days following its conclusion, samples of the anogenital region, oral mucosa, and injection site were collected. Anytime a patient had lesions that were thought to be of suspected herpetic origin, samples of the suspected herpetic lesions were taken.

Study Results:

The data showed that Imlygic DNA was present in all the samples that were collected from the patients. The oral mucosa had the highest percentage of samples and subjects with IMLYGIC DNA during cycles 1 and 2 of treatment, while it was highest during cycle 2 for the blood, urine, injection site, and occlusive dressings. Thirty days after the end of treatment, samples from patients with detectable Talimogene Laherparepvec DNA in the blood, urine, oral mucosa, and anogenital area were negative. Even for patients with detectable DNA in injected lesions, none of the specimens had detectable Talimogene Laherparepvec DNA 60 days following the completion of treatment.

Composition:

Each vial contains 1 milliliter (mL) of deliverable Talimogene Laherparepvec at concentrations of either 10^6 (1 million) PFU per mL or 10^8 (100 million) PFU (plaque forming units) per mL, as well as the excipients sodium chloride (8.5 mg), sodium dihydrogen phosphate dihydrate (2.44 mg), myoinositol (40 milligrams), sorbitol (20 milligrams), and water for preparing an injection.

After thawing from the frozen state, Talimogene Laherparepvec contains 10^6 (1 million) PFU (plaque-forming units) per mL vial of a clear to semi-translucent liquid. The 10^8 (100 million) PFU (plaque forming units) per mL vial of Talimogene Laherparepvec contains a semi-translucent to opaque liquid after thawing. Each vial's liquid may contain white, discernible, irregularly shaped virus particles. Additionally, traces of fetal bovine serum, DNA, and proteins from VERO cells may be present in each vial of Talimogene Laherparepvec. The injection has no preservatives in it.

Adverse Reactions Reported:

• Conditions at the Administration Site and General Disorders

  • Fatigue.

  • Pyrexia.

  • At the injection site, there is pain and tenderness.

  • Influenza-like symptoms.

• Gastrointestinal Adverse Reactions

  • Nausea and vomiting.

  • Constipation and/ or diarrhea.

  • Pain in the abdomen.

• Adverse Reactions Related to Musculoskeletal and Connective Tissue:

  • Myalgia.

  • Arthralgia.

  • Pain in the extremities.

• Adverse Reactions Related to Nervous System:

  • Headache.

  • Dizziness.

• Respiratory, Thoracic, and Mediastinal Disorders Adverse Reactions:

  • Oropharyngeal pain.

Instructions for Talimogene Laherparepvec Injection Use:

Women who are pregnant and people with weak immunity should not prepare or administer Talimogene Laherparepvec injection. Also, they should not have direct contact with the injection sites, bandages, or bodily fluids of patients receiving treatment. Accidental exposure should be avoided, and a standard protocol for biohazard handling, administration, and disposal precautions should be followed.

• Handling:

  • While preparing or administering Talimogene Laherparepvec injection, put on personal defense gear like a protective gown or laboratory coat, safety or protective glasses, or a face shield, and gloves).

  • Talimogene Laherparepvec injection spills should be cleaned up immediately and should be treated with a virucidal agent like 1 % sodium hypochlorite or 70 % isopropyl alcohol and then blotted with absorbent materials.

  • All items (such as vials, syringes, needles, cotton gauze, gloves, masks, or dressings) that may have come into contact with Talimogene Laherparepvec injection should be disposed of as biohazardous waste.

• Preparation:

  • Thawing:

    • Determination of total volume for injection (approx 4 ml) is established.

    • Frozen vials are kept at room temperature until they become liquid. The room temperature determined is 20 degrees Celsius to 25 degrees Celsius.

    • Vials are not exposed to high temperatures.

    • The original packaging is maintained during the process of thawing.

    • The vials are not shaken vigorously but swirl gently.

    • The injection is administered immediately or stored

  • Syringe Preparation:

    • For withdrawal, a detachable 18-26 gauge needle may be used, and for injection, a non-detachable 22-26 gauge needle may be used.

    • For better injection control, smaller-unit syringes like 0.5 mL insulin syringes are used.

    • Remove the vial cap with an aseptic technique and transfer the product into the syringe(s) while noting the total volume.

    • When filling syringes with the product, try to avoid creating aerosols and, if one is available, use a biological safety cabinet.

• Intralesional Injection- Inject medication under cutaneous, subcutaneous, or nodal lesions that are visible and palpable to the touch.

  • Pre-injection Preparation:

    • The lesion and its surrounding areas are cleaned with an alcohol swab and are allowed to dry.

    • Topical or local anesthesia is injected or administered at the site of injection, which is the periphery of the lesion.

  • Injection:

    • Cutaneous, subcutaneous, and/or nodal structures lesions that are discernible by touch, palpable, or detectable under ultrasound guidance should be treated intralesionally with the medication.

    • The drug is administered intralesionally under ultrasound guidance into visible, palpable, or detectable cutaneous, subcutaneous, and/or nodal lesions.

    • To achieve even and thorough dispersion, inject the drug into the lesion along multiple tracks using a single insertion point as far as the needle's radial reach will allow.

    • If a lesion exceeds the needle's radial reach, multiple insertion points may be used.

    • While injecting, the drug is completely emptied out without pulling the needle out of the lesion.

    • Continue injecting the remaining dose while rerouting the needle as necessary.

    • To prevent solution leakage at the insertion point, the needle is slowly removed from the lesion.

    • The process is repeated for the other lesions.

    • A new needle is used every time for injecting different lesions.

• Post-injection Preparation:

  • Pressure is applied at the site of injection for a minimum of 30 seconds.

  • The site of injections is made sterile using an alcohol swab.

  • Use new gloves and apply a dry occlusive dressing and an absorbent pad to the injected lesions. The dressing is also made sterile using an alcohol swab.

  • Encourage patients to cover any injection sites for at least the first week following each treatment appointment or for longer if the site is weeping or oozing. Any loose dressing should be immediately replaced.

  • The injection site should not be touched or scratched by the patient as it may cause the medicine solution to be transferred to other body parts.

• Storage:

  • It is stored and transported in a frozen state. The temperature should be maintained at -90 degrees Celsius to -70 degrees Celsius.

  • It is protected from direct sunlight.

  • It is kept frozen in the carton until ready for use.

  • Thawing is done only prior to administration.

  • Draw thawed solution into the syringe only when it is time to administer.

  • Avoid refreezing the vials once they are thawed.

Drug Dosage Form and its Strengths:

• Initial Dose- 1 milliliter (ml) single-use (light green cap) vial of the solution with 10^6 (1 million) plaque-forming units (PFU) per milliliter of solution

• Subsequent Doses- 1 mL single-use vial (royal blue cap) of a solution containing 10^8 (100 million) plaque-forming units.

• Recommended Dosing Schedule- Each treatment session's total injection volume for all injected lesions should not be more than 4 mL. It might not be possible to inject all lesions during the course of the treatment or at each visit for treatment. At subsequent treatment visits, lesion(s) that have already been injected or that haven't been yet may be injected. Up to 4 mL of Talimogene Laherparepvec at a concentration of 10^6 (1 million) PFU per mL is the initial dose that is advised. For subsequent administrations, a maximum dose of 4 mL of Talimogene Laherparepvec at a concentration of 10^8 (100 million) PFU per mL is advised.

Drug Precautions and Warnings:

• Accidental Exposure to Talimogene Laherparepvec Injection- Exposure to the drug can cause the transfer of herpetic infection. Healthcare workers who are immunocompromised or pregnant should not administer the injection. Healthcare workers should take all the precautionary measures while administering the drug and waste disposal.

• Herpetic Infections- Serious herpetic infections have been reported in clinical trials. Patients who suspect or develop herpes-like lesions should practice good hygiene to stop the spread of the virus. In such cases, patients and their close contacts with suspected herpes infections should immediately notify their doctors.

• Complications at the Injection Site- Patients who are treated with Talimogene Laherparepvec are susceptible to necrosis and ulceration of the tumor tissue. Cellulitis and bacterial infections are often reported during clinical trials. In cases of persistent infection and delayed wound healing, weigh the risks and benefits of the drug before continuing treatment.

• Plasmacytoma at the Site of Injection- Plasmacytoma is a plasma cell tumor that can develop in either bony or soft tissue and can develop anywhere in the body without showing signs of a systemic illness. It has been reported in a few cases of drug administration where the patient was suffering from multiple myeloma. Hence all the benefits and risks should be properly evaluated before injecting such patients.

• Airway Obstruction- Obstruction to the air passage has been reported in a few cases of Talimogene Laherparepvec injections, and hence it has to be administered cautiously.

• Hepatic Bleeding- Transcutaneous hepatic route of injection is contraindicated. During clinical trials, it was noted that patients who were administered drugs via this route reported hepatic bleeding.

Drug Use in Specific Population:

• Pregnancy- There have not been any adequate or carefully monitored studies with Talimogene Laherparepvec on expectant mothers. The potential risks to the fetus and newborn should be discussed with the patient if she becomes pregnant while taking Talimogene Laherparepvec. When taking Talimogene Laherparepvec, pregnant women should be advised to use an effective form of contraception to avoid getting pregnant.

• Lactation- The presence of Talimogene Laherparepvec in human milk, its effects on nursing infants, or its impact on milk production are unknown. It is important to consider the advantages of breastfeeding for a child's development and health, as well as the mother's medical need for Talimogene Laherparepvec. Since medicinal products can be traced in human milk and the effects of the drug on breast milk are unknown, and hence doctors need to decide whether the mother should stop breastfeeding or continue it.

• Pediatric Use- No data available for safety and efficacy in pediatric patients.

• Geriatric Patients- Geriatric patients (those over 65) and younger patients did not exhibit any overall differences in safety or efficacy in clinical studies.

• Renal and Hepatic Impairment- No clinical studies are available to understand the efficacy of the drug on renal and hepatic impairment.

• Fertility- Clinical trials to obtain information on the effect of the drug on the fertility of men and women have not been conducted.

Clinical Studies:

• Trial Type- Multicenter, open-label, randomized clinical study. In the trial, the evaluation of the safety and efficacy of intralesional injection of Talimogene Laherparepvec was compared to that of GM- CSF (granulocyte-macrophage colony-stimulating factor).

• Patient Inclusion- Patients in stages IIIB and IIIC and stage IV of melanoma participated in the study. The tumor in these patients could not be surgically resected. The previous systemic treatment, which was ongoing for the patients, was continued.

• Patient Exclusion- The study excluded patients who had active bone malignancy, extended visceral disease, predominant ocular or mucosal melanoma, active cerebral metastases, signs of immunosuppression, or who were being treated with a systemic antiherpetic drug.

• Study Procedure- Treatment duration was either six months or till all the lesions were injected with the drug. The treatment continued even if the lesion grew larger or a new lesion developed, provided the patient did not experience intolerable side effects or the researcher felt stopping the treatment or switching to another treatment modality for melanoma kept in the patient’s best interests. After completing six months of treatment, patients were instructed to continue their regimen for up to 12 months or until clinically relevant disease progression (defined as disease progression accompanied by a decline in performance status and/or the need for alternative therapy, in the investigator's opinion) was noticed in them. Unless there were no injectable lesions left or the disease had progressed, patients who responded to a treatment of 12 months after treatment initiation could continue treatment for another six months. For at least 36 months, all patients were to be followed up on for survival status.

• Clinical Study Result- The test results showed that no important data was obtained for the overall survival rate between the Talimogene Laherparepvec and the GM-CSF (granulocyte-macrophage colony-stimulating factor) was found.