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Tremelimumab – Uses, Dosage, Side Effects, Interaction – Rxharun

Tremelimumab – Uses, Dosage, Side Effects, Interaction

Tremelimumab, formerly known as ticilimumab, is a fully human IgG2 monoclonal antibody directed against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). CTLA-4 is a cell surface receptor expressed on activated T cells to act as a negative regulator for T cells. By binding to CTLA-4, tremelimumab enhances the T cell-mediated killing of tumors and reduces tumor growth.[rx] Because CTLA-4 is an immune checkpoint that plays a vital role in regulating T cell-mediated immune response, tremelimumab is considered an immune checkpoint inhibitor, which is an emerging cancer immunotherapy drug class.[rx]

A drug that binds to the protein CTLA-4 to help immune cells kill cancer cells better and is used to treat different types of cancer. Tremelimumab is used with durvalumab to treat adults with hepatocellular carcinoma (a type of liver cancer) that cannot be removed by surgery. It is also used with durvalumab and platinum chemotherapy to treat adults with non-small cell lung cancer that has spread to other parts of the body and does not have an abnormal EGFR or ALK gene. It is also being studied in the treatment of other types of cancer. Tremelimumab may block CTLA-4 and help the immune system kill cancer cells. It is a type of monoclonal antibody and a type of immune checkpoint inhibitor. Also called Imjudo.

Tremelimumab was first approved by the FDA in October 2022 to be used in combination with durvalumab to treat hepatocellular carcinoma.[rx] It is also being investigated in other cancers, such as colon cancer, pancreatic cancer, non-small cell lung cancer (NSCLC), and malignant melanoma,[rx]

Mechanism of action

T-cell activation is influenced by several processes. T cell receptors (TCR), which are expressed on T cells, bind to the cognate antigen processed and presented by major histocompatibility complex (MHC) expressed on antigen-presenting cells (APC).[rx] This interaction generates a TCR signal to activate T cells. In addition to the TCR signal, optimal T cell activation requires a costimulatory signal, produced when CD80 and CD86, expressed on the surface of APCs, bind to receptors expressed on T cells.1 CD80 and CD86 are also referred to together as B7 molecules.[rx] In response to these signals, activated T cells can be further differentiated into specific T cell subtypes with specialized functions.[rx]

Immune checkpoints are proteins that control the intensity and duration of T cell activation and response. CD28 and CTLA-4 are homologous receptors expressed on CD4+ and CD8+ T cell surfaces.[rx] These immune checkpoints have opposing regulatory functions on T cell activity: CD28 is a positive regulator of T cell activity, while CTLA-4 is a negative regulator suppressing T cell activation and proliferation, as well as IL-2 gene transcription.[rx,rx] B7 molecules act as ligands to both of these receptors,[rx] and the balance between CD28 and CTLA-4 expression and signaling influences the extent of T cell activation. In cancer immunotherapy, CTLA-4 has been investigated as a therapeutic target as blocking this receptor can enhance the activation of tumor-specific T cells, allowing them to exert cytotoxic effects on tumor cells.[rx]

Tremelimumab is an antibody directed against CTLA-4. By binding to CTLA-4, tremelimumab blocks the interaction of CTLA-4 with its ligands, CD80 and CD86, limiting its negative regulatory effect on T-cell activation. Inhibition of CTLA-4 leads to increased proliferation of T cells in tumors and promotes T cell-mediated cytotoxicity.[rx]

Tremelimumab is a cytotoxic agent that works to decrease tumor growth.[rx] It binds to its target, human CTLA-4, with high selectivity [rx] and subnanomolar affinity.[rx] Tremelimumab caused increased IL-2 production in a dose-dependent manner in ex-vivo blood stimulation assays using peripheral blood mononuclear cells (PBMCs) from healthy volunteers and patients with cancer, indicating that tremelimumab stimulated T cell-mediated cytotoxicity. Tremelimumab also increased the proliferation of effector T cells.[rx] In vitro, there was no evidence of nonspecific cytokine release induced by tremelimumab or drug binding to Fc receptors.[rxrx]

Tremelimumab aims to stimulate an immune system attack on tumors. Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, there is also an inhibitory mechanism (immune checkpoint) that interrupts this destruction. Tremelimumab turns off this inhibitory mechanism and allows CTLs to continue to destroy the cancer cells.[4]

Tremelimumab binds to the protein CTLA-4, which is expressed on the surface of activated T lymphocytes and inhibits the killing of cancer cells.[rx] Tremelimumab blocks the binding of the antigen-presenting cell ligands B7.1 and B7.2 to CTLA-4, resulting in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation; subsequently, B7.1 or B7.2 may interact with another T-cell surface receptor protein, CD28, resulting in a B7-CD28-mediated T-cell activation unopposed by B7-CTLA-4-mediated inhibition.[rx]

Indications

  • Tremelimumab is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma in combination with durvalumab.[rx] It is also indicated in combination with durvalumab and platinum-based chemotherapy for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.[rx]
  • Metastatic Non-Small Cell Lung Cancer
  • Unresectable Hepatocellular Carcinoma (HCC)

Contraindications

  • overactive thyroid gland
  • a condition with low thyroid hormone levels
  • diabetes
  • decreased function of the adrenal gland
  • inflammation of the middle tissue heart muscle
  • a type of inflammation of the lung called interstitial pneumonitis
  • inflammation of the large intestine
  • a hole in the intestine
  • kidney inflammation
  • high blood sugar
  • abnormal liver function tests
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • pancreatitis
  • inflammation of the pituitary gland

Dosage

Tremelimumab-act is available in the following dosage form(s) and strength(s):

  • Injection: 25 mg/1.25 mL (20 mg/mL) solution in a single-dose vial.
  • Injection: 300 mg/15 mL (20 mg/mL) solution in a single-dose vial.

Dosage

  • It is essential that the manufacturer’s labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Dosage and Administration

  • Administer tremelimumab-actl as an intravenous infusion over 60 minutes after dilution.
  • The recommended dosage of tremelimumab-actl for the treatment of uHCC in adults is based on body weight as follows:
  • Body weight 30 kg and more: tremelimumab-actl 300 mg as a single dose in combination with durvalumab 1,500 mg at Cycle 1/Day 1, followed by durvalumab 1,500 mg as a single agent every 4 weeks.
  • Body weight less than 30 kg: tremelimumab-actl 4 mg/kg as a single dose in combination with durvalumab 20 mg/kg at Cycle 1/Day 1, followed by durvalumab 20 mg/kg as a single agent every 4 weeks.
  • After Cycle 1 of combination therapy, administer durvalumab as a single agent every 4 weeks until disease progression or unacceptable toxicity occurs.
  • See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions.

Side Effects

Most common

  • Bleeding gums
  • body aches or pain
  • bone pain
  • chest pain or tightness
  • chills
  • constipation
  • coughing up blood
  • depressed mood
  • difficulty swallowing
  • dry skin and hair
  • diarrhea
  • dizziness
  • ear congestion
  • feeling cold
  • hoarseness or husky voice
  • headache
  • increased menstrual flow or vaginal bleeding
  • loss of voice
  • muscle cramps, spasms, pain, stiffness, tenderness, or weakness
  • nervousness
  • nosebleeds
  • paralysis
  • prolonged bleeding from cuts
  • red or dark brown urine
  • red or black, tarry stools
  • sensitivity to heat
  • sleeplessness
  • slow heartbeat
  • sneezing
  • sore throat
  • stomach cramps, tenderness, or pain
  • stuffy or runny nose
  • swollen glands in the neck
  • trouble breathing
  • trouble sleeping
  • unusual tiredness or weakness
  • weight gain or loss

More Common

  • Agitation
  • bloating
  • blood in the urine or stools
  • bloody or cloudy urine
  • coma
  • confusion
  • darkened urine
  • darkening of the skin
  • decreased urine output
  • drowsiness
  • hostility
  • irritability
  • lethargy
  • lightheadedness
  • muscle twitching
  • fainting
  • fast heartbeat
  • fever
  • a general feeling of discomfort or illness
  • indigestion
  • loss of appetite
  • mental depression
  • nausea
  • pains in the stomach, side, or abdomen, possibly radiating to the back
  • pale skin
  • pinpoint red spots on the skin
  • rapid, shallow breathing
  • rapid weight gain
  • seizures
  • skin rash
  • stupor
  • sweating
  • swelling of the face, ankles, or hands
  • swelling of the face, feet, or lower legs
  • thickening of bronchial secretions
  • unusual bleeding or bruising
  • vomiting
  • yellow eyes or skin

Rare

  • Light-colored stools
  • sudden severe weakness
  • upper right abdominal or stomach pain
  • Anxiety
  • back, leg, or stomach pain
  • blistering, peeling, or loosening of the skin
  • blue or pale skin
  • blurred vision or other change in vision
  • burning, tingling, numbness, or pain in the hands, arms, feet, or legs
  • burning feeling in the chest or stomach
  • chest discomfort
  • difficulty in chewing or talking
  • difficulty in moving
  • double vision
  • drooping eyelids
  • eye pain, tearing
  • facial swelling
  • inability to move the arms and legs
  • joint pain
  • numbness or tingling in the fingers, face, or feet
  • pain, swelling, or redness in the joints
  • painful or difficult urination
  • red irritated eyes
  • red skin lesions, often with a purple center
  • redness, soreness, or itching skin
  • redness of the eye
  • seeing flashes or sparks of light
  • seeing floating spots before the eyes
  • the sensation of pins and needles
  • sensitivity of the eye to light
  • severe headache
  • sores, ulcers, or white spots on the lips or in the mouth
  • stabbing pain
  • stiff neck or back
  • stomach upset or discomfort
  • sudden numbness and weakness in the arms and legs
  • swollen, painful, or tender lymph glands in the neck, armpit, or groin
  • swollen or painful glands
  • veil or curtain appearing across part of the vision
  • Lack or loss of strength
  • loss or thinning of the hair
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Drug Interactions

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Pregnancy and Lactation

FDA pregnancy category – Not assigned 

Pregnancy

Based on findings from animal studies and its mechanism of action, tremelimumab-act can cause fetal harm when administered to a pregnant woman. There are no available data on the use of tremelimumab-act in pregnant women. In animal studies, CTLA-4 blockade is associated with an increased risk of immune-mediated rejection of the developing fetus and fetal death.

Lactation

There are no data on the presence of tremelimumab-act in human milk, its effects on a breastfed child, or on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to tremelimumab-act are unknown. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with tremelimumab-actual and for 3 months after the last dose. Refer to the prescribing information for agents administered in combination with tremelimumab-act for breastfeeding recommendations, as appropriate.

Advice to Patients

  • Advise the patient to read the FDA-approved patient labeling (Medication Guide).
  • Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of tremelimumab-actl in combination with durvalumab.
  • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath.
  • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain.
  • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding.
  • Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, type 1 diabetes mellitus, or hypophysitis.
  • Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.
  • Dermatological reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of severe dermatological reactions.
  • Pancreatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of pancreatitis.
  • Other immune-mediated adverse reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of aseptic meningitis, immune thrombocytopenia, myocarditis, hemolytic anemia, myositis, uveitis, keratitis, and myasthenia gravis.
  • Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions.
  • Advise females of reproductive potential that tremelimumab-actl can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy.
  • Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of tremelimumab-actl.
  • Advise female patients not to breastfeed while taking tremelimumab-actl and for at least 3 months after the last dose.
References
Consumer Information – TrustArc The Leader in Privacy Management SoftwareLooking online for info on your child's health? Here are some tipsJanja Kristan - Chief Administrative Officer - AACI | LinkedIn
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