Recent Developments In Cancer Vaccines-yamuna

Recent Developments In Cancer Vaccines : 

Recent Developments In Cancer Vaccines By, K.YAMUNA, I M.Pharm (Pharmaceutics) C.L.Baid Metha College of Pharmacy

CANCER : 

CANCER Cancer is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues. Cancer cells can spread to other parts of the body through the blood and lymph systems. (METASTASIS) When genetic material (DNA) of a cell becomes damaged or changed, it produces mutations that affect normal cell growth and division. Thus cells do not die when they should and new cells form when the body does not need them. The extra cells may form a mass called tumor.

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Not all tumors are cancerous; tumors can be benign or malignant. Benign tumors aren't cancerous. They can often be removed, and, in most cases, they do not come back. Cells in benign tumors do not spread to other parts of the body. Malignant tumors are cancerous. Cells in these tumors can invade nearby tissues and spread to other parts of the body. The spread of cancer from one part of the body to another is called metastasis.

Causes for Cancer : 

Causes for Cancer Mutation due to chemical carcinogens- Alcohol, tobacco smoke. Mutation due to ionizing radiations- Radon, UV. Viral or Bacterial infections- HPV, HBV, etc. Hormonal imbalances- hyper estrogenic states in promotes endometrial cancer. Immune system dysfunction- HIV infection, AIDS. Heredity- Inherited mutant genes (BRCA1, BRCA2)

The Immune system & Cancer : 

To the immune system, cancer cells and normal cells differ in a very subtle way. They carry both self antigens and tumor specific antigens. Also, cancer cells don't stimulate a strong immune response. They shed some types of molecules and become less visible to the immune system. Hence cancer cells are tolerated rather than attacked. The Immune system & Cancer

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Thus the main targets to make the cancer cells more visible are the “TUMOR SPECIFIC ANTIGENS”. This concept backs the entire idea of “CANCER VACCINES”. Two broad categories of cancer vaccines Cancer preventive vaccines (Prophylactic) Cancer treatment vaccines (Therapeutic)

Types of cancer vaccines : 

Types of cancer vaccines Antigen vaccines Dendritic cell vaccines Tumor cell vaccines DNA vaccines Idiotype vaccines

Antigen Vaccines : 

Antigen Vaccines The tumor specific antigens (TSA) are utilized in this type. Proteins on the surface of tumor (TSA) are injected into the cancerous area of the patient. This stimulates the immune system, producing increased amounts of antibodies or CTLs. Eg: Cervical cancer vaccines, Hepatitis B vaccine.

Dendritic cell vaccine : 

Dendritic cell vaccine Dendritic cells are a type of white blood cells. They are antigen presenting cells. They are powerful stimulators of immune system. Here, some Dendritic cells from the patient are extracted; grown in laboratory while feeding them cancer-associated antigens. The cells process and present cancer-associated genes to T cells and B cells.

Tumor Cell Vaccines : 

Tumor Cell Vaccines These are produced by using either cancer cells of the patient (AUTOLOGOUS) or from another patient (ALLOGENIC). These cells are killed and injected into the patient. Thus an immune response is stimulated against the antigens on the dead cells.

DNA Vaccines : 

DNA Vaccines Here, the genetic code (DNA) for the protein (antigen) produced by the cancerous cell is identified. Bits of this DNA from the patient’s cell are injected back into the patient. This instructs the other cells to constantly produce some antigens. The increase in antigens forces the immune system to produce more T cells.

Idiotype Vaccines : 

Idiotype Vaccines Antibodies that are produced by a cancerous B cells may serve as antigen markers for some diseases. These are called “ IDIOTYPE ANTIBODIES”. These ID-Antibodies are very unique to an individual patient’s cancer. These antibodies that mimic antigens are extracted from the patient. When injected in large amounts they are able to stimulate an immune response targeting cancerous B cells.

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Cancer Vaccines in Market

Cervical cancer : 

Cervical cancer Cervical cancer is malignant neoplasm of the cervix uteri or cervical area. Human papillomavirus (HPV) infection - necessary factor Other risk factors: Smoking, HIV infection, Chlamydia infection, dietary factors, hormonal contraception, multiple pregnancies, exposure to the hormonal drug diethylstilbestrol (DES) and a family history of cervical cancer.

Classification of Cervical Cancer : 

Classification of Cervical Cancer The WHO was descriptive about the lesions and classified into MILD, MODERATE and SEVERE dysplasia or Carcinoma in situ (CIS). The term, Cervical Intraepithelial Neoplasia (CIN) was developed to place emphasis on the spectrum of abnormality in these lesions, and to help standardize treatment. It classifies mild dysplasia as CIN1, moderate dysplasia as CIN2, and severe dysplasia and CIS as CIN3. The Bethesda system: Low-grade Squamous Intraepithelial Lesion (LSIL) CIN1 High-grade Squamous Intraepithelial Lesion (HSIL) CIN2&3

Current Treatments for Cervical Cancer : 

Current Treatments for Cervical Cancer Surgery – Hysterectomy, Trachelectomy or Loop electrical excision procedure (LOOP). Radiation therapy: External or Internal (Brachytherapy). Chemotherapy: Cisplatin based. Hycamtin+cisplatin (FDA approved)

Prevention of Cervical Cancer : 

Prevention of Cervical Cancer Awareness Regular screening Preventive Vaccination Gardasil – Merck & Co. Cervarix - GSK

GARDASIL : 

GARDASIL A non-infectious recombinant, quadrivalent vaccine. Clinical indication: Prevention of premalignant genital lesions (cervical, vulvar and vaginal), cervical cancer and external genital warts (condyloma acuminata) causally related to Human Papillomavirus (HPV) types 6, 11, 16 and 18

rDNA Technique : 

rDNA Technique

Preparation of Gardasil : 

Preparation of Gardasil Made by recombinant technique. Prepared from highly purified VLPs of the major capsid (L1) protein of HPV types 6,11,16,18. The L1 proteins are produced by separate fermentations in recombinant Saccharmomyces cerevisiae and self-assembled into VLPs. The purified VLPs from the yeast are then adsorbed on preformed aluminium-containing adjuvant (amorphous aluminium hydroxyphosphate sulphate).

Formulation Aspects : 

Formulation Aspects Suspension for intramuscular injection (Deltoid region) in Prefilled syringe Single dose vial Description: Prior to agitation Clear liquid with white precipitate. After agitation White cloudy liquid.

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Label Claim: 1 dose (0.5 ml) contains approximately: HPV Type 6 (L1) - 20 mcg HPV type 11(L1) - 40 mcg HPV type 16(L1) - 40 mcg HPV type 18(L1) - 20 mcg Adjuvant - Amorphous aluminium hydroxyphosphate sulphate adjuvant (225 mcg Al) Excipients-NaCl, L-Histidine,Polysorbate,Sodium borate, Water for injection.

Dosage : 

Dosage Should be administered i.m. as 3 separate 0.5ml doses according to the following schedule: First dose- At elected date Second dose- 2 months after 1st dose Third dose- 6 months after 1st dose All three doses should be given within one year. No dilution or reconstitution required. The full recommended dose of the vaccine should be used. Caution: Shake well before use. Contraindication: Hypersensitivity to API of vaccine; Severe febrile illness and pregnancy. Not for Pediatrics (below age 9). For women from 10-25 years of age.

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Shelf life – 3 years. Storage - Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. Packaging - 0.5 ml suspension in a pre-filled syringe (Type 1 glass) with plunger stopper (siliconized FluroTec-coated bromobutyl elastomer or non-coated chlorobutyl elastomer) and tip cap (bromobutyl) with needle guard (safety) device, without needle or with one or two needle(s) - pack size of 1,10 or 20.

ADR’s : 

ADR’s Very Common: Pyrexia, erythema, pain, swelling, bruising, pruritus (at the injection site). In Clinical trials: Very rare: Bronchospasm Rare: Utricaria. Post marketing Experience: Lymphadenopathy, Hypersensitivity reactions including anaphylactic/anaphylactoid reactions, Guillain-Barré syndrome, dizziness,headache, syncope sometimes accompanied by tonic-clonic movements, nausea, vomiting, arthralgia, myalgia, asthensia, chills, fatigue and malaise.

CERVARIX : 

CERVARIX Non infectious, recombinant, bivalent vaccine. Preventive against HPV types 16 and 18 that cause about 70% of cervical cancer. Regulatory affairs: May 2007- approval in Australia for women (10-45 years of age). 25 AUG 2007- launched at Philippines. SEP 2007- Approved by European union. Awaiting FDA approval by late 2009.

Biotechnology : 

Biotechnology L1 protein in the form of non-infectious virus-like particles (VLPs) are produced by recombinant DNA technology using a Baculovirus expression system which uses Hi-5 Rix4446 cells derived from Trichoplusia ni. The adjuvant AS04 used contains an aluminium salt and monophosphoryl lipid A. This boosts the naturally occurring antibodies.

Formulation Aspects : 

Formulation Aspects A turbid white suspension for injection. Upon storage, a fine white deposit with a clear colorless supernatant may be observed. Available in vials in packs of 1, 10 and 100, or in pre-filled syringes with or without needles in packs of 1 and 10.

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Label Claim: 1 dose (0.5 ml) contains: HPV type 16(L1) - 20 mcg HPV type 18(L1) - 20 mcg Adjuvant: AS04 containing 3-O-desacyl-4'- monophosphoryl lipid A (MPL)3 50 micrograms. Adsorbed on aluminium hydroxide, hydrated (Al(OH)3) 0.5 milligrams Al3+ in total. Excipients: NaCl, Sodium dihydrogen phosphate, water for injection.

Dosage Regimen : 

Dosage Regimen Cervarix is for intramuscular injection in the deltoid region. The recommended vaccination schedule is 0, 1, 6 months. It is recommended that subjects who receive a first dose of Cervarix complete the 3-dose vaccination course with Cervarix. Contraindications: Hypersensitivity to API of vaccine; Severe febrile illness and pregnancy.

ADR’s : 

ADR’s Nervous system disorders : Very common: headache Uncommon: dizziness Gastrointestinal disorders: Common: Nausea, vomiting, diarrhoea and abdominal pain. Skin and subcutaneous tissue disorders: Common: Itching/Pruritus, rash, urticaria Musculoskeletal and connective tissue disorders : Very common: Myalgia Common: Arthralgia Infections and infestations: Uncommon: Upper respiratory tract infection General disorders and administration site conditions: Very common: Pain, redness, swelling; fatigue. Common: fever (38°C). Uncommon: Induration & local paraesthesia.

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Shelf life – 4 years. Storage - Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original package in order to protect from light. should be administered as soon as possible after being removed from the refrigerator. However, stability data generated indicate that Cervarix presented in monodose containers remains stable and can be administered in case it has been stored outside the refrigerator up to three days at temperatures between 8°C and 25°C or up to one day at temperatures between 25°C and 37°C. Caution: Shake well before use.

Cervarix vs Gardasil : 

Cervarix vs Gardasil Cervarix is used by the UK government for its national programme of vaccination for teenage girls. Cervarix was chosen over Gardasil apparently for cost reasons. A study found that Cervarix generated over two times more antibodies than Gardasil for HPV type 16 and over six times more for HPV type 18 at seven months in all women aged 18–45 years (P<0.0001). At seven months Cervarix also induced 2.7 times more memory B cells than Gardasil for both HPV types 16 and 18 (P<0.0001) in women with no detectable B-cell response before vaccination. Cervarix has been used to vaccinate girls aged 12–13 and 17–18 against HPV as part of the UK Government’s cervical cancer vaccination campaign. Cervarix is found to produce immunity for 6.4 years.

Future of Cancer vaccines : 

Future of Cancer vaccines A wide number of cancer vaccines are under various stages of clinical trials. Lung cancer vaccine Lucanix (NovaRx) is under trial. Its tricks the cancer by reducing its immune system suppressing activity. Vaccines for Breast cancer, ovarian cancer, prostrate cancer and many more are under active clinical trials.

References : 

References National Cancer Institute www.cancer.gov WWW.wikipedia.com www.sifynews.com

Acknowledgements : 

Acknowledgements Cancer institute, Adyar, Chennai. Mr. Kumaravel Rajan

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Thank you