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Thursday 25 April 2019
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Cancer vaccines and issues for pharmacy

PRACTICAL THERAPEUTICS

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Nicola Stoner PhD MRPharmS
(SPresc and IPresc) Dip Clin Pharm RICR FCPP
Consultant Pharmacist - Cancer
Oxford Cancer and Haematology Centre & Oxford Cancer Research Centre, Churchill Hospital,
Oxford University Hospitals NHS Trust
Oxford, UK.
Visiting Professor,
The School of Chemistry, Food and Pharmacy,
University of Reading
Email: nicola.stoner@ouh.nhs.uk
 
Vaccines boost the immune system’s natural ability to protect the body against disease-causing infectious organisms. Traditional vaccines contain killed, altered, or parts of microbes. Cancer vaccines belong to a class of medicines known as biological response modifiers, and are designed to activate B cells and killer T cells, directing them to recognise and act against specific types of cancer. Cancer vaccines can be genetically modified. They can also be classed as virotherapy. 
 
There are two types of cancer vaccine: prophylactic and therapeutic vaccines. Prophylactic vaccines are intended to prevent cancer from developing in healthy people. Therapeutic vaccines are intended to treat an existing cancer by stimulating an immune response to the cancer. The most common side-effects of cancer vaccines include inflammation at the site of injection, including redness, pain, swelling, warming of the skin, itchiness, and occasionally a rash and flu-like symptoms including fever, chills, weakness, dizziness, nausea or vomiting, muscle ache, fatigue, headache, and occasional breathing difficulties. Blood pressure may also be affected, and hypersensitivity can occur.
 
Cancer prophylactic vaccines are similar to traditional vaccines and target the antigens of infectious agents that cause or contribute to the development of cancer. Hepatitis B (HPB) vaccine, which was originally approved in 1981, was the first cancer preventative vaccine to be successfully developed and marketed. Chronic HPB infection can lead to hepatocellular carcinoma, an adenocarcinoma, which is the most common type of liver cancer. HPB vaccine is a recombinant DNA vaccine.
There are two prophylactic cancer vaccines licensed and available in Europe: Gardasil® and Cervarix®. These vaccines protect against infection by types 16 and 18 human papillomavirus (HPV), which cause approximately 70% of all cases of cervical cancer worldwide, as well as some vaginal, vulvar, anal, penile and oropharyngeal cancers. Gardasil® also protects against infection by HPV types 6 and 11, which cause approximately 90% of all cases of genital warts in males and females.
 
There are other cancer-preventative vaccines in clinical trials. Some examples of the carcinogenic viruses and microbes that could be targeted for future prophylactic cancer vaccines include Kaposi sarcoma-associated herpes virus to prevent Kaposi sarcoma, Epstein-Barr virus to prevent Burkitt, Hodgkin’s and non-Hodgkin’s lymphoma, Helicobacter pylori to prevent stomach cancer and Schistosoma hematobium to prevent bladder cancer.(1)
 
Cancer treatment vaccines are designed to treat cancers that have already developed, and are intended to delay or stop cancer cell growth, to cause tumour shrinkage, to prevent cancer from recurring, or to eliminate cancer cells not killed by other forms of treatment. The development of treatment vaccines has required a detailed understanding of how the immune system and cancer cells interact. The immune system does not usually target cancer cells as they are not deemed ‘foreign’, as cancer cells carry both ‘self-antigens’ as well as specific ‘cancer-associated’ antigens. Cancer cells can genetically change and lose their cancer-associated antigens, and can also suppress the anti-cancer immune responses by killer T cells, thus avoiding immune system attack.
 
Treatment vaccines are therefore more challenging to develop than preventative vaccines, as they must be able to stimulate a specific immune response against the correct antigen. This immune response must be able to overcome the barriers that cancer cells use to protect themselves from attack by B cells and killer T cells. The advances in the understanding of how cancer cells escape recognition and attack by the immune system has enabled the design and clinical trials of successful cancer treatment vaccines.(2)
 
Provenge
Provenge® is the only licensed cancer vaccine, and has only been available in the USA since April 2010. Provenge® is licensed for metastatic prostate cancer, and is designed to stimulate an immune response by T-cells to prostatic acid phosphatase (PAP), an antigen found on most prostate cancer cells.(3) 
There are many cancer treatment vaccines in clinical trials for a variety of tumours – pancreas, prostate, bladder, brain, breast, cervical, kidney, melanoma, lung, multiple myeloma, leukaemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, and other solid tumours. Some examples of cancer treatment vaccines in phase III clinical trials include peptide vaccine GV1001 (TeloVac),(4) IMA901,(5) and TroVax®.(6)
 
Vaccines in development
TeloVac
TeloVac (telomerase peptide vaccine GV1001) is currently being assessed for efficacy in a prospective, phase III, randomised, open label, multicentre study in advanced metastatic pancreatic cancer. GV1001 is a 16-amino acid peptide vaccine representing the human telomerase reverse transcriptase catalytic subunit. The aim of the vaccine is to induce an immune response against the protein telomerase, which is widely expressed in pancreatic cancer.
 
The trial compares the combination of gemcitabine and capecitabine with concurrent and sequential immunotherapy with the telomerase peptide vaccine GV1001. The study will assess whether an immune response to GV1001 is induced, the nature of the response, and if patient survival is increased.(4)
 
IMA901
A phase III clinical trial of IMA901 in combination with sunitinib for renal cell carcinoma is currently recruiting patients in the USA and Europe. The primary objective of this phase III study is to investigate whether IMA901 can prolong overall survival in patients with metastatic and/or locally advanced renal cell carcinoma (RCC) when added to standard first-line therapy with sunitinib. Patients are randomised to either sunitinib in combination with IMA901, or sunitinib alone. IMA901 is a cancer vaccine comprising ten different tumour-associated peptides, which are expressed in the majority of patients with renal cell carcinoma. It is an immunotherapy that stimulates T lymphocytes.(5)
 
TroVax
TroVax®  is a therapeutic vaccine comprising the modified vaccinia virus Ankara (MVA) vector, which encodes the 5T4 antigen. TroVax®  stimulates the immune system to destroy cancer cells that express the 5T4 tumour antigen, which is present in approximately 85% of solid tumours. TroVax® is being assessed in phase III clinical trials for RCC, colorectal cancer and prostate cancer. The phase III clinical trial for renal cell cancer, TRIST, showed no increased survival compared to placebo. However, there may be subgroups of patients who will significantly benefit from the treatment, which needs further investigation in future trials.(6)
 
Issues for pharmacy
The main issues include:
  • Procurement
  • Storage
  • Transport
  • Presentation
  • Reconstitution or dilution (if required). 
Most vaccines need to be stored in the fridge or freezer, so it is essential that appropriate storage conditions be adhered to in line with each individual vaccine to ensure that they remain stable. Temperatures need to be monitored as per standard practice, and fridges or freezers need to be secure and with restricted access. It would be deemed good practice for each vaccine to be stored either on separate shelves, or in separated containers.
 
Most vaccines can be drawn up and administered at the bedside, but there may be situations when complex dilutions or reconstitution require pharmacy input. Clinical pharmacists will need to be aware of the toxicity profile and administration instructions so that they can support the multidisciplinary team. The pharmacist will need to be aware of the licensed status of the vaccine. If the vaccine is not licensed, the pharmacist should be aware as to whether it is available on a compassionate use basis or in a clinical trial. The appropriate legislation and local operating procedures would need to be adhered to accordingly.
 
Some cancer vaccines, for example TroVax®, are classified as gene therapy or genetically modified. Some cancer vaccines will be in a group of medicines known as virotherapy, which uses viruses to treat the disease. All these medicines would come under the umbrella of biological therapy. For both virotherapy and genetically modified vaccines or gene therapy, the vaccine would need to be classified as to the biological class of risk and the biological containment level. 
 
For gene therapy and genetically modified vaccines, the regulations of genetically modified organisms would need to be adhered to. Guidance on the pharmacy handling of gene therapy products is available, and would apply to genetically modified cancer vaccines that are classified as gene therapy.(7)
The main principals for handling genetically modified vaccines or virotherapy are that the vaccines need to be handled in a way that protects the product, the person handling the vaccine and the environment. These products are classified as one of four classes (classes 1,2,3 and 4), and the classification determines the level of containment required to control the risk. There are four corresponding levels of containment (containment level 1,2,3 and 4). Containment is where control measures are put in place to limit contact between the product, humans and the environment, to provide a high level of safety. In most cases, these medicines would be classified as class 1 or class 2. Class 1 is unlikely to result in harm to humans or the environment and requires containment level 1. Containment level 1 requires universal precautions, such as wearing a disposable apron and gloves. Class 2 or higher agents are able to cause human disease. The class of product is assessed via a risk assessment.
 
For genetically modified vaccines, a specific risk assessment would be required in accordance with the Health and Safety Executive (in the UK) or similar organisation. The risk assessment would need to include the risk to humans and the environment, the identification of the harmful effects, the characteristics of the proposed activity, the properties of the genetically modified organism, the severity and the risk of the potential effects, the control measures needed, and the disposal methods. Most genetically modified vaccines are unable to replicate, and if they are able to replicate, it would be under specific cellular conditions outside of which they would not replicate.(7–11)
 
Standard operating procedures
Standard operating procedures (SOPs) would need to be in place for handling cancer vaccines that are classified as virotherapy or gene therapy. Standard operating procedures that cover all clinical biological agents, including cell-based therapies, therapeutic genes, vaccines, virotherapy, gene therapy and genetically modified organisms would cover all eventualities. A SOP on the management of this group of medicines would describe the systems in place for managing the safe clinical use of this group of medicines, which represent a negligible to moderate hazard (classes 1 and 2), to ensure compliance with national regulatory, local organisational, and departmental requirements. This SOP would also state the risk assessments required, the training required for staff, and any other health and safety requirements.(7)  
 
A second SOP on the handling of this group of medicines would cover the general extra safety requirements for handling a biological agent from procurement, storage, dispensing, administration to the patient, and disposal. This SOP would be supplemented by agent specific instructions.(7) There would also need to be a SOP on incidents involving biological agents, which would detail how to deal with accidental exposure and spillage, and any specific reporting requirements.(7) Staff involved in handling cancer vaccines classified as virotherapy or gene therapy would need to be trained on the SOPs that need to be followed for this group of medicines.(7) 
 
Conclusions
There is European guidance available for pharmacists on handling genetically modified organisms or gene therapy.(7) This can be adapted for cancer vaccines that are genetically modified and classified as gene medicines. Adherence to national guidance and regulations is vital.
 
Key points
  • There are two types of cancer vaccine: prophylactic and therapeutic.
  • Gardasil and Cervarix are two prophylactic cancer vaccines licensed and available in Europe.
  • Most vaccines can be drawn up and administered at the bedside, but there might be situations when complex dilutions or reconstitution require pharmacy input.
  • There is European guidance available for pharmacists on handling genetically modified organisms or gene therapy, which can be adapted for cancer vaccines that are classified as gene medicines.
  • Pharmacists will need to be aware of the toxicity profile and administration instructions for the vaccine so that they can support the multidisciplinary team. 
 
References
  1. International Agency for Research on Cancer. Agents classified by the IARC Monographs 2011;volumes 1–100. 
  2. Palucka K, Ueno H, Banchereau J. Recent developments in cancer vaccines. J Immunol 2011;186(3):1325–31.
  3. US Food and Drug Administration (FDA) Package Insert 2012. Provenge® www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts... (accessed 2 July 2012).
  4. National Cancer Institute. Phase III randomized study of chemoimmunotherapy comprising gemcitabine hydrochloride and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer. www.cancer.gov/clinicaltrials/search/view?cdrid=528021&version=HealthPro... (accessed 2 July 2012).
  5. ClinicalTrials.gov. A randomized, controlled phase III study investigating IMA901 multipeptide cancer vaccine in patients receiving sunitinib as first-line therapy for advanced/metastatic renal cell carcinoma. http://clinicaltrials.gov/ct2/show/NCT01265901 (accessed 2 July 2012). 
  6. Amato RJ et al. Vaccination of metastatic renal cancer patients with MVA-5T4: A randomized, double-blind, placebo-controlled phase III study. Clin Cancer Res 2010;16(22);5539–47.  
  7. Vulto AG et al (2007) European Association of Hospital Pharmacists (EAHP) guidance on the pharmacy handling of gene medicines. EJHP 2007;13(5):29–39.
  8. Health and Safety Executive. The SACGM Compendium of guidance. Part 1: Introduction to the legislation and general health and safety issues. www.hse.gov.uk/biosafety/gmo/acgm/acgmcomp/part1.pdf (accessed 2 July 2012).
  9. Health and Safety Executive. The SACGM Compendium of guidance. Part 6: Guidance on the use of genetically modified microorganisms in a clinical setting. www.hse.gov.uk/biosafety/gmo/acgm/acgmcomp/part6.pdf (accessed 2 July 2012).
  10. UKSI. The Genetically Modified Organisms (Contained Use) Regulations 2000. 2831: 2000. www.legislation.gov.uk/uksi/2000/2831/pdfs/uksi_20002831_en.pdf (accessed 2 July 2012).
  11. European Parliament. Directive 2000/54/EC of the European Parliament and of the Council of 18 September 2000 on the protection of workers from risks related to exposure to biological agents at work (seventh individual directive within the meaning of Article 16(1) of Directive 89/391/EEC). 2000/54/EC;2000.

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