IMMUNOCIDIN. Description and Uses. NovaVive Technical Department

Transcription

1 IMMUNOCIDIN Description and Uses NovaVive Technical Department 1

2 Immunocidin Presentation Immunocidin is packaged in a boxed, 2.5 ml vial The active ingredient of Immunocidin is a mycobacterial cell wall fragment (MCWF) of the non-pathogenic, soil bacterium, Mycobacterium phlei Immunocidin is regulated as an immune stimulant 2

3 Immunocidin Mode of Action Immunocidin exhibits anticancer activity by two mechanisms: MCWF Dendritic cells Monocytes Cytokines: IL-6,IL-8, IL-10,IL-12, IL-18, TNF-α NK cells C T cells Indirect: immunomodulatory effect via the induction of anticancer cytokines and/or the stimulation of anti-cancer lymphocytes Cell wall Nucleic Acid Direct Macrophages Indirect Anti-cancer activity NK T cells Direct: by the induction of apoptosis (planned cell death); thereby reducing cancer cell division Cancer cells Apoptosis or cell lysis 3

4 Immunocidin Indications For the treatment of canine mammary tumours Recommended Use Immunocidin is used for the immunotherapy of mixed mammary tumour and mammary adenocarcinoma in dogs Although Immunocidin is administered by intratumoural injection, the response is generalized and untreated sites frequently undergo regression as well 4

5 Immunocidin Mammary Tumours Mixed mammary tumours and mammary adenocarcinomas are more common in female dogs that have not been spayed The risk of developing a mammary tumour in bitches spayed after their second estrus, is 26% (1 in 4) The risk in dogs spayed before their first heat is 0.5% Therefore, the incidence of mammary cancers is dependant on if, or when, a dog is spayed 5

6 Immunocidin Canine mixed mammary tumours and mammary adenocarcinomas can vary in size and location depending on the duration of the disease Tumours can be small or large They can affect one, or multiple mammary glands The cancers often affect the draining lymph nodes Early detection is key for successful treatment 6

7 Immunocidin Treatment Options for Canine Mammary Tumours Currently, surgery is the most common method of treatment. In an attempt to try and minimize recurrence, the surgical procedure involves the removal of the tumour, the associated mammary chain and, often, the associated draining lymph nodes Immunocidin can be used as the sole treatment for mammary tumours It can also be used in conjunction with surgery; in cases where the tumour is large and resection of tissue could be a problem Immunocidin can be used prior to surgery to decrease the size of the tumour(s) ( debulking ) prior to resection Immunocidin can also be used subsequent to surgery to enhance a systemic effect and help remove tissues and cells that might have been missed The use of Immunocidin, alone or in combination with surgery, gives the veterinarian a better tool to minimize metastases 7

8 Immunocidin Preparation for Injection Before use, Immunocidin should be fully re-suspend by shaking the vial or rotating it between the hands until the emulsion is homogeneous Heating the vial under warm water, at approximately 65 O C, will assist the re-suspension process and will not adversely affect the contents. Unused vial contents can be re-refrigerated and used at a later time with no loss of potency Inject the tumour as soon as possible after re-suspension Use a 20 gauge needle or smaller (do not exceed this size) to minimize leak-back loss of product from injection site 8

9 Immunocidin Dosage and Administration The entire tumour and a small region of adjacent and underlying tissue must be thoroughly infiltrated The tumour tissue may be very firm, and excessive pressure on the syringe plunger may be required to infiltrate the entire site The actual dosage varies with tumour size. 1 ml should be considered the minimum dose for any tumour The average dose is 2.5 ml but can range from 1 to 10 ml depending on the size of the tumour and the severity of the case The maximum dose should never exceed 1 ml of Immunocidin per cubic centimetre of tumour The average cumulative dose is about 7.5 to 10 ml (or 3-4 treatments) to achieve remission 9

10 Immunocidin Administration Notes The injection may produce some pain anesthetics or analgesics may be used with no decrease in efficacy Treatment should be repeated every 1 to 3 weeks until the tumour is resolved generally repeated at 10 to 14 day intervals Tumours that fail to respond after 4 treatments should be considered refractory Immunocidin is well tolerated by aged dogs with chronic cardiovascular and renal disease This makes immunotherapy, without surgery, an attractive treatment alternative for those patients that are poor surgical risks 10

11 Immunocidin Treatment Observations A mild, transient fever may be observed (generally < 24 hrs). This is a normal consequence of cytokine release particularly IL-1 and will actually increase the immune response Drowsiness and an increase metabolic rate leading to a decrease in appetite, is also a common cytokine-response There may be some initial swelling and mild sensitivity at the site as the immune system responds to the tumour Superficial tumours may develop a necro-purulant discharge of killed tumour cells. This is NORMAL, and a good sign. Only tumour tissue is destroyed and not healthy cells Clients should be informed that the tumour may drain for several weeks. This purulent material may be aspirated with a sterile syringe and needle. Small draining fistulas can be sealed with astringent applications: silver nitrate or styptic powders All tumour cells will basically die and the immune system will resorb the dead cells and tissue Once all the tumour cells are dead and the cellular debris removed, the body will heal the site in the same fashion as with any normal wound 11

12 Immunocidin Concurrent Administration with Surgery Canine mammary tumours may be treated 2 to 4 weeks prior to surgery to prime the immune system and/or debulk the tumours for surgical removal The use of Immunocidin followed by the surgical removal of the tumour and, if desirable, the proximal mammary glands and drainage lymph nodes will significantly extend the average, tumour-free survival time more than will surgery alone Immunocidin is efficacious when used alone; and can exert a systemic clean-up of missed or metastasised tumour cells when used as an adjunct to surgery 12

13 Immunocidin Treatment Results Immunocidin has been shown to be equally efficacious with mixed mammary tumours and mammary adenocarinomas Over 90% of dogs will respond to treatment, with more than a 50% reduction in tumour size Between 65% and 85% of dogs will go into remission These results are dependent on the severity, progression and duration of the tumour 13

14 Immunocidin Contraindications and Solutions The concurrent use of corticosteroids or ACTH may reduce the efficacy of Immunocidin. E.g., Dexamethasone, Flucort, etc. Animals with a history of hyper-immune responses (vaccination reactions, allergies, etc.) should be monitored closely In the event of urticaria, lymphadenitis or cellulitis, discontinue therapy Anaphylaxis is extremely rare but not unfeasible The use of NSAIDs does not decrease the efficacy of Immunocidin. Meloxicam or phenylbutazone can be used to alleviate pain or reduce the fever 14

15 Immunocidin Storage and Handling Store in a refrigerator at 2-7 O C. Do not freeze Mix well immediately prior to use to ensure emulsification Immunocidin is supplied in 2.5 ml, multi-dose vials Store opened vials with remaining content in a refrigerator as soon as possible after use 15

16 Veterinary Oncology The Seven Most Common Cancers in Dogs (in order of prevalence) 1 Mast cell tumour (mastocytoma) Lymphoma Hemangiosarcoma Osteosarcoma Melanoma Mammary tumours (in younger female and male dogs) Squamous cell carcinoma The most commonly diagnosed cancer in older female dogs (and cats) is mammary cancer. 2 Worldwide, mammary tumours account for approximately 70% of all aged-dog cancers 1 Brakke Consulting Survey, Merlo DF, et al., Cancer incidence in pet dogs: findings of the Animal Tumor Registry of Genoa, Italy. J Vet Intern Med Jul-Aug;22(4):

17 Veterinary Oncology Common Veterinary Treatment Options Surgery Chemotherapy Immunotherapy Other, highly specialized treatment options Radiation therapy Microwave ablation therapy Radioactive seed implantation therapy (Brachytherapy) Photodynamic therapy 17

18 Veterinary Oncology Treatment Options Surgery Although surgery is the most common veterinary approach to small animal oncology cases, it may not be applicable to all types of tumours or in cases of metastastatic cancer 18

19 Veterinary Oncology Treatment Options Chemotherapy Only two chemotherapeutics have been registered for use in veterinary medicine: Palladia (toceranib, Zoetis) for mast cell tumours Approx. 40% of dogs respond, but less than 14% demonstrate total remission Highly toxic and not readily available to general practitioners (Veterinary oncologists) Doxophos (doxorubicin, Oasmia) for lymphoma (MUMS approval in USA) Lymphoma is considered a minor use condition by the US FDA Not registered in Canada And one therapeutic vaccine: ONCEPT (therapeutic, USDA approved vaccine, Merial) for oral melanoma Used in association with surgery for oral melanoma in dogs All other chemotherapeutics are human products that are used off-label 19

20 Veterinary Oncology Treatment Options Use of Off-Label Chemotherapeutics Practically all chemotherapy agents used in veterinary medicine are off-label, and all generate many side effects in the dog Chemotherapeutics are not commonly used in general veterinary practice because of their toxic nature, the risks and liabilities associated with their use, and the specific regulations regarding how these compounds are to be handled [Veterinary] oncologists are familiar with the off-label properties of these chemicals and most usage of these drugs will be in specialized veterinary oncology facilities 20

21 Veterinary Oncology Treatment Options Wellness and Palliative Care Not all clients will elect cancer therapy Some clients may opt for corticosteroids and/or pain medications to reduce the effects of cancer in terminal cases Common medications may include, prednisone, NSAIDs, opioids or off-label intravenous MCWF products, such as diluted Immunocidin NovaVive is currently developing new formulations with different indications and routes of administration. These products have both palliative and anti-cancer effects, and will allow a patient to look, feel and act better while the cancer is being treated. Even if tumour remission is not fully achieved, the patient will lead a better quality of life until either death occurs or life is humanely terminated 21

22 Veterinary Oncology Treatment Options Off-Label Immunotherapy For a number of years, there have been mycobacterial cell wall products that are used intravenously in horses 1 and cattle 2 Current NovaVive studies are investigating new and appropriate intravenous formulations for use in dogs and cats To date, the results from pre-clinical trials are very encouraging Veterinarians and veterinary oncologists who want to discuss off-label uses of Immunocidin should contact the NovaVive Technical Department 1 Equimune I.V. and Settle 2 Immunoboost 22

23 Other Cancer Studies The following are Clinical Case Pilot Studies Cancers Treated: Canine mammary tumour Canine mast cell tumour (mastocytoma) Bladder transitional cell carcinoma Salivary gland carcinoma Nasal squamous cell carcinoma 23

24 Pilot Clinical Studies Mixed Mammary Tumour Skol: Spayed female, mixed breed, 10 y.o., 16 kg No previous treatment Four Immunocidin intratumoural treatments Pre-treatment After 4 th Treatment 24

25 Pilot Clinical Studies Mast Cell Tumour (Mastocytoma) Teko: Male, Brazilian terrier, 13 y.o., 11.2 kg No previous treatment Four Immunocidin intratumoural treatments Pre-treatment After 4 th Treatment 25

26 Pilot Clinical Studies Bladder Transitional Cell Carcinoma Kiko: Male, mixed breed, 10 y.o., 12 kg Previously treated with piroxicam, cystectomy, doxorubicin x5 treatments, mitoxantrone x5 treatments Eight Immunocidin treatments by ultrasound directed, trans-abdominal injection, each 10 to 14 days Pre-treatment After the 8 th Treatment 66% size reduction 26

27 Pilot Clinical Studies Salivary Gland Carcinoma Signalment: Male, Collie cross, 5 y.o., 24.3 kg Previous chemotherapy treatment treatment unknown Four intratumoural Immunocidin treatments at 14 day intervals Prior to Immunocidin Treatment 27

28 Pilot Clinical Studies Salivary Gland Carcinoma A typical progression of Immunocidin treatment and healing Prior to 1 st Immunocidin treatment 5 weeks after first treatment Tumour ulceration and flattening 14 weeks after first treatment Healing by secondary intention 22 weeks after first treatment 28

29 Pilot Clinical Studies Nasal Squamous Cell Carcinoma No history supplied. No final outcome recorded Intratumoural Immunocidin treatments Prior to first Immunocidin treatment At 3 rd treatment At 4 th treatment 29

30 Efficacy of Mycobacterial Cell Wall Fraction (MCWF) in the treatment of osteosarcoma in dogs 1 Intramuscular Immunocidin Introduction Osteosarcoma is the most common bone tumour in dogs Metastatic spread from the primary tumour is the general cause of death (generally to the lungs) Early diagnosed cases are normally treated by amputation of the affected limb Immunocidin has been previously used as an adjunct to surgery Patients 18 dogs with osteosarcoma: 12 with no metastases (Group 1) and 6 with local invasion and/or regional lymph node involvement (Group 2) Treatment Regimen Intramuscular Immunocidin on the day of surgery and each 7 days for 4 more treatments and then each14 days for an additional 7 treatments Dose rates: up to 8 kg, 0.1 ml 9-15 kg, 0.2 ml kg, 0.3 ml over 26 kg, 0.4 ml Results Survival at 6 months 12 months 24 months 36 months Group 1 11/12 (92%) 9/12 (75%) 8/12 (67%) 6/12 (50%) Group 2 6/6 (100%) 3/6 (50%) 1/6 (17%) 0 1 Mangieri J., Fiallos R., Van der Linden I., Hockley D., Masic A. NovaVive Inc., Belleville, Ontario, Canada. 30

31 Efficacy of Mycobacterial Cell Wall Extract (MCWF) in the treatment of appendicular osteosarcoma in dogs 1 Intravenous Immunocidin Formulation Introduction Immunocidin has been used intramuscularly as an adjunctive therapy to amputation for osteosarcoma This pilot study involved the intravenous use of a 1:3 diluted formulation developed from Immunocidin Patients 8 dogs with appendicular osteosarcoma and no radiographic indication of spread to the lungs Treatment Regimen Surgery and intravenous chemotherapy once weekly for six weeks: cisplatin 70 mg/m 2 Two weeks after the last cisplatin injection: diluted Immunocidin injected intravenously each week for 12 weeks Dose rates: < 5 kg, 0.05 ml 5-10 kg, 0.1 ml kg, 0.25 ml kg, 0.5 ml >50 kg, 0.75 ml Results Survival at 6 months 12 months 18 months 24 months 36 months 42 months Conclusion 8/8 (100%) 6/8 (75%) 4/8 (50%) 3/8 (38%) 3/8 (38%) 1/8 (12.5%) The normally accepted survival time for dogs treated for osteosarcoma by amputation and cisplatin chemotherapy is 12 to 18 months. In this small pilot study, the mean survival time following surgery was 23.5 months, with three of eight dogs surviving more than 36 months. These results encourage investigations of MCWE alone, and in conjunction with other chemotherapeutics 1 Mangieri J., Tondi A., Hockley D., Masic A. NovaVive Inc., Belleville, Ontario, Canada. 31

32 Immunocidin Intravenous Safety Studies Two intravenous safety studies have been performed with Immunocidin in healthy dogs of mixed sex, age and of weight The Immunocidin was diluted 1:3 with either the recipients blood or normal saline Either 1 ml (equivalent to 0.25 ml of Immunocidin) or 2 ml (equivalent to 0.5 ml of Immunocidin) was injected intravenously at 7 day intervals for 4 injections No deaths or significant adverse reactions were observed All animals were euthanized 14 days after the final injection No gross pathological lesions were observed in any organs Histological changes in the lungs, liver, bone marrow, myocardium, skeletal muscle and spleen were consistent with immune system activation Conclusions: It is safe to administer 0.25 ml of diluted Immunocidin intravenously to dogs weighing less than 15 kg; and 0.5 ml to dogs weighing more than 15 kg Safety precautions should include pre-warming the vial, diluting Immunocidin with 0.9% NaCl, making sure the emulsion is well mixed and administering the product by slow injection 32

33 IMMUNOCIDIN For additional information, contact NovaVive Inc. General inquiries: