description and uses - benson · • the most commonly diagnosed cancer in older female dogs (and...

IMMUNOCIDIN

Description and Uses

NovaVive Technical Department

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®

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

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Immunocidin

Immunocidin exhibits anti-

cancer activity by two

mechanisms:

Indirect: immunomodulatory

effect via the induction of anti-

cancer cytokines and/or the

stimulation of anti-cancer

lymphocytes

Direct: by the induction of

apoptosis (planned cell

death); thereby reducing

cancer cell division

Dendritic cells

Macrophages

Monocytes

Direct

Cytokines: IL-6,IL-8, IL-10 ,IL-12, IL-18, TNF-α

Cell wall

Nucleic Acid

Cancer cells

Indirect Anti-cancer

activity

C T cells

NK cells

NK T cells

Apoptosis or cell lysis

MCWF

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Immunocidin

Mode of Action

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

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Immunocidin

Indications

• 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

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Immunocidin

Mammary Tumours

• 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

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Immunocidin

• 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

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Immunocidin

Treatment Options for Canine Mammary Tumours

• 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 65OC, 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

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Immunocidin

Preparation for Injection

• 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

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Immunocidin

Dosage and Administration

• 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

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Immunocidin

Administration Notes

• 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

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Immunocidin

Treatment Observations

• 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

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Immunocidin

Concurrent Administration with Surgery

• 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

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Immunocidin

Treatment Results

• 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

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Immunocidin

Contraindications and Solutions

• Store in a refrigerator at 2-7OC. 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

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Immunocidin

Storage and Handling

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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, 2009

2 Merlo DF, et al., Cancer incidence in pet dogs: findings of the Animal Tumor Registry of Genoa, Italy. J Vet Intern Med. 2008 Jul-Aug;22(4):976-84.

Surgery

Chemotherapy

Immunotherapy

Other, highly specialized treatment options

Radiation therapy

Microwave ablation therapy

Radioactive seed implantation therapy (Brachytherapy)

Photodynamic therapy

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Veterinary Oncology

Common Veterinary Treatment Options

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

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Veterinary Oncology – Treatment Options

Surgery

• 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

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Chemotherapy

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

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Use of Off-Label Chemotherapeutics

• 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

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Wellness and Palliative Care

For a number of years, there have been mycobacterial cell wall products that are used intravenously in horses1 and cattle2

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

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1 Equimune I.V. and Settle

2 Immunoboost


Off-Label Immunotherapy

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

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Other Cancer Studies

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Skol: Spayed female, mixed breed, 10 y.o., 16 kg

No previous treatment

Four Immunocidin intratumoural treatments

Pre-treatment After 4th Treatment

Pilot Clinical Studies

Mixed Mammary Tumour

Teko: Male, Brazilian terrier, 13 y.o., 11.2 kg

No previous treatment

Four Immunocidin intratumoural treatments

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Pre-treatment After 4th Treatment


Mast Cell Tumour (Mastocytoma)

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

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Pre-treatment After the 8th Treatment

66% size

reduction


Bladder Transitional Cell Carcinoma

Signalment: Male, Collie cross, 5 y.o., 24.3 kg

Previous chemotherapy treatment – treatment unknown

Four intratumoural Immunocidin treatments at 14 day intervals

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Prior to Immunocidin Treatment


Salivary Gland Carcinoma

A typical progression of Immunocidin treatment and healing

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Prior to 1st 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


Salivary Gland Carcinoma

No history supplied. No final outcome recorded

Intratumoural Immunocidin treatments

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At 3rd treatment At 4th treatment

Prior to first Immunocidin treatment


Nasal Squamous Cell Carcinoma

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 16-25 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

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Efficacy of Mycobacterial Cell Wall Fraction (MCWF) in the

treatment of osteosarcoma in dogs1

1 Mangieri J., Fiallos R. , Van der Linden I., Hockley D., Masic A. NovaVive Inc., Belleville, Ontario, Canada.

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/m2

• 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 10-25 kg, 0.25 mL 25-50 kg, 0.5 mL >50 kg, 0.75 mL

Results

Survival at 6 months 12 months 18 months 24 months 36 months 42 months

8/8 (100%) 6/8 (75%) 4/8 (50%) 3/8 (38%) 3/8 (38%) 1/8 (12.5%)

Conclusion

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

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Efficacy of Mycobacterial Cell Wall Extract (MCWF) in the

treatment of appendicular osteosarcoma in dogs1

1 Mangieri J., Tondi A., Hockley D., Masic A. NovaVive Inc., Belleville, Ontario, Canada.

• 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

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Immunocidin

Intravenous Safety Studies

IMMUNOCIDIN

For additional information, contact NovaVive Inc.

General inquiries: 613 391 3837

[email protected]

[email protected]

www.novavive.ca

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®

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