Scientific information

Autologous Dendritic Cell Cancer Vaccine

A Health Professional Information (Summary Product Information)

Route of Administration: Intravenous

Dosage form Total 12.0 ml in 2 vials

Non-medicinal Ingredients

No known clinically relevant non-medicinal ingredients

Indications & Clincal Use

Denvax is comprised of mature Dendritic cells given along with various cytokines. The source of dendritic cells is patient's own mononuclear cells transformed into cancer-specific dendritic cells by culturing them in the laboratory. Denvax is indicated as adjunctive immunological therapy for the management of patients in stage IV cancers (detailed later) who are not satisfactorily controlled by conventional chemotherapy, surgery and radiotherapy. This therapy is proposed to be useful in delaying cancer progression in treated patients of solid cancers, non-Hodgkin's lymphoma and multiple myeloma.

Geriatrics (>65 years of age)

Systemic studies in geriatrics patients have been conducted and the product Denvax is found safe. (See Warnings and Precautions also)

Pediatrics (<16 years of age)

The safety and efficacy in patients less than 16 years of age has not been established. (See Warnings and Precautions also)

CONTRAINDICATIONS

Denvax is contraindicated in patients who have demonstrated hypersensitivity to the dendritic cells or to any of the components of the formulation.

Warnings & Precautions

General

There are no general warnings with Denvax in all malignancies, of any stage.

Discontinuation of Treatment with Denvax

The treatment can be stopped abruptly without causing any known adverse effects.

Concomitant Use with Chemotherapy/ Radiation

Denvax can be concomitantly given with chemotherapy or radiation therapy but should preferably be given before or after 72 hours of chemotherapy and before or after 24 hours of radiation. During this period the dendritic cells effectively settle down in lymph nodes and generate T and B cell immunity for generating effective anti-cancer immunology.

Concomitant Use with Steroid

Concomitant use of steroids does not hamper the effect of Denvax.

Carcinogenesis and Mutagenesis

The constituents of Denvax do not contain any live malignant cells. It has zero potential to induce malignancy into the patient. Denvax does not promote new cancer formation or aggravate the existing cancer.

Dependence and Tolerance

There is no evidence of dependence and tolerance with Denvax therapy. Discontinuing Denvax treatment will not affect normal immunophysiology of the recipient. It does not enhance the chances of cancer progression.

Special Precautions:
Pregnant Women

There is no adequate and well-controlled study to establish the safety and efficacy of Denvax therapy in pregnant females.

Nursing Women

There are no evidences to prove safety of Denvax therapy in nursing mothers. It has not been used in pregnant or nursing mothers and should be used ONLY if absolutely required.

Geriatrics:

Denvax therapy is safe to be given to the elderly (>65years of age) and is well tolerated. Minor adverse events reported with adults and geriatric population remains in the same ratio.

Monitoring and Laboratory Tests

Clinical data do not indicate that routine monitoring of clinical laboratory parameters is necessary for the safe use of Denvax. The Denvax treatment can even be used in association with other immune regulatory drugs like Dexamethasone and Prednisolone is essential. Cellular immune responses, mainstream of cancer cell therapy will remain functional while generated humoral responses will be hampered.

Adverse Reaction

Commonly Observed Adverse Reactions

The most commonly observed adverse events associated with the usage of Denvax are fever, eliciting within half to two hours of infusion; fever with chills and rigors in the same time period; lethargy; somnolence and fatigue. Vomiting remains the most common adverse reaction and Denvax is ideally given along with intravenous anti-emetics.

Adverse Events leading to Discontinuation

There are no absolute contraindications to Denvax therapy. In a few patients of multiple myeloma, hematuria was reported with first and second dose of therapy along with fever, chills and rigor. The hematuria presented itself in first stream of urine and subsided without any intervention. Occasional patients of osteosarcoma reported increase in pain at the site of disease for 24 to 48 hrs. Later, it resulted in feeling of low pain threshold than pain present before Denvax treatment plan.

Clinical Trials Adverse Drug Reactions

Because clinical trials were conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Drug Interactions

Overview

Denvax is not metabolized to a significant extent in humans and does not interfere with the metabolism of commonly administered chemotherapy drugs. There have been few drug interactions described in which the pharmacokinetics of Denvax or other co-administered drugs were affected to an appreciable extent.

Drug-Drug Interactions

The drug interaction data described in this subsection were obtained from studies involving healthy adults and adult patients with cancer.

Chemotherapy drugs

There is no interaction between Denvax, and other chemotherapy drugs used concomitantly. Consequently, Denvax may be used in combination with other commonly used anticancer drugs without concern for alteration of the plasma concentrations of Denvax or the other anticancer drugs.

Drug-Food Interactions

Denvax may be given intravenously, with or without food.

Drug-Herb Interactions

Interaction with herbal products has not been established.

Action & Clinical Pharmacology

Mechanism of Action

Denvax comprises of 60-70% live, mature dendritic cells along with monocyte growth medium, including cytokines namely IL-2, IL-4, IL-12, IL-6, GM-CSF, G-CSF and TNF-alpha in various proportions. dendritic cells, obtained from patient's peripheral blood mononuclear cells (CD 14+), are cultured ex-vivo on cell-surface treated plates, in the presence of cytokines and nutritional media. On the 6th day of culture, these cells are matured in the presence of tumor lysate (antigenic repertoire). These mature dendritic cells are harvested on the 8th day of culture, for administration. Denvax (amounting to 10.0 ml) is administered intravenously as infusion in 100.0 ml DNS. The cell medium is assessed for aerobic, anaerobic and mycoplasma contamination by routine culture and ELISA techniques. Dendritic cells are counted by Trypan blue exclusion staining for viability and is 90% at the time of packaging. CD83, CD86 and DRII marker studies are done to confirm maturation response.

Upon administration, studies suggest that dendritic cells along with chemokines are transported to lymph nodes within half an hour of infusion. Due to their dendritic processes, dendritic cells attract naïve T cells on their surfaces resulting in their transformation to Committed T lymphocytes. Each dendritic cell has the ability to target up to 5000 T-cells per hour and generate tremendous anti-cancer immunity. B cell activation albeit with low potential also takes place by dendritic cell activation, resulting in production of antibodies against cancer cells. Committed T cells eventually are released in circulatory system and target micro-metastases attacking and killing them. Cancer progression is stopped or delayed resulting in clinical response. Humoral immune response may affect and contribute towards lowering of symptoms of nausea, cachexia and pain associated with advanced disease. The identity of humoral immunity remains to be elucidated.

Pharmacokinetics

All pharmacological actions following Denvax administration are due to the activity of the adoptive immunology by recruiting T and B cells; dendritic cells are neither metabolized in liver nor kidney but accumulated in lymph nodes. Deeper lymph nodes around tumor tissue often become prominent after Denvax treatment.

Absorption

Following intravenous infusion of Denvax, dendritic cells reach to lymph nodes within half to one hour of completion of infusion.

Distribution

Dendritic cells are carried to deeper lymph nodes and are not found in peripheral circulation after 2 hours of infusion.

Metabolism

The cytokines used for the preparation of Denvax are metabolized along with normal metabolic responses; the major component of Denvax is autologous dendritic cell and this does not come under purview of metabolism.

Excretion

Denvax is a cell preparation and is not excreted via the excretory mechanisms.

Bioequivalence of Dosage Forms

Denvax is supplied in two vials having slight variation in constituents and is packed so to create the potency of two vials as separate units. Both vials are finally mixed in infusion at the time of delivery. The vials are to be stored between 4-8oC and have shelf life of 24-30 hours at this temperature.

Storage and Stability

Vials Store at 4-8oC
Viability: Viable 30 hours from package time till infusion.

Dosage Forms, Composition & Packaging

Available as a light pink to pink colored turbid solution (turbidity visible on shaking) packed in two vials, used as single dose, to be given intravenously only. To be diluted in 100 ml of DNS/NS for infusion. (DNS is Dextrose Normal Saline/ NS is Norma Saline)

Dosage Forms

For Palliative Care Settings: To be given every 21 days for three doses. To be given thereafter as monthly dose, or as decided by physician.

Cancer Indications

Breast Cancer including ER/PR/Her2neu negative cancer Hepatocellular

Carcinoma

Gallbladder Cancer

Ovarian Carcinoma

Head and Neck Cancer

Non-Small Cell Lung Cancer

Prostate Cancer

Renal Cell Carcinoma including metastatic disease Thyroid Cancer

Non-Hodgkin's Lymphoma including CD20 negative cancer Multiple

Myeloma

Osteosarcoma

Chondrosarcoma

Soft tissue sarcoma

The Denvax treatment can be given in two settings:

a) Palliative Care;

b) Preventing Relapses.

Palliative care settings:

Denvax treatment is given on monthly basis and should continue if clinical benefits are appreciable. In clinical trials, it has been seen that precisely three doses of Denvax treatment will produce a cumulative effect and can be guidance for efficacy of treatment and its continuation.

Preventing relapse:

In patients achieving CR (complete response) by conventional treatment, Denvax can be given for three months as monthly dose. The relapse rate decreases considerably. Denvax therapy can be extended up to 6 months to 1 year for further reducing the cancer relapse rate to 90%, as compared to historical controls. In highly malignant cancers, giving Denvax treatment for prolonged periods even up to 3 years prevents relapse. Cancers like hepato-biliary cancers, operated gallbladder cancer, glioma multiforme, NSCCL, Osteosarcoma and Head and Neck cancer have shown complete remission with prolonged treatment, in pilot studies done under controlled conditions.

Pharmaceutical information

Denvax contains no active drug component. Denvax is autologous dendritic cell vaccine. It contains one million (+/- 5%) dendritic cells of which 70% (+/- 2%) are mature dendritic cells along with IL-2, IL-4, IL-6, IL-12, GM-CSF, G-CSF, TNF-alpha. During cell culture, IL-4 and GM- CSF are added for transforming mononuclear cells (CD14+) into mature dendritic cells (CD83, CD86, DEC205 positive). Denvax is composed of patient's own mononuclear cells extracted from peripheral blood. Apheresis, a procedure to draw CD14+ cells is not mandatory for dendritic cell culture. The patient's total leucocytes count signifies the amount of whole blood required for making one Denvax dose.

Cancer and The Immune System

Cancer is caused by mutations. It could be familial, environmental or of unknown etiology. During cancer development, self-cells become non-self cells. Mutating cells acquire a shield mechanism for evading immune attack. They may hide their antigenic nature by topographic shield or produce IL-10 for negative chemotaxis or develop an unknown hidden mechanism to evade their arrest. Once the cancer cells start proliferating, the immune mechanisms become so ineffective, that it actually starts contributing towards cancer proliferation. At this stage, cancer develops rapidly and profoundly. Otherwise cancer growth may become slower or delayed if immune system is still able to check it irregularly.

The deranged immune system can be corrected passively by chemotherapy and/or surgery. If it happens this way, cancer patients become cancer survivors, or otherwise, cancer returns with vengeance making itself more resistant to chemotherapeutic drugs used earlier. Normal anti-cancer immunology can be enhanced in laboratory also. The process is similar to the normal immune process except that it is being done in controlled condition in cell surface treated petri-plates. The peripheral blood mononuclear cells are isolated from peripheral blood and cultured with specific cytokines for changing their morphology to dendritic cells. The dendritic cells are given a basic information of cancer type, by adding tumor associated antigens (TAA) and tumor specific antigens (TSA) to the culture plates. Dendritic cells recognize the antigen feedback and respond by producing specific antigenic peptides (representation) on their surfaces. These mature dendritic cells are re-infused to the same patient after eight days of culture for generating specific anti-cancer immunity. After infusion, these dendritic cells along with specific cytokines are carried to various lymph nodes and station themselves in these lymph nodes. They start their physiological action on naïve T cells.

Upon physiological contact with dendrites of DC, T cells become committed in the vicinity of dendritic cells. Each dendriric cell is having a potential to mature 3000-5000 T cells/hour. Dendritic cell survives on an average of 3 weeks to months, and during this period it is able to selectively transform trillions of T cells. The robust anticancer immunology doesn't allow new malignant cells to grow and stops or delays tumor progression. dendritic cells leading to IL-12 and TNF-alpha generation also generate humoral immunology helpful in reducing cachexia.

Toxicology

No acute toxicity has been reported from 1600 doses given to 300 patients in different stages of cancer.

Chronic Toxicity

For systemic toxicity the National Cancer Toxicity scale is used.

For local vaccine toxicities, the following scale was used:

Grade 1, erythema and induration <20 mm

Grade 2, erythema and induration >20 mm, without ulcerarion

Grade 3, ulceration and painful adenopathy

Grade 4, permanent dysfunction related to local toxicity

Carcinogenesis and Mutagenesis

Patients receiving more than 12 doses of Denvax have not reported any new cancer formation after discontinuation of Denvax for more than 24 months.

References

Steinman RM, Dhodapkar M. active immunization against cancer with dendritic cells: the near future. Int. J. Cancer.2001;94:459-473. Nestle OF, Banchereau J, Hart D. Dendritic cells: On the move from bench to bedside. Nature Medicine.2001;7:761-765. Engleman EG. Dendritic cell based cancer immunotherapy. Semin Oncol.2003;30:23-29.

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