Sipuleucel (Provenge)

An immunotherapy for prostate cancer.

Stimulates the immune system, but, unlike traditional vaccines, does not prevent the inception of the disease.

Efficacy based on ability to stimulate antigen presenting cells (APCs) to recognize prostatic acid phosphatase antigen, which is present in 95% of prostate.

Autologous cellular immunotherapy.

Stimulates antitumor activity by inducing an immune response against prostatic acid phosphatase.

Produced by taking cells antigen presenting cells, dendritic, from a patient with prostate cancer, and incorporating them into a vaccine.

Therapy results in tumor cell lysis that may lead to the release of secondary tumor antigens that effect a broader immune response, termed antigen spread.

Works to kill cancer cells by driving T cells into them.

Treatment begins with leukaphoresis where white blood cells are harvested, most importantly dentritic antigen presenting cells are then sent to a manufacturing facility.

These cells or incubated with a recombinant fusion protein consisting of prostatic acid phosphatase, an antigen that is highly expressed in most prostate cancer cells, and granulocyte macrophage colony stimulating factor.

I This vaccine improves overall survival in metastatic castration resistant prostate cancer.

Treatment lasts for just one month, as patients receive a series of three biweekly doses over a 4 week period.

Three or four days after the initial blood draw, only the activated cells are infused into the patient activating in immune system response against PAP-expressing prostate cancer cells.

The procedures conducted three times over a period of six weeks.

Shown to increase prostate cancer patients’ lives by an average of 4.1 months.

Common side effects include chills, fever, and headache, while receiving the infusion.

More severe complications, such as stroke, are rare.

Sipuleucel an autologous active cellular immunotherapy.

A type of therapeutic vaccine.

Treatment requires collecting the patient’s antigen-presenting cells (APCs, specifically dendritic cells) by leukapheresis and then loaded ex-vivo with a fusion protein consisting of prostatic acid phosphatase (PAP) and granulocyte macrophage colony-stimulating factor (GM-CSF).

Consists of autologous peripheral blood mononuclear cells, including antigen presenting cells activated ex vivo with a recombinant fusion protein.

The relationship in prostate cancer between tumor infiltrating lymphocytes (TILs). and survival is unclear.

High TIL infiltrates have been associated with increased risk of recurrence, future metastases, and poor cancer specific survival.

PA2024 consists of prostate antigen, prostatic acid phosphatase, that is fused to granulocyte-macrophage colony stimulating factor, an immune cell activator.

After culturing the fusion protein with the dendritic cells it is then re-infused into the patient thus activating T cells via class I and class II HLA molecules and stimulating an immune response against prostatic acid phosphatase.

Manufactured by culturing peripheral blood mononuclear cells with PA2024, a recombinant protein consisting of the PAP antigen linked with granulocyte-macrophage colony stimulating factor.

Peripheral blood mononuclear cells are obtained by leukapheresis on weeks 0, 2. and 4.

Peripheral blood mononuclear cells cultured with PA2024 infused back into the patient over 3 infusions administered every 2 weeks.

In a phase I-II trial 31 patients treated with this preparation experience the most common adverse reactions of fever, myalgia and mild urinary complaints (Small EJ et al).

In the above trial only three patients had a PSA decline greater than 50% from baseline, but 38% of patients developed an immune response specific to PAP: conclusion was that PSA may not be a valid indicator of a meaningful anticancer response for Immune based treatments.

In a phase 2 trial of 21 patients with hormonally refractive prostate cancer there was again an overall lack of effect on PSA levels and tumor progression was defined as soft tissue progressive disease, two or more new lesions on bone scan: using this definition the median time to progression was 118 days (Burch PA et al).

In a phase III trial of 127 asymptomatic men with with castrate resistant prostate cancer (CRPC) randomized in a 2:1 ratio, sipleucel-T or placebo: no significant difference in time to tumor progression, but a 4.5 month improvement in overall survival (Small EJ etal).

In a double blind placebo controlled trial involving 512 patients with metastatic castration resistant prostate cancer to receive sipuleucel-T or placebo: there was a reduction of 22% in risk of death with sipuleucel, 4.1 month improvement in survival (Immunotherapy for Prostate Adenocarcinoma Treatment study (IMPACT).

Associated with a discordance between observed survival benefit and lack of effect on disease progression.

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