Immunotherapy

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SPECIAL FEATURE

Immunotherapy

Abstract

A paradigm shiftin oncology has been the development of biologic compounds that are not directly cytotoxic, but which canhave significant anti-cancer effects. Immunotherapy represents one such biologic approach to cancer treatment, and prostatecancer is a good immunologic target since it is a highly differentiated gender-specific organ that expresses suitable antigens restricted to the prostate gland. Sipuleucel-T, an investigative active immunotherapy treatment, uses a novel method to stimulate the immune system to attack prostate cancer. Completed phase III studies with sipuleucel-T in metastatic androgen-independent prostate cancer patients show an increase in median overall survival and a mild toxicity profile that does not appear to preclude subsequent treatment with chemotherapy

Cancer Immunotherapy

The concept of using immunologic approaches to treat cancer was described in the literature as early as 1898 by Coley,¹

and has continued since then as an active area of investigation. A key obstacle in this approach to treatment is the ability to entrain the immune response to attack a detected cancer, since the tumors that exist at the time of diagnosis of advanced

metastatic disease have already demonstrated an ability to avoid elimination by the immune system. In prostate cancer, tissue-specific proteins such as prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), and prostate-specific membrane antigen (PSMA)^2,3 have been studied extensively. Animal models have demonstrated the ability to recognize and attack specific prostate cancer-related antigens resulting in the initiation of T-cellmediated immune responses.^4-6 Several immunotherapy approaches are under current investigation for prostate cancer either by nonspecific methods of immunostimulation, exemplified by CTLA-4 receptor blockade, cytokine therapies such as interleukin 12, B7.1 ligand, or toll-like receptor-9-activating oligonucleotides;^7-9 or by antigen-specific targeted therapies including whole-cell vaccines, viral vaccines, and anti-prostate antibody therapies. ^2,3

Adenocarcinoma of the prostate accounts for nearly 30,000 deaths each year, second only to lung cancer in male cancer fatalities.¹⁰ Compared to other malignancies, prostate cancer has been considered relatively resistant to chemotherapy¹¹ and

only one chemotherapy treatment, docetaxel in combination with prednisone, has been shown to improve survival in androgen-independent metastatic disease.¹² Median life expectancy of men with metastatic androgen independent prostate cancer (AIPC) is less than 2 years and the treatment goal in these patients is to extend survival and preserve physical functionality. However, for the asymptomatic metastatic AIPC patient who is reluctant to undergo or is otherwise ineligible for

chemotherapy, there is no alternative treatment approved by the Food and Drug Administration (FDA) that has been shown

to extend survival, and further approaches that have lower toxicology profiles than current chemotherapeutics are needed.

Prostate cancer in particular represents an ideal immunotherapy target since it is a highly difterentiated, gender-specific organ

characterized by a number of proteins that are restricted to prostatic tissue such as PSA, PAP, and PSMA. PAP was chosen as

a suitable target antigen because this protein is expressed at detectable levels in more than 95% of prostate cancers^14,15 and

has been shown to be an eftective antigen in animal models.¹⁶

Sipuleucel-T Immunotherapy

Traditional passive immunization employs subcutaneous injections to deliver antigen to antigen presenting cells (APCs), which are present in the epidermis and dermis. In the standard passive immunization technique, multiple intradermal injections may be required to reach a sufficient number of professional APCs to have the potential to induce a strong immune response. Active immunotherapy stimulates the host’s intrinsic immone response and of the various active immunotherapy approaches under active study in prostate cancer, sipuleucel-T (APC80¹⁵, Dendreon Corporation, Seattle, WA) is the only agent to date that has reported the completion of phase III clinical trials.¹⁷

Sipuleucel-T is a novel active immunotherapy treatment that is designed to stimulate an eftective immune response against prostate cancer. The sipuleucel-T procedure harvests a relatively large quantity of the patient’s own (autologous) peripheral

blood mononuclear cells—including APCs and lymphocytes–and incubates them directly with a recombinant protein containing a prostate-specific antigen. Theoretically, this method is intended to provide exposure of a large number of APCs to the desired antigen and does so away from the immunosuppressive condition that characterizes cancer patients, thereby allowing a potentially stronger immune stimulation.^18,19 The sipuleucel-T process uses a rational recombinant fusion construct, designated PA2024, consisting of full-length PAP protein linked to granulocyte macrophage-colony stimulating factor (GM-CSF). PAP, as mentioned above, is expressed in almost all prostate cancers,^14,15 and GM-CSF acts as an immune stimulator.²⁰ To date, 8 phase I/II studies and several phase III studies, altogether totaling over 400 patients, have been completed with sipuleucel-T.^17,20-22

Preparation of Sipuleucel-T

Sipuleucel-T is prepared by a routine leukapheresis process that collects the patient’s own leukocytes,²³ which are immediately transferred to a central laboratory where they are incubated with the PAP-containing PA2024 fusion protein for approximately 40 hours as shown in Figure 1. The cells are separated by buoyant density centrifugation and washed to remove excess recombinant protein and infused back into the patient where they have the potential to stimulate an immune response against PAP-expressing tumor cells throughout the body. A complete course of sipuleucel-T therapy consists of product preparation and intravenous administration at weeks 0, 2, and 4 for a total of 3 doses as depicted in Figure 2.

Clinical Results from Sipuleucel-T Studies

In a randomized, double-blind, placebo-controlled phase III study, designated D9901, 127 patients with metastatic asymptomatic AIPC were allocated in a 2:1 ratio to receive treatment with either sipuleucel-T or placebo. Patients treated with

sipuleucel-T experienced a median survival of 25.9 months compared to 21.4 months in controls, representing a 4.5-month increase in survival (p=0.010, log-rank; hazard ratio (HR) 1.71) and a 41% decrease in the risk of death at 36 months. A prespecified 3-year survival assessment found that 34% of patients who received sipuleucel-T were alive compared to 11% of patients who received placebo (p=0.005).¹⁷ An analysis of chemotherapy usage in these patients determined that the sipuleucel-T survival benefit was not due to chemotherapy that patients may have received after sipuleucel-T since similar numbers of subjects in each treatment group went on to receive chemotherapy.17 In patients who received sipuleucel-T, median time to objective disease progression was 11.7 weeks compared to 10.0 weeks for control patients (p=0.052, log-rank; HR 1.45).¹⁷

A second identically-designed phase III study, D9902A, which was stopped at a prespecified interim analysis after 98 patients,

showed results that were supportive of D9901. An integrated analysis of both studies included 225 patients and demonstrated

a survival benefit of 4.3 months (p=0.011).²⁴

Other phase III studies of sipuleucel-T include P-11, a study of 176 non-metastatic asymptomatic patients with rising PSA that

has recently been completed. In addition, D9902B is a confirmatory phase III, doubleblind, placebo-controlled study designed

to randomize approximately 500 asymptomatic or mildly symptomatic patients with metastatic AIPC to assess overall survival

and time to progression following treatment with sipuleucel-T.

Safety Profile of Sipuleucel-T

Sipuleucel-T has demonstrated a relatively mild toxicity profile with most adverse events less than or equal to grade 2 in severity.^17,21,22 The most common adverse events observed with sipuleucel-T versus controls in the D9901 study were considered to be infusion-related reactions and included rigors (59.8% versus 8.9%), and pyrexia (29.3% versus 2.2%). Other adverse events included tremor (9.8% versus 0%), and feeling cold (8.5% versus 0%).¹⁷ Most of these symptoms resolved within 1-2 days without recurrence. A Biologics License Application for sipuleucel-T on the basis of the D9901 and D9902A studies has been submitted to the FDA and a regulatory decision is anticipated sometime during 2007.

Future Directions

Sipuleucel-T immunotherapy has shown a survival benefit in advanced AIPC and the large phase III study, D9902B, will

provide additional confirmatory data in this patient population. Analyses of these and other data will help in the design of

additional studies with sipuleucel-T and should be useful in defining the role of this active autologous immunotherapy

approach in conjunction with chemotherapy and/or other biologic treatments. The mild toxicity profile observed in sipuleucel-T studies suggests a potential role for this treatment methodology as part of multimodality management prior to treatment with chemotherapy. For example, a recent exploratory analysis of sipuleucel-T data found that patients who went on to receive docetaxel chemotherapy after sipuleucel-T immunotherapy experienced 9.1 months longer survival compared to patients who received placebo prior to docetaxel.²⁵ Information on the effects of sipuleucel-T treatment in earlier stage androgen-dependent disease will be available upon completion of the P-11 study data analyses that are now in progress.

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