Dendritic Cell–Based Approaches
Sipuleucel-T is an autologous active cellular immunotherapy product that consists of autologous peripheral blood mononuclear cells (PBMCs) pulsed ex vivo and activated in vitro with a recombinant fusion protein (PA2024). The recombinant fusion protein, PA2024, is composed of a full-length PAP linked via its COOH terminus to the NH2 terminus of full-length GM-CSF.[45, 46] When administered in vivo, GM-CSF promotes the growth and antigen-presenting capabilities of dendritic cells, leading to T-cell cross-priming. The preparation of sipuleucel-T involves a standard leukapheresis of approximately 1.5 to 2.0 total blood volumes with isolation of PBMCs through density-gradient centrifugation to allow for the removal of platelets and monocytes. The product is then incubated with the recombinant fusion protein PAP2024. After the desired clinical dose has been formulated, the final product is then transported to the respective facility and infused into the patient within 8 hours of formulation. Multiple phase I/II sequential trials evaluated the clinical and immune effects of sipuleucel-T in patients with CRPC. In a trial that included 31 patients with metastatic or non-metastatic CRPC, treatment with sipuleucel-T was administered in weeks 0, 4, and 8, with a fourth infusion in week 24 only to those patients whose disease was stable or better after the initial three infusions. In all patients receiving sipuleucel-T, a T-cell response developed that was defined by the immune response to the recall antigen influenza and to the naive antigen KLH (keyhold limpet hemocyanin). Antibodies to PAP and GM-CSF were also evaluated by specific enzyme-linked immunosorbent assay (ELISA) on serum samples obtained at baseline and then every 4 weeks. None of the patients had pre-existing antibodies to PAP, whereas after treatment, 16 of 31 patients (52%) had antibodies.
Three small prospective phase II studies that included patients with castrate-resistant and androgen-dependent, biochemically relapsed disease initially demonstrated the safety and modest clinical activity of sipuleucel-T in prostate cancer. The first trial, which included 19 men with CRPC, demonstrated a modest PSA response in 2 of the 19 patients (PSA decline > 50% compared with baseline) and no objective disease response in those with Response Evaluation Criteria in Solid Tumors (RECIST)-defined measurable disease. In terms of immune parameters, T-cell responses to PAP2024 were elicited in all evaluated patients; the responses lasted for the entire duration of the clinical trial. Similarly, two small single-institution studies demonstrated that treatment with sipuleucel-T alone or in combination with bevacizumab(Drug information on bevacizumab) (Avastin), a monoclonal humanized antibody against all active isoforms of vascular endothelial growth factor (VEGF), leads to an increase in PSA doubling time in patients with androgen-dependent, biochemically relapsed prostate cancer. While the study of sipuleucel-T monotherapy demonstrated a median increase in PSA doubling time of 62% (4.9 months before treatment vs 7.9 months after treatment; P = .09; signed-rank test), the median increase in PSA doubling time when bevacizumab was added to sipuleucel- T appeared to be greater than 150% (6.9 months vs 12.7 months; P = .01). Although no immune parameters were reported in the monotherapy trial, all patients in the combination study with bevacizumab demonstrated induction of an immune response against sipuleucel-T.
The phase III development program for sipuleucel-T included 2 parallel randomized, double-blind, placebo-controlled studies, D9901 and D9902A.[51,52] D9901 was a multi-institution double-blind, placebo-controlled, randomized phase III trial designed to test the effect of sipuleucel-T on time to progression (TTP) and OS in 127 men with asymptomatic metastatic CRPC. Patients in this trial were randomized in a 2:1 ratio to receive 3 infusions of sipuleucel-T (n=82) or placebo (n=45) every 2 weeks. On disease progression, placebo patients received a similar product made with frozen leukapheresis cells. D9902A was an identical study to D9901 but was prematurely stopped after the initial TTP results from D9901 were reported. Thus, the study was underpowered; it ultimately enrolled only 98 patients.
The primary endpoint of both studies was TTP. Imaging studies were completed every 8 weeks until week 32, then every 12 weeks thereafter, and progression was confirmed by independent review. PSA was not used to determine disease progression or to trigger radiographic evaluations. The median TTP for patients receiving sipuleucel-T in study D9901 was 11.7 weeks, compared with 10.0 weeks for placebo (P = .052; HR, 1.45). Similarly, the TTPs in study D9902A were 10.9 and 9.9 weeks, respectively (P =.719; HR, 1.09). Of the 147 patients from both trials who received sipuleucel-T, only 5 had a PSA reduction of > 50%; the overall PSA response rate was 4.8%. No objective responses were observed in those patients with measurable disease who received sipuleucel-T.
While neither study was powered to determine the impact of sipuleucel-T on OS, a pre-planned 3-year OS assessment was carried out. The median OS in the D9901 study was 25.9 months for sipuleucel-T–treated patients and 21.4 months for those who received placebo (P = .01; HR, 1.70). Although no survival benefit was observed in the D9902A trial (19 months vs 15.7 months; P = .331), when both trials were integrated together, the median OS was 23.2 months for sipuleucel-T and 18.9 months for placebo (P = .011). Similarly, the percentage of patients alive at 36 months was 33% for those who received sipuleucel-T and 15% for those who received placebo. The OS benefit found in these studies was maintained after adjusting for multiple predefined CRPC prognostic factors,[53,54] including the subsequent use of docetaxel(Drug information on docetaxel)-based chemotherapy (P = .022). Also provocative was the strong correlation between CD54 up-regulation and survival (P = .009), observed in both studies. CD54, also known as intracellular adhesion molecule 1, is expressed on dendritic cells and plays an important role in the synapse between dendritic cells and T cells.
To confirm the survival impact of sipuleucel-T, 512 men with metastatic CRPC were randomized (in a 2:1 ratio) in a phase III, double-blind, placebo-controlled, multicenter trial called the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) study. Eligibility for this trial was similar to that in previous CRPC studies.[51,52] All patients were stratified according to Gleason grade, number of bone metastases, and bisphosphonate use. Progressive disease (PD) was independently monitored using PSA and imaging studies at weeks 6, 14, 26, and 34, and every 12 weeks thereafter. During the trial, placebo patients in whom PD developed could enroll in an open-label salvage protocol and receive APC8015F, a product manufactured according to the same specifications as sipuleucel-T from cells cryopreserved at the time the placebo was prepared.
Survival was the primary endpoint of the study, and it was analyzed on the basis of a stratified Cox regression model, with adjustment for the natural logarithm of the baseline levels of PSA and lactate dehydrogenase and stratified according to randomization factors.[54,55] The median OS was 25.8 months for sipuleucel-T–treated patients and 21.7 months for patients who received placebo, with an adjusted HR for death of 0.78 (95% confidence interval [CI], 0.61 to 0.98), which represents a relative reduction in the risk of death of 22% (P = .03). Similar results were obtained with the use of the unadjusted, stratified model and the log-rank test (HR, 0.77; 95% CI, 0.61 to 0.97; P = .02). The reduction in the risk of death from prostate cancer in the sipuleucel-T group (HR, 0.77; 95% CI, 0.61 to 0.98; P = .04) was similar to the reduction in the risk of death from any cause. There was no difference in the median time to objective PD (3.7 months in the sipuleucel-T group vs 3.6 months in the placebo group; HR, 0.95; 95% CI, 0.77 to 1.17; P = .63). Similar results were observed for the time to clinical PD (HR, 0.92; 95% CI, 0.75 to 1.12; P = .40). Only one patient who received sipuleucel-T achieved a partial remission; 2.6% had a PSA decline of < 50%. The estimated effect of sipuleucel-T treatment in those patients who received subsequent docetaxel-based chemotherapy was consistent with the results of the primary efficacy analysis (HR for death, 0.78; 95% CI, 0.62 to 0.98; P = .03).
With regard to immune changes during the study, titers of antibodies against the immunizing antigen PA2024 at any time after baseline were observed in 100 of 151 patients (66.2%) in the sipuleucel-T group and in 2 of 70 patients (2.9%) in the placebo group. Similarly, titers of antibodies against PAP were observed in 43 of 151 patients (28.5%) in the sipuleucel-T group and in 1 of 70 patients (1.4%) in the placebo group. At week 6 of treatment, T-cell proliferation responses (stimulation index, >5) to PA2024 were observed in 73% of patients in the sipuleucel-T group compared with 12% in the placebo group. No changes in the immune correlative studies conducted in this trial correlated with outcome.
Overall, therapy with sipuleucel-T is well tolerated. Almost all patients in the IMPACT trial received all three planned infusions, and no patient withdrew from the study secondary to toxicity. The most common toxicities were grade 1 and grade 2 and included chills, fever (pyrexia), headache, influenza-like illness, myalgia, hypertension, hyperhidrosis, and groin pain. Most of these adverse events occurred within 1 day after infusion and resolved within 1 to 2 days. Among patients in the sipuleucel-T group, grade 3 events that were reported for at least 1 patient within 1 day after infusion were chills (in 4 patients), fatigue (in 3 patients), and back pain, hypertension, hypokalemia, and muscular weakness (in 2 patients each); one grade 4 event was reported (intravenous catheter–associated bacteremia).
The management of CRPC has evolved slowly over the past decade. The evolution of docetaxel-based chemotherapy as a standard of care has been notable but until recently was an isolated therapeutic development. The recent FDA approval of sipuleucel-T and cabazitaxel, and the anticipated approval of abiraterone, will over a very short period of time add three new agents to the treatment armamentarium, all of which independently have improved OS in prostate cancer.
Unlike cabazitaxel and abiraterone, which in addition to a survival advantage have clear evidence of objective anti-tumor activity (as documented by both response rates and impact on PFS), sipuleucel-T’s demonstrated ability to improve OS occurs without evidence of a measurable anti-tumor effect (TTP, objective response rate, and serologic response [PSA reduction]). Some clinicians find it somewhat perplexing that despite the lack of tumor burden reduction when measurable disease was present, treatment with sipuleucel-T was nonetheless able to impact the natural history of this disease in a positive manner. Although sensitivity analyses in the IMPACT trial demonstrated that subsequent treatment (mostly docetaxel-based chemotherapy) did not account for the survival difference observed, the study design was not powered to detect such a difference.
An especially intriguing—but still unanswered—question is what the true mechanism of action of sipuleucel-T is. Therapy with sipuleucel-T has been demonstrated to produce antigen-specific T-cell responses, and patients with elevated antibody titers after treatment appear to have improved survival compared with those without titer elevations. However, these findings require further validation. A better understanding of the immune effects of sipuleucel-T is needed to help improve the selection of patients who are likely to derive the greatest benefit from treatment with this agent.
With the rapid introduction of a number of new agents and the clinical limitations of sipuleucel-T, the question of how to optimally integrate sipuleucel-T into the management paradigm will require additional study and clinical experience. Some early observations can be made in an effort to help guide clinicians in making management choices. Given the absence of direct anti-tumor activity, sipuleucel-T should not be presented to patients as—or utilized as—a “bridge” therapy between treatments (ie, administration of sipuleucel-T will not delay the need for chemotherapy in a patient with a clinical picture of rapidly progressive radiographic disease or with early disease-related symptoms (progressive pain, fatigue, weight loss, etc) With the anticipated approval of abiraterone, the use of corticosteroids in combination with this lyase inhibitor will no doubt raise issues regarding the potential impact of long-term corticosteroid use on the “effectiveness” of sipuleucel-T; there currently is no evidence to guide decision making regarding this vaccine and subsequent use of corticosteroids.
Notwithstanding the challenges involved in the development of immunotherapy for prostate cancer, the regulatory approval of sipuleucel-T has opened the door to multiple opportunities for immune drug development. Future studies will require thoughtful clinical trial designs, including appropriate patient selection and translational and clinical endpoints.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.