Robust Sipuleucel-T Immune Activity Is Detailed in Pooled Data Analysis

Daniel P. Petrylak, MD

Professor, Medical Oncology Director, Prostate Cancer Research Group Yale Cancer Center Leader, Genitourinary Cancers Medical Oncology Team Smilow Cancer Hospital at Yale-New Haven

New Haven, CT

Patients who received sipuleucel-T (Provenge) developed immune parameters that correlated with improved overall survival, giving researchers a better understanding of how the immunotherapy works at a cellular level and suggesting that these parameters should be the focus of further studies on the treatment.

The results of the study were published in the journal Cancer Immunology, Immunotherapy.¹

The FDA approved sipuleucel-T in 2010 to treat patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). The autologous cellular immunotherapy was the first of its kind approved to treat any type of cancer. Since then, the treatment has received a fair degree of scrutiny, especially since the clinical trials that led to its approval demonstrated an improvement in overall survival, but not in progression-free survival.

The study results should help put such concerns to rest, said Daniel P. Petrylak, MD, one of the authors of the paper. “This is evidence,” he said, “that this product works.”

Sipuleucel-T is created by culturing a patient’s own isolated peripheral blood mononuclear cells, including antigenpresenting cells (APCs). When each dose is prepared, those cells are activated with a fusion protein of the antigen prostatic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor. As a result, when the treated cancer cells are reintroduced into a patient’s body, T cells attack them. The treatment is given to patients in three doses.

Table. Patient Characteristics in Three Key Studies¹

Sipuleucel-T

Control

Patients

488

249

Median age

72

71

ECOG status n (%)

0

393 (80.5%)

199 (79.9%)

1

95 (19.5%)

50 (20.1%)

Gleason sum n (%)

≤6

74 (15.2%)

31 (12.4%)

≥7

413 (84.6%)

217 (87.1%)

Bone metastases >10 n (%)

211 (43.2%)

97 (39.0%)

ECOG indicates Eastern Cooperative Oncology Group.

In order to determine which immune parameters correlate with better overall survival, the study’s authors analyzed three phase III studies⎯D9901, D9902A, and IMPACT⎯in which a total of 737 participants with mCRPC had been randomized 2:1 to receive either sipuleucel-T or a control product (Table). More detailed data involving peripheral immune responses were available only for a subset of patients who took sipuleucel-T during the IMPACT trial, which investigators called a limitation of this review study.

The three parameters the authors used to characterize immunologic responses were the number of APCs, APC activation (measured by CD54 upregulation), and total nucleated cell (TNC) numbers observed in successive doses of sipuleucel-T prepared for study participants.

In the pooled studies overall, the researchers found that APC activation increased in the first dose preparation by a median of 6.2 times (95% CI, 4.7—7.7); by a median of 10.6 times with the second dose preparation (95% CI, 7.8–13.7); and by a median of 10.5 times with the third dose preparation (95% CI, 7.9–13.7) (both P < .001 compared with the first dose). The median APC activation across the three dose preparations was 26.7 (95% CI, 21.5—33.6).

The study found that APC and TNC counts were consistent among the three doses. The median cumulative number of TNCs was 9.70 x 10⁹ (95% CI, 6.97 x 10⁹ —13.55 x 10⁹), while the median cumulative number of APCs was 1.84 x 10⁹ (95% CI, 1.27 x 10⁹—2.88 x 10⁹). Cumulative APC activation, number of APCs, and number of TNCs all correlated with improved overall survival (P < .05).

In a subset of patients who provided blood for immune response determination, progressively more antigen-specific T cells were observed after the second and third doses of sipuleucel-T.

The authors wrote that this analysis supports the supposition that the first infusion of activated, antigen-loaded APCs is able to prime T cells. Those T cells produce cytokines that further activate APCs. By doing so, sipuleucel-T engages the immune system early in the treatment of prostate cancer. APCs are activated ex vivo and end up generating long-lived immune responses once in vivo.

The study’s results “tell us that the immune system and APCs are activated when targeted by Provenge, and that the subsequent cytokines that are induced are upregulated—and that correlates with survival,” Petrylak said. “This is not going to change how we use the therapy, but it may change how some people view it.”

The authors wrote that their findings provide a rationale for larger studies investigating the clinical efficacy of novel immunomodulatory agents, and that, with more such agents available, combination studies with sipuleucel-T should be explored.

Petrylak added that researchers should focus on how to sequence Provenge and four other therapies available to CRPC patients.

“We don’t understand the biology as well as we should,” Petrylak said. “We need good tests to tell us which drug is the best one to use in a given situation. There’s no scientific way of doing this, at this point, and that’s really what the disappointment is. But that tells us where we have to work in the next couple of years to figure this out.”

Reference

1. Sheikh NA, Petrylak D, Kantoff PW, et al. Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer [published online ahead of print August 3, 2012]. Cancer Immunol Immunother. doi: 10.1007/s00262-012-1317-2.