James Boyd Whitmore

Humoral Immune Response against Nontargeted Tumor Antigens after Treatment with Sipuleucel-T and Its Association with Improved Clinical Outcome

Purpose: Antitumor activity of cancer immunotherapies may elicit immune responses to nontargeted (secondary) tumor antigens, or antigen spread. We evaluated humoral antigen spread after treatment with sipuleucel-T, an immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), designed to target prostatic acid phosphatase (PAP; primary antigen). Experimental Design: Serum samples from patients with mCRPC enrolled in the placebo-controlled phase III IMPACT study (evaluable n = 142) were used to assess humoral antigen spread after treatment with sipuleucel-T. Immunoglobulin G (IgG) responses to self-antigens (including tumor antigens) were surveyed using protein microarrays and confirmed using Luminex xMAP. IgG responses were subsequently validated in ProACT (n = 33), an independent phase II study of sipuleucel-T. Association of IgG responses with overall survival (OS) was assessed using multivariate Cox models adjusted for baseline prostate-specific antigen (PSA) and lactate dehydrogenase levels. Results: In patients from IMPACT and ProACT, levels of IgG against multiple secondary antigens, including PSA, KLK2/hK2, K-Ras, E-Ras, LGALS8/PCTA-1/galectin-8, and LGALS3/galectin-3, were elevated after treatment with sipuleucel-T (P < 0.01), but not control. IgG responses (≥2-fold elevation posttreatment) occurred in ≥25% of patients, appeared by 2 weeks after sipuleucel-T treatment, and persisted for up to 6 months. IgG responses to PSA and LGALS3 were associated with improved OS in sipuleucel-T–treated patients from IMPACT (P ≤ 0.05). Conclusions: Sipuleucel-T induced humoral antigen spread in patients with mCRPC. IgG responses were associated with improved OS in IMPACT. The methods and results reported may identify pharmacodynamic biomarkers of clinical outcome after sipuleucel-T treatment, and help in clinical assessments of other cancer immunotherapies. Clin Cancer Res; 21(16); 3619–30. ©2015 AACR. See related commentary by Hellstrom and Hellstrom, p. 3581

Integrated Safety Data From 4 Randomized, Double-Blind, Controlled Trials of Autologous Cellular Immunotherapy With Sipuleucel-T in Patients With Prostate Cancer

PURPOSE We describe the safety of sipuleucel-T using an integrated analysis of 4 randomized, controlled studies in patients with prostate cancer. MATERIALS AND METHODS Adverse events, survival data and laboratory evaluations were examined for common, rare and latent events. RESULTS In 5% or more of sipuleucel-T cases some adverse events were reported at a rate at least twice that in controls, including chills in 53.1%, pyrexia in 31.3%, headache in 18.1%, myalgia in 11.8%, influenza-like illness in 9.7% and hyperhidrosis in 5.0%. These events generally occurred within 1 day of infusion, were grade 1 or 2 in severity and resolved in 2 days or less. The incidence of serious adverse events reported was 24.0% in sipuleucel-T cases and 25.1% in controls. Grade 3 or greater adverse events were reported within 1 day of infusion in 40 of 601 sipuleucel-T cases (6.7%) and 7 of 303 controls (2.3%). The incidence rate of reported cerebrovascular events was 3.5% for sipuleucel-T cases and 2.6% in controls. CONCLUSIONS Sipuleucel-T therapy in patients with prostate cancer has a side effect profile that is characterized by mild to moderate, short-term, reversible adverse events. There was no evidence of a treatment related increase in autoimmune complications or secondary malignancies after treatment with sipuleucel-T. Sipuleucel-T can be administered safely in the outpatient setting.

Re: Interdisciplinary Critique of Sipuleucel-T as Immunotherapy in Castration-Resistant Prostate Cancer

Vol. 104, Issue 18 | September 19, 2012 References 1. Huber ML, Haynes L, Parker C, Iversen P. Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer. J Natl Cancer Inst. 2012;104(4):273–279. 2. Kantoff PW, Higano CS, Shore ND, et al.; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–422. 3. Murali-Krishna K, Ahmed R. Cutting edge: naive T cells masquerading as memory cells. J Immunol. 2000;165(4):1733–1737. 4. Brown IE, Blank C, Kline J, Kacha AK, Gajewski TF. Homeostatic proliferation as an isolated variable reverses CD8+ T cell anergy and promotes tumor rejection. J Immunol. 2006;177(7):4521–4529. 5. Kline J, Brown IE, Zha YY, et al. Homeostatic proliferation plus regulatory T-cell depletion promotes potent rejection of B16 melanoma. Clin Cancer Res. 2008;14(10):3156–3167. 6. Goldrath AW, Bogatzki LY, Bevan MJ. Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J Exp Med. 2000;192(4):557–564. 7. Schietinger A, Delrow JJ, Basom RS, Blattman JN, Greenberg PD. Rescued tolerant CD8 T cells are preprogrammed to reestablish the tolerant state. Science. 2012;335(6069):723–727. 8. Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23(10):2346–2357.

An overview of sipuleucel-T: Autologous cellular immunotherapy for prostate cancer

Sipuleucel-T, the first autologous active cellular immunotherapy approved by the United States Food and Drug Administration, is designed to stimulate an immune response to prostate cancer. Sipuleucel-T is manufactured by culturing a patient’s peripheral blood mononuclear cells (including antigen presenting cells) with a recombinant protein comprising a tumor-associated antigen (prostatic acid phosphatase) and granulocyte-macrophage colony stimulating factor. Treatment consists of 3 infusions at approximately 2-week intervals, resulting in a prime-boost pattern of immune activation, a robust antigen-specific cellular and humoral immune response, and, consequently, a survival benefit in subjects with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer. Adverse events are generally mild to moderate and resolve within 2 d. Serious adverse events occur at a low rate. As the first autologous cellular immunotherapy to demonstrate a survival benefit, sipuleucel-T is a novel oncologic therapeutic that warrants the reassessment of the current prostate cancer treatment paradigm.

Time to disease-related pain and first opioid use in patients with metastatic castration-resistant prostate cancer treated with sipuleucel-T

Background:Sipuleucel-T has demonstrated improved overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). This analysis examined the effect of sipuleucel-T on time to disease-related pain (TDRP) and time to first use of opioid analgesics (TFOA) in mCRPC using data pooled from three randomized phase III studies in men with asymptomatic or minimally symptomatic mCRPC (D9901 (NCT00005947), D9902A (NCT01133704), D9902B (IMPACT; NCT00065442)).Methods:Four-hundred and twenty-eight asymptomatic patients were analyzed for TDRP; 737 patients were analyzed for TFOA. Pain status was collected using logs adjudicated by blinded, independent reviewers. Opioid use for cancer-related pain was identified from medically reviewed reports of concomitant medication. Disease-related pain was defined as pain post enrollment. TDRP and TFOA were analyzed using the Kaplan–Meier method and Cox regression.Results:Treatment with sipuleucel-T was not associated with a significant difference in TDRP (hazard ratio (HR)=0.819; 95% confidence interval (CI): 0.616–1.089; P=0.170; median TDRP 5.6 months for sipuleucel-T and 5.3 months for control, respectively), although 39.3% of sipuleucel-T-treated patients and 18.9% of control patients were pain-free at 12 months. However, there was a significant delay in TFOA with sipuleucel-T (HR=0.755; 95% CI: 0.579–0.985; P=0.038). Median TFOA for sipuleucel-T was 12.6, and 9.7 months for control, with 50.6% and 43.1% opioid-free at 12 months, respectively. Kaplan–Meier curves for both end points began to diverge at 6 months.Conclusions:Sipuleucel-T was associated with longer TFOA but not significantly longer TDRP. Both end points demonstrated evidence of a delayed treatment effect, consistent with an active immunotherapy.

Quality of life after sipuleucel-T therapy: results from a randomized, double-blind study in patients with androgen-dependent prostate cancer.

OBJECTIVE To collect and analyze quality-of-life (QOL) data from PROvenge Treatment and Early Cancer Treatment trial (PROTECT, NCT00779402), a phase III, randomized controlled trial of sipuleucel-T in patients with asymptomatic androgen-dependent prostate cancer. METHODS Patients experiencing prostate-specific antigen relapse after radical prostatectomy entered a 3- to 4-month run-in phase of androgen-deprivation therapy (ADT), followed by 2:1 randomization to sipuleucel-T or control. QOL was assessed throughout the run-in and 26-week post-randomization phases using the Brief Fatigue Inventory (BFI), Linear Analog Self-Assessment (LASA) scale, Global Rating of Change (GRoC) scale, and an elicited symptoms list. RESULTS One hundred seventy-six patients were randomized into 2 groups, the sipuleucel-T group (n = 117) or the control group (n = 59). The sample provided 80% power to detect a difference in fatigue interference score between treatment arms of 0.9 points. QOL declined predictably during ADT. At week 26, 26.2% of sipuleucel-T-treated patients and 21.6% of control-treated patients (P = .68) reported fatigue in the previous week, and the mean score for fatigue interference in the past 24 hours was 0.9 for both arms (P = .88). Results were comparable for usual fatigue (P = .91) and worst fatigue (P >.99). Mean LASA scores decreased in both groups (P = .26). The proportion of patients reporting better overall QOL on GRoC was similar (P = .62). CONCLUSION There is no clinically significant negative impact on QOL after sipuleucel-T treatment compared with control after a period of ADT in patients with asymptomatic androgen-dependent prostate cancer.

An analysis of leukapheresis and central venous catheter use in the randomized, placebo controlled, phase 3 IMPACT trial of Sipuleucel-T for metastatic castrate resistant prostate cancer.

PURPOSE Sipuleucel-T is an autologous cellular immunotherapy. We review the safety of the leukapheresis procedure required for sipuleucel-T preparation and complications related to venous catheter use in the randomized, placebo controlled phase 3 IMPACT (IMmunotherapy for ProstAte Cancer Trial) study (NCT 00065442). MATERIALS AND METHODS A total of 512 patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer were enrolled in the study. All patients were scheduled to undergo 3 standard 1.5 to 2.0 blood volume leukapheresis procedures at 2-week intervals. Leukapheresis related adverse events and those related to venous catheter use were reviewed. Immune cell counts were examined throughout the treatment course. RESULTS Of 512 enrolled patients 506 underwent 1 or more leukapheresis procedures and were included in this analysis. Adverse events were comparable between the sipuleucel-T and control arms. Leukapheresis related adverse events were primarily associated with transient hypocalcemia (39.3%). Most leukapheresis related adverse events (97%) were of mild/moderate intensity. Median white blood cell count and absolute monocyte and lymphocyte counts were stable and within normal ranges throughout the treatment course. Of all patients 23.3% had a central venous catheter placed primarily for leukapheresis. Patients with vs without a central venous catheter had a higher risk of infection potentially related to catheter use (11.9% vs 1.3%, p <0.0001) and a trend toward a higher incidence of venous vascular events potentially related to catheter use, excluding the central nervous system (5.9% vs 2.1%, p = 0.06). CONCLUSIONS Adverse events related to leukapheresis are manageable and quickly reversible. The majority of patients can undergo leukapheresis without a central venous catheter. Central venous catheters are associated with an increased risk of infections and venous vascular events. Peripheral intravenous access should be used when feasible.

Survival Outcomes of Sipuleucel-T Phase III Studies: Impact of Control-Arm Cross-Over to Salvage Immunotherapy

Control-arm patients from three prostate cancer clinical trials of sipuleucel-T (an autologous APC–based therapy) received APC therapy from their cryopreserved cells. Overall survival may have increased, which suggests that APC therapy may be more robust than estimated. Sipuleucel-T is an autologous cellular immunotherapy for asymptomatic/minimally symptomatic metastatic castrate-resistant prostate cancer (CRPC). After disease progression, control-arm patients on three double-blind, randomized phase III sipuleucel-T trials were offered, in nonrandomized open-label protocols, APC8015F, an autologous immunotherapy made from cells cryopreserved at the time of control manufacture. These exploratory analyses evaluated potential effects on survival outcomes associated with such treatment. Of 249 control-treated patients, 165 (66.3%) received APC8015F. We explored the effects of APC8015F on the overall survival (OS; Cox regression) of control-arm patients and treatment effects of sipuleucel-T versus control adjusted for APC8015F treatment [iterative parameter estimation model (IPE)]. The median time to first APC8015F infusion was 5.2 months (range, 1.8–33.1) after randomization and 2.2 months (0.5–14.6) after progression. After disease progression, median survival was longer for APC8015F-treated versus control-only treated patients [20.0 vs. 9.8 months; HR, 0.53; 95% confidence interval (CI), 0.38–0.74; P < 0.001]; however, baseline characteristics were more favorable for APC8015F-treated patients. Multivariate regression analyses identified lactate dehydrogenase, alkaline phosphatase, hemoglobin, ECOG status, age, and number of bone metastases as potential (P < 0.1) independent predictors of postprogression survival. After adjusting for these predictors, APC8015F (HR, 0.78; 95% CI, 0.54–1.11; P = 0.17) treatment trended toward improved survival. Estimated median OS benefit for sipuleucel-T versus control adjusted for APC8015F treatment was 3.9 months if APC8015F had no effect and was 8.1 months if APC8015F was equally as effective as sipuleucel-T. Exploratory analyses indicate that APC8015F treatment may have extended patient survival, suggesting the sipuleucel-T OS advantage in CRPC may be more robust than previously estimated. Cancer Immunol Res; 3(9); 1063–9. ©2015 AACR.

An analysis to quantify the overall survival (OS) benefit of sipuleucel-T accounting for the crossover in the control arm of the IMPACT study.

144 Background: Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). Our previous analyses on the effect of salvage crossover treatment with a product constructed from previously frozen cells (APC8015F) on OS in the control arms of mCRPC studies of sipuleucel-T suggested a positive treatment effect with salvage therapy (George DJ et al. JCO 2011;29:abstr 139). To quantify how treatment with APC8015F might have impacted the OS of the IMPACT study, we performed an exploratory analysis adjusting for the potential bias that salvage APC8015F might have had in estimating the OS advantage of sipuleucel-T. METHODS After objective disease progression, patients (pts) in the control arm were offered 3 infusions of APC8015F, an autologous immunotherapy made from cells cryopreserved at the time of control generation. A rank-preserving structural failure time (RPSFT) model, as previously described, was applied to adjust the sipuleucel-T treatment effect. RESULTS In the 512-pt IMPACT study, there was a 4.1-month median improvement in OS (25.8 vs 21.7 months) for sipuleucel-T compared to control (HR=0.78; 95% CI: 0.61, 0.98; p=0.032). 109/171 (64%) of control pts received APC8015F; other post-progression interventions were balanced. Median OS was 23.8 months for control pts receiving APC8015F and 11.6 months for control pts not receiving APC8015F. Using the RPSFT model, and assuming APC8015F was equally as effective as sipuleucel-T, the estimate of median OS for control was 18.0 months (HR=0.60, 95% CI: 0.41, 0.95), representing a 7.8-month median improvement in OS in favor of sipuleucel-T. Results from extensions of the RPFST model, where APC8015F is assumed to have less treatment effect than sipuleucel-T, will be presented. CONCLUSIONS Adjusting for a positive effect of APC8015F in the control arm resulted in a sipuleucel-T OS treatment benefit in the IMPACT study ranging from 4.1 to 7.8 months. These results support a greater treatment effect of sipuleucel-T than reported in the IMPACT study and should be factored into future studies without APC8015F crossover.

Relationship of sipuleucel-T with time to first use of opioid analgesics (TFOA) in patients (pts) with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC) on the IMPACT trial.

74 Background: Sipuleucel-T (sip-T) is an autologous cellular immunotherapy which was shown to prolong survival in pts with mCRPC in the pivotal IMPACT trial (NCT00065442) (Kantoff PW et al. N Engl J Med 2010;363:411-22). TFOA was a prespecified secondary end point but was subsequently removed as an end point following a protocol amendment to expand enrollment to include minimally symptomatic pts in addition to asymptomatic pts. TFOA data were nevertheless collected in the 512 pts enrolled in the trial. METHODS At baseline, pts were required to have an average pain score <4 on a 10-point visual analog scale and no ongoing opioid analgesic use (OAU). Concomitant medications were collected until confirmed objective disease progression. OAU was identified by medical review of preferred drug names in the coded concomitant medication information on case report forms (CRFs). OAU unrelated to cancer pain (e.g. meperidine used for infusion reactions) was excluded by medical review of CRFs. Pts not reporting OAU were censored at the time of protocol amendment. TFOA was analyzed using a Cox regression model with adjustment for baseline PSA and LDH. RESULTS 341 sip-T- and 171 placebo-treated patients were evaluated. Median TFOA was 11.9 months (mo) with sip-T vs 8.3 mo for placebo (hazard ratio=0.727; 95% confidence interval 0.536, 0.987; p=0.041). Censoring rate was high (sip-T, 66.9%; placebo, 61.4%). Median follow-up for OAU was 5.2 mo (sip-T, 5.3 mo; placebo, 5.0 mo). Kaplan-Meier estimates of being opioid free at 12 mo were 48.7% for sip-T vs 39.7% for placebo; curve separation began at 6 mo. Significant independent baseline predictors of shorter TFOA were: higher PSA, alkaline phosphatase; younger age; higher number of bone metastases; Gleason score ≥8; ECOG performance status 1; higher weight; and prior primary radiotherapy. CONCLUSIONS Relative to placebo, sip-T delays the TFOA in patients with asymptomatic or minimally symptomatic mCRPC. CLINICAL TRIAL INFORMATION NCT00065442.