Challenges and Lessons Learned in Autologous Chimeric Antigen Receptor T-Cell Therapy Development from a Statistical Perspective.

Chimeric antigen receptor (CAR) T-cell therapy is a human gene therapy product where T cells from a patient are genetically modified to enable them to recognize desired target antigen(s) more effectively. In recent years, promising antitumor activity has been seen with autologous CAR T cells. Since 2017, six CAR T-cell therapies for the treatment of hematological malignancies have been approved by the Food and Drug Administration (FDA).

Sample size calculation for mixture model based on geometric average hazard ratio and its applications to nonproportional hazard.

With the advent of cancer immunotherapy, some special features including delayed treatment effect, cure rate, diminishing treatment effect and crossing survival are often observed in survival analysis. They violate the proportional hazard model assumption and pose a unique challenge for the conventional trial design and analysis strategies. Many methods like cure rate model have been developed based on mixture model to incorporate some of these features.

Real-World Outcomes with Chimeric Antigen Receptor T Cell Therapies in Large B Cell Lymphoma: A Systematic Review and Meta-Analysis.

Chimeric antigen receptor T cell (CAR-T) therapies, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), are innovative treatments for patients with relapsed or refractory (r/r) large B cell lymphoma (LBCL). Following initial regulatory approvals, real-world evidence (RWE) of clinical outcomes with these therapies has been accumulating rapidly. Notably, several large registry studies have been published recently.

Celebrating LGBT+ History Month 2023.

As LGBT+ History Month kicks off, BVLGBT+ president James Whitmore introduces the society's role model campaign.

Toxicity and Efficacy Probability Interval Design for Phase I Adoptive Cell Therapy Dose-Finding Clinical Trials.

Recent trials of adoptive cell therapy (ACT), such as the chimeric antigen receptor (CAR) T-cell therapy, have demonstrated promising therapeutic effects for cancer patients. A main issue in the product development is to determine the appropriate dose of ACT. Traditional phase I trial designs for cytotoxic agents explicitly assume that toxicity increases monotonically with dose levels and implicitly assume the same for efficacy to justify dose escalation.

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

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.

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.

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.

Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial.

Objective: To explore the prognostic and predictive value of baseline variables in 512 patients with metastatic castration-resistant prostate cancer from the phase III Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial who were randomized to receive sipuleucel-T or control.

Methods: The most powerful of these prognostic factors, baseline prostate-specific antigen (PSA), was subdivided into quartiles to evaluate treatment effect patterns. Cox regression analyses were used to assess predictors of overall survival (OS) and sipuleucel-T treatment effect within PSA quartiles.

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.

Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer.

Purpose: Sipuleucel-T, the first FDA-approved autologous cellular immunotherapy for treatment of advanced prostate cancer, is manufactured by activating peripheral blood mononuclear cells, including antigen presenting cells (APCs), with a fusion protein containing prostatic acid phosphatase. Analysis of data from three phase 3 trials was performed to immunologically characterize this therapy during the course of the three doses, and to relate the immunological responses to overall survival (OS).

Methods: Sipuleucel-T product characteristics [APC numbers, APC activation (CD54 upregulation), and total nucleated cell (TNC) numbers] were assessed in three randomized, controlled phase 3 studies (N = 737).

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.

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.

Etanercept in adult patients with early onset ankylosing spondylitis.

Objective: To determine whether twice-weekly subcutaneous etanercept improves the signs and symptoms of adult patients with early onset ankylosing spondylitis (AS).

Methods: A retrospective analysis was performed on a subgroup of patients with AS with onset < 18 years of age from a multicenter, double-blind, placebo-controlled, randomized study of etanercept in the treatment of patients with AS. Twenty patients met criteria and are presented.

Long-term safety and efficacy of etanercept in children with polyarticular-course juvenile rheumatoid arthritis.

Objective: Previous studies showed that etanercept treatment in patients with polyarticular-course juvenile rheumatoid arthritis (JRA) provided rapid clinical improvement that was sustained for up to 2 years. The goal of our study was to provide data on safety and efficacy after 4 years of etanercept treatment in patients with JRA.

Methods: Patients with active polyarticular-course JRA who participated in an efficacy study continued etanercept treatment in an open-label extension.

Etanercept treatment in adults with established rheumatoid arthritis: 7 years of clinical experience.

Objective: To evaluate safety and efficacy of longterm etanercept treatment in patients with disease modifying antirheumatic drug (DMARD) refractory rheumatoid arthritis (RA).

Methods: Safety results are reported for 714 patients who received etanercept in one of 7 initial trials or a longterm extension. Efficacy results are reported for 581 patients who enrolled in the extension.

Real-world utilization of DMARDs and biologics in rheumatoid arthritis: the RADIUS (Rheumatoid Arthritis Disease-Modifying Anti-Rheumatic Drug Intervention and Utilization Study) study.

Objective: Rheumatoid Arthritis (RA) Disease-Modifying Anti-Rheumatic Drug (DMARD) Intervention and Utilization Study (RADIUS) is a unique, real-world, prospective, 5-year, observational study of over 10 000 patients with RA. RADIUS provides a snapshot of use patterns, effectiveness, and safety of DMARDs, biologics, and combination therapies used to manage RA in clinical practice.

Research Design And Methods: Patients with RA requiring a new DMARD or biologic (addition or switch) were eligible for the RADIUS study.

Longterm safety, efficacy, and radiographic outcome with etanercept treatment in patients with early rheumatoid arthritis.

Objective: To evaluate safety, efficacy, and radiographic progression in patients with early rheumatoid arthritis (RA) undergoing longterm treatment with etanercept.

Methods: Patients with early RA (disease duration of 3 years or less) who had completed a 2-year efficacy study comparing etanercept and methotrexate (MTX) were followed in an extension where they received 25 mg etanercept twice weekly. Safety was summarized descriptively and compared with data from the efficacy study.

Etanercept (Enbrel) in patients with rheumatoid arthritis with recent onset versus established disease: improvement in disability.

Objective: To compare etanercept-induced improvement in disability of patients with recent onset of rheumatoid arthritis (RA) to that of patients with established RA.

Methods: Health Assessment Questionnaire (HAQ) scores were collected over 3 years in 2 groups of patients with RA who were treated with etanercept. The first group consisted of 207 patients with recent onset RA (mean duration of 1 year) who had not previously received methotrexate, and the second group consisted of 464 patients with established RA (mean duration of 12 years) who had failed one or more disease-modifying antirheumatic drugs.

Pneumococcal vaccine response in psoriatic arthritis patients during treatment with etanercept.

Objective: Therapeutics used to treat inflammatory diseases, including psoriatic arthritis (PsA), may potentially interfere with normal immune system function. Immune system function can be assessed by evaluating response to vaccination. We assessed the ability of patients with PsA treated with etanercept to produce antibodies in response to pneumococcal antigen challenge.

Anemia and its relationship to clinical outcome in heart failure.

Background: Anemia is often observed in patients with chronic heart failure (CHF), but its implications for patient outcomes are not well understood. The goal of this study was to investigate the relationship between anemia, severity of CHF, and clinical outcomes.

Methods And Results: Hemoglobin concentration (Hb) was measured in 912 subjects with CHF enrolled in the Randomized Etanercept North American Strategy to Study Antagonism of Cytokines (RENAISSANCE) trial.

4-1BB-specific monoclonal antibody promotes the generation of tumor-specific immune responses by direct activation of CD8 T cells in a CD40-dependent manner.

4-1BB (CD137) is a member of the TNFR superfamily (TNFRSF9). T cell expression of 4-1BB is restricted to activated cells, and cross-linking has been shown to deliver a costimulatory signal. Here we have shown that treatment of tumor-bearing mice with agonistic 4-1BB-specific Abs can lead to T cell-mediated tumor rejection.