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Neurology and Therapy Dec 2020Since 2010, 27 mixed-treatment comparisons (MTCs) of disease-modifying therapies (DMTs) for multiple sclerosis have been published. However, there has been continued... (Review)
Review
BACKGROUND
Since 2010, 27 mixed-treatment comparisons (MTCs) of disease-modifying therapies (DMTs) for multiple sclerosis have been published. However, there has been continued evolution in the field of MTCs. Additionally, limitations in methodological approach and reporting transparency, even in the most recent publications, makes interpretation and comparison of existing studies difficult.
OBJECTIVES
The objectives of this study are twofold: (1) to estimate the efficacy and safety of DMTs at European Commission-approved doses compared with placebo in adults with relapsing-remitting multiple sclerosis (RRMS) using MTC, and (2) to identify and address methodological challenges when performing MTC in RRMS, thereby creating a baseline for comparisons with future treatments.
METHODS
Searches were completed in 14 databases, including MEDLINE, Embase, CENTRAL, CDSR and DARE, from inception to June 2018 to identify published or unpublished prospective, randomised controlled trials of all European Union-approved DMTs or DMTs expected to be approved in the near future in RRMS or rapidly-evolving severe RRMS. No language or date restrictions were applied. Studies were included in the MTC if they were judged to have sufficiently similar characteristics, based on the following: patient age; proportion of male participants; Expanded Disability Status Scale (EDSS) score; duration of disease; number of relapses prior to enrolment and proportion of previously treated patients. Background information from the included studies, as well as effect size and confidence intervals (where relevant) of defined outcomes were extracted. Reporting of the MTC was consistent with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) network meta-analysis guidelines.
RESULTS
In total, 33 studies were included in the MTC. Annualised relapse rate (ARR 28 trials) was significantly reduced in all treatments compared with placebo. Alemtuzumab had the highest probability (63%) of being the most effective treatment in terms of ARR compared with placebo (rate ratio [RR] 0.28, 95% credible interval [CrI] 0.21-0.38), followed by natalizumab (30% probability; RR 0.32, 95% CrI 0.23-0.43). The risk of 3- and 6-month confirmed disability progression (CDP3M, 13 trials; CDP6M, 14 trials) were similar; CDP6M was significantly reduced for alemtuzumab (hazard ratio [HR] 0.365; 95% CrI 0.165-0.725), ocrelizumab (HR 0.405, 95% CrI 0.188-0.853) and natalizumab (HR 0.459, 95% CrI 0.252-0.840) relative to placebo. There were no significant differences in the odds of serious adverse events (SAEs, 6 trials) between any treatment and placebo. The results of the MTC were limited by the lack of studies reporting direct comparisons between the included treatments and by heterogeneous reporting of key outcome data.
CONCLUSIONS
Meta-analyses confirmed the benefit of all DMTs in terms of relapse rate compared with placebo with a comparable rate of SAEs for the DMTs that could be included in the network. The rigor and transparency of reporting in this study provide a benchmark for comparisons with future new agents.
PubMed: 32989721
DOI: 10.1007/s40120-020-00212-5 -
Journal of Endocrinological... Feb 2020Autoimmune thyroid events (ATEs) are common side effects after alemtuzumab (ALZ) therapy in patients with multiple sclerosis (MS). Our purpose was to reach more robust... (Meta-Analysis)
Meta-Analysis
PURPOSE
Autoimmune thyroid events (ATEs) are common side effects after alemtuzumab (ALZ) therapy in patients with multiple sclerosis (MS). Our purpose was to reach more robust evidence on prevalence and outcome of the spectrum of alemtuzumab-induced autoimmune thyroid events in patients with multiple sclerosis.
METHODS
PubMed and Scopus were systematically searched through July 2019. Studies dealing with patients without personal history of thyroid dysfunctions and affected by MS treated with ALZ and reporting ATEs were selected. Data on prevalence and outcome of ATEs were extracted. A proportion of meta-analysis with random-effects model was performed.
RESULTS
Considering the overall pooled number of 1362 MS patients treated with ALZ (seven included studies), a 33% prevalence of newly diagnosed ATEs was recorded. Among all ATEs, Graves' disease (GD) was the most represented [63% of cases, 95% confidence interval (CI) 52-74%], followed by Hashimoto thyroiditis (15%, 95% CI 10-22%). Interestingly, GD showed a fluctuating course in 15% of cases (95% CI 8-25%). Of all GD, 12% (95% CI 2-42%) likely had spontaneous remission, 56% (95% CI 34-76%) required only antithyroid drugs, 22% (95% CI 13-32%) needed additional RAI, and 11% (95% CI 0.9-29%) underwent definitive surgery.
CONCLUSION
Among different categories of ATEs, Graves' hyperthyroidism was the most common thyroid dysfunction, occurring in more than half of cases. Antithyroid drugs should represent the first-line treatment for ALZ-induced GD patients. However, alemtuzumab-induced GD could not be considered as having a more favourable outcome than conventional GD, given the substantial chance to encounter a fluctuating and unpredictable course.
Topics: Alemtuzumab; Antineoplastic Agents, Immunological; Antithyroid Agents; Humans; Multiple Sclerosis; Observational Studies as Topic; Randomized Controlled Trials as Topic; Thyroid Diseases
PubMed: 31452116
DOI: 10.1007/s40618-019-01105-7 -
Vaccines Jul 2021Understanding the risks of COVID-19 in patients with Multiple Sclerosis (MS) receiving disease-modifying therapies (DMTs) and their immune reactions is vital to analyze... (Review)
Review
Understanding the risks of COVID-19 in patients with Multiple Sclerosis (MS) receiving disease-modifying therapies (DMTs) and their immune reactions is vital to analyze vaccine response dynamics. A systematic review on COVID-19 course and outcomes in patients receiving different DMTs was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Emerging data on SARS-CoV-2 vaccines was used to elaborate recommendations. Data from 4417 patients suggest that MS per se do not portend a higher risk of severe COVID-19. As for the general population, advanced age, comorbidities, and higher disability significantly impact COVID-19 outcomes. Most DMTs have a negligible influence on COVID-19 incidence and outcome, while for those causing severe lymphopenia and hypogammaglobulinemia, such as anti-CD20 therapies, there might be a tendency of increased hospitalization, worse outcomes and a higher risk of re-infection. Blunted immune responses have been reported for many DMTs, with vaccination implications. Clinical evidence does not support an increased risk of MS relapse or vaccination failure, but vaccination timing needs to be individually tailored. For cladribine and alemtuzumab, it is recommended to wait 3-6 months after the last cycle until vaccination. For the general anti-CD20 therapies, vaccination must be deferred toward the end of the cycle and the next dose administered at least 4-6 weeks after completing vaccination. Serological status after vaccination is highly encouraged. Growing clinical evidence and continuous surveillance are extremely important to continue guiding future treatment strategies and vaccination protocols.
PubMed: 34358189
DOI: 10.3390/vaccines9070773 -
Transplant Immunology Oct 2012To compare the efficacy and safety of alemtuzumab versus traditional antibodies for induction therapy in renal transplantation. (Comparative Study)
Comparative Study Meta-Analysis Review
OBJECTIVE
To compare the efficacy and safety of alemtuzumab versus traditional antibodies for induction therapy in renal transplantation.
METHODS
Literature searches for all randomized controlled trials comparing alemtuzumab with traditional antibodies for post renal transplant induction therapy were performed using MEDLINE, EMBASE and the Cochrane Library. Quality assessment was performed in each trial. Meta-analyses were performed to demonstrate the pooled effects of relative risk (RR) with 95% confidence intervals (CI).
RESULTS
A total of 808 participants from six randomized controlled trials (RCTs) were included. Alemtuzumab was associated with lower incidence of biopsy-proven acute rejection over traditional antibodies (RR 0.63, CI 0.45-0.87, p=0.005). This difference remained when only studies comparing alemtuzumab with rabbit antithymocyte globulin were included (RR 0.32, CI 0.11-0.91, p=0.03), but lost significance when only patients at high-risk were included (RR 0.86, CI 0.48-1.55, p=0.62). No significant differences were detected between alemtuzumab and traditional antibodies in terms of delayed graft function, patient death, graft loss, and safety profile.
CONCLUSIONS
Alemtuzumab induction is superior to traditional antibodies in preventing AR in renal transplantation, but this benefit may not extend to recipients at high immunologic risk. The lower rejection rates do not translate into a uniform increase in graft or patient survival.
Topics: Acute Disease; Alemtuzumab; Animals; Antibodies, Monoclonal, Humanized; Antigens, CD; Antigens, Neoplasm; Antilymphocyte Serum; CD52 Antigen; Glycoproteins; Graft Rejection; Humans; Immune Tolerance; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Rabbits; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 22960043
DOI: 10.1016/j.trim.2012.08.006 -
Clinical Pharmacokinetics Feb 2018Alemtuzumab is a humanized monoclonal antibody against CD52 and causes depletion of T and B lymphocytes, monocytes, and NK cells. Alemtuzumab is registered for the... (Comparative Study)
Comparative Study
Alemtuzumab is a humanized monoclonal antibody against CD52 and causes depletion of T and B lymphocytes, monocytes, and NK cells. Alemtuzumab is registered for the treatment of multiple sclerosis (MS) and is also used in chronic lymphocytic leukemia (CLL). Alemtuzumab is used off-label in kidney transplantation as induction and anti-rejection therapy. The objective of this review is to present a review of the pharmacokinetics, pharmacodynamics, and use of alemtuzumab in kidney transplantation. A systematic literature search was conducted using Ovid Medline, Embase, and Cochrane Central Register of controlled trials. No pharmacokinetic or dose-finding studies of alemtuzumab have been performed in kidney transplantation. Although such studies were conducted in patients with CLL and MS, these findings cannot be directly extrapolated to transplant recipients, because CLL patients have a much higher load of CD52-positive cells and, therefore, target-mediated clearance will differ between these two indications. Alemtuzumab used as induction therapy in kidney transplantation results in a lower incidence of acute rejection compared to basiliximab therapy and comparable results as compared with rabbit anti-thymocyte globulin (rATG). Alemtuzumab used as anti-rejection therapy results in a comparable graft survival rate compared with rATG, although infusion-related side effects appear to be less. There is a need for pharmacokinetic and dose-finding studies of alemtuzumab in kidney transplant recipients to establish the optimal balance between efficacy and toxicity. Furthermore, randomized controlled trials with sufficient follow-up are necessary to provide further evidence for the treatment of severe kidney transplant rejection.
Topics: Alemtuzumab; Animals; Antineoplastic Agents, Immunological; Basiliximab; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Treatment Outcome
PubMed: 28669130
DOI: 10.1007/s40262-017-0573-x -
Transplantation Reviews (Orlando, Fla.) Dec 2023Recommendations of the use of antibody induction treatments in kidney transplant recipients (KTR) are based on moderate quality and historical studies. This systematic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Recommendations of the use of antibody induction treatments in kidney transplant recipients (KTR) are based on moderate quality and historical studies. This systematic review aims to reevaluate, based on actual studies, the effects of different antibody preparations when used in specific KTR subgroups.
METHODS
We searched MEDLINE and CENTRAL and selected randomized controlled trials (RCT) and observational studies looking at different antibody preparations used as induction in KTR. Comparisons were categorized into different KTR subgroups: standard, high risk of rejection, high risk of delayed graft function (DGF), living donor, and elderly KTR. Two authors independently assessed the risk of bias.
RESULTS
Thirty-seven RCT and 99 observational studies were finally included. Compared to anti-interleukin-2-receptor antibodies (IL2RA), anti-thymocyte globulin (ATG) reduced the risk of acute rejection at two years in standard KTR (RR 0.74, 95%CI 0.61-0.89) and high risk of rejection KTR (RR 0.55, 95%CI 0.43-0.72), but without decreasing the risk of graft loss. We did not find significant differences comparing ATG vs. alemtuzumab or different ATG dosages in any KTR group.
CONCLUSIONS
Despite many studies carried out on induction treatment in KTR, their heterogeneity and short follow-up preclude definitive conclusions to determine the optimal induction therapy. Compared with IL2RA, ATG reduced rejection in standard-risk, highly sensitized, and living donor graft recipients, but not in high DGF risk or elderly recipients. More studies are needed to demonstrate beneficial effects in other KTR subgroups and overall patient and graft survival.
Topics: Humans; Aged; Antilymphocyte Serum; Immunosuppressive Agents; Kidney Transplantation; Alemtuzumab; Antibodies; Graft Rejection; Lymphocytes; Transplant Recipients; Graft Survival
PubMed: 37774445
DOI: 10.1016/j.trre.2023.100795 -
Medicine Jul 2017Alemtuzumab (ALEM) is widely used as an induction therapy for organ transplantation, and numerous randomized controlled trials (RCTs) have been published to evaluate its... (Comparative Study)
Comparative Study Meta-Analysis Review
Alemtuzumab (ALEM) is widely used as an induction therapy for organ transplantation, and numerous randomized controlled trials (RCTs) have been published to evaluate its efficacy and safety in kidney transplantation as compared with antithymocyte globulin (ATG). The purpose of this study was to compare the benefits and safety of ALEM with those of ATG for induction therapy.A systematic literature search in three electronic databases, including PubMed, EmBase, and Cochrane Library, since inception through October 2016, was conducted to identify potential RCTs for inclusion. Trials that investigated the risk of biopsy-proven acute rejection (BPAR), mortality, graft failure, delayed graft function (DGF), chronic allograft nephropathy (CAN), infections, cytomegalovirus (CMV) infections, new-onset diabetes mellitus after transplant (NODAT), and granulocyte colony stimulation factor (GCSF) use in kidney transplant recipients who received ALEM or ATG as an induction therapy were included. Relative risk (RR) and 95% confidence intervals (CIs) were calculated using a random-effects model.Six RCTs involving 446 kidney transplantation patients were included in this meta-analysis. The effects of ALEM therapy were not significantly different from those of ATG therapy, including the incidence of BPAR (RR: 0.77; 95% CI: 0.51-1.18; P = .229), mortality (RR: 0.64; 95% CI: 0.30-1.39; P = .263), graft failure (RR: 0.81; 95% CI: 0.49-1.33; P = .411), DGF (RR: 1.00; 95% CI: 0.60-1.67; P = .999), CAN (RR: 1.42; 95% CI: 0.44-4.57; P = .556), infections (RR: 1.00; 95% CI: 0.74-1.35; P = .989), CMV infections (RR: 0.70; 95% CI: 0.38-1.30; P = .263), NODAT (RR: 0.50; 95% CI: 0.18-1.36; P = .174), and GCSF use (RR: 1.16; 95% CI: 0.81-1.66; P = .413). Sensitivity analyses were consistent with the overall analysis for all effects except CAN, suggesting that the risk of CAN might be higher with ALEM therapy than ATG therapy (RR: 2.45; 95% CI: 1.02-5.94; P = .046).The findings of this study suggest that the beneficial effects of ALEM therapy are greater than those of ATG therapy in kidney transplantation patients; however, the effects were not statistically significant because of the limited number of trials. Further large-scale RCTs are needed to verify the treatment effects of ALEM.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney Transplantation; Randomized Controlled Trials as Topic
PubMed: 28700465
DOI: 10.1097/MD.0000000000007151 -
Frontiers in Immunology 2024The objective of this study is to evaluate the risk of secondary autoimmune diseases in multiple sclerosis (MS) patients treated with alemtuzumab (ALZ) through a... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND PURPOSE
The objective of this study is to evaluate the risk of secondary autoimmune diseases in multiple sclerosis (MS) patients treated with alemtuzumab (ALZ) through a meta-analysis.
METHODS
PubMed, Web of Science, OVID, EMBASE, and Cochrane central register of controlled trials were searched. Information and data were screened and extracted by 2 researchers. The obtained data were analyzed using the R software meta package. Quality assessment was conducted using the Newcastle-Ottawa Scale (NOS). The causes of heterogeneity were analyzed using subgroup analysis and sensitivity analysis. Publication bias was evaluated using funnel plots and Egger's test.
RESULTS
The search retrieved a total of 3530 papers from the databases. After screening, a total of 37 studies were included in the meta-analysis. The analysis results indicate that the pooled incidence rate of overall secondary autoimmune events (SAEs) in the included studies was 0.2824 [0.2348, 0.3300] (I²=94%, p<0.01). The overall incidence of autoimmune thyroid events (ATE) was 0.2257 [0.1810, 0.2703] (I²=94%, p<0.01). Among them, the rate of serious autoimmune thyroid events (SATE) was 0.0541 [0.0396, 0.0687] (I²=0%, p=0.44). The incidence rates of different thyroid events were as follows: Graves' disease (GD), 0.2266 [0.1632, 0.2900] (I²=83%, p<0.01); Hashimoto thyroiditis (HT), 0.0844 [0.0000, 0.2262] (I²=81%, p=0.02); Hashimoto thyroiditis with hypothyroidism (HTwH), 0.0499 [0.0058, 0.0940] (I²=37%, p=0.21); fluctuating thyroid dysfunction (FTD), 0.0219 [0.0015, 0.0424] (I²=0%, p=0.40); transient thyroiditis (TT), 0.0178 [0.0062, 0.0295] (I²=0%, p=0.94). The overall incidence of hematological events was 0.0431 [0.0274, 0.0621] (I²=70%, p<0.01). The incidence rates from high to low were as follows: lymphopenia, 0.0367 [0.0000, 0.0776] (I²=81%, p=0.02); Idiopathic thrombocytopenic purpura (ITP), 0.0258 [0.0199, 0.0323] (I²=25%, p=0.15); Hemolytic anemia (HA), 0.0177 [0.0081, 0.0391] (I²=29%, p=0.23); pancytopenia, 0.0136 [0.0000, 0.0314] (I²=0%, p=0.67); Neutropenia, 0.0081 [0.0000, 0.0183] (I²=0%, p=0.42). After excluding thyroid and hematological diseases, the combined incidence of other related SAEs was 0.0061 [0.0014, 0.0109] (I²=50%, p=0.02). The incidence of each disease ranked from highest to lowest as: skin psoriasis (SP), 0.0430 [0.0000, 0.0929] (I²=0%, p=0.57); alopecia areata (AA), 0.0159 [0.0024, 0.0372] (I²=19%, p=0.29); vitiligo, 0.0134 [0.0044, 0.0223] (I²=0%, p=0.81); inflammatory atrichia (IA), 0.0103 [0.0000, 0.0232] (I²=0%, p=0.43); chronic urticaria (CU), 0.0107 [0.0000, 0.0233] (I²=0%, p=0.60); and nephropathy, 0.0051 [0.0000, 0.0263] (I²=62%, p=0.02).
CONCLUSION
The occurrence of secondary autoimmune diseases in patients with MS treated with ALZ is noteworthy, particularly in the form of thyroid events and hematological events. Clinicians should monitor the overall condition of patients promptly for early management and avoid delayed diagnosis and treatment.
SYSTEMATIC REVIEW REGISTRATION
inplasy.com/inplasy-2024-4-0048/, identifier INPLASY202440048.
Topics: Humans; Alemtuzumab; Multiple Sclerosis; Autoimmune Diseases; Incidence; Hashimoto Disease
PubMed: 38690271
DOI: 10.3389/fimmu.2024.1343971 -
CNS Drugs Oct 2016This study aimed to test the number needed to treat to benefit (NNTB) and to harm (NNTH), and the likelihood to be helped or harmed (LHH) when assessing benefits, risks,... (Meta-Analysis)
Meta-Analysis Review
Benefit-Risk of Therapies for Relapsing-Remitting Multiple Sclerosis: Testing the Number Needed to Treat to Benefit (NNTB), Number Needed to Treat to Harm (NNTH) and the Likelihood to be Helped or Harmed (LHH): A Systematic Review and Meta-Analysis.
OBJECTIVE
This study aimed to test the number needed to treat to benefit (NNTB) and to harm (NNTH), and the likelihood to be helped or harmed (LHH) when assessing benefits, risks, and benefit-risk ratios of disease-modifying treatments (DMTs) approved for relapsing-remitting multiple sclerosis (RRMS).
METHODS
In May 2016, we conducted a systematic review using the PubMed and Cochrane Central Register of Controlled Trials databases to identify phase III, randomized controlled trials with a duration of ≥2 years that assessed first-line (dimethyl fumarate [DMF], glatiramer acetate [GA], β-interferons [IFN], and teriflunomide) or second-line (alemtuzumab, fingolimod, and natalizumab) DMTs in patients with RRMS. Meta-analyses were performed to estimate relative risks (RRs) on annualized relapse rate (ARR), proportion of relapse-free patients (PPR-F), disability progression (PP-F-CDPS3M), and safety outcomes. NNTB and NNTH values were calculated applying RRs to control event rates. LHH was calculated as NNTH/NNTB ratio.
RESULTS
The lowest NNTBs on ARR, PPR-F, and PP-F-CDPS3M were found with IFN-β-1a-SC (NNTB 3, 95 % CI 2-4; NNTB 7, 95 % CI 4-18; NNTB 4, 95 % CI 3-7, respectively) and natalizumab (NNTB 2, 95 % CI 2-3; NNTB 4, 95 % CI 3-6; NNTB 9, 95 % CI 6-19, respectively). The lowest NNTH on adverse events leading to treatment discontinuation was found with IFN-β-1b (NNTH 14, 95 % 2-426) versus placebo; a protective effect was noted with alemtuzumab versus IFN-β-1a-SC (NNTB 22, 95 % 17-41). LHHs >1 were more frequent with IFN-β-1a-SC and natalizumab.
CONCLUSIONS
These metrics may be valuable for benefit-risk assessments, as they reflect baseline risks and are easily interpreted. Before making treatment decisions, clinicians must acknowledge that a higher RR reduction with drug A as compared with drug B (versus a common comparator in trial A and trial B, respectively) does not necessarily mean that the number of patients needed to be treated for one patient to encounter one aditional outcome of interest over a defined period of time is lower with drug A than with drug B. Overall, IFN-β-1a-SC and natalizumab seem to have the most favorable benefit-risk ratios among first- and second-line DMTs, respectively.
Topics: Humans; Immunologic Factors; Multiple Sclerosis, Relapsing-Remitting; Risk Assessment
PubMed: 27538416
DOI: 10.1007/s40263-016-0377-9 -
Human Vaccines & Immunotherapeutics 2014Cancer immunotherapy is a rapidly growing field in oncology. One attractive feature of cancer immunotherapy is the purported combination of minimal toxicity and durable... (Review)
Review
Cancer immunotherapy is a rapidly growing field in oncology. One attractive feature of cancer immunotherapy is the purported combination of minimal toxicity and durable responses. However such treatments are often very expensive. Given the wide-spread concern over rising health care costs, it is important for all stakeholders to be well-informed on the cost and cost-effectiveness of cancer immunotherapies. We performed a comprehensive literature review of cost and cost-effectiveness research on therapeutic cancer vaccines and monoclonal antibodies, to better understand the economic impacts of these treatments. We summarized our literature searches into three tables by types of papers: systematic review of economic studies of a specific agent, cost and cost-effectiveness analysis. Our review showed that out of the sixteen immunotherapy agents approved, nine had relevant published economic studies. Five out of the nine studied immunotherapy agents had been covered in systematic reviews. Among those, only one (rituximab for non-Hodgkin lymphoma) was found to be cost-effective. Of the four immunotherapy drugs not covered in systematic reviews (alemtuzumab, ipilimumab, sipuleucel-T, ofatumumab), high incremental cost-effectiveness ratio (ICER) was reported for each. Many immunotherapies have not had economic evaluations, and those that have been studied show high ICERs or frank lack of cost-effectiveness. One major hurdle in improving the cost-effectiveness of cancer immunotherapies is to identify predictive biomarkers for selecting appropriate patients as recipients of these expensive therapies. We discuss the implications surrounding the economic factors involved in cancer immunotherapies and suggest that further research on cost and cost-effectiveness of newer cancer vaccines and immunotherapies are warranted as this is a rapidly growing field with many new drugs on the horizon.
Topics: Antibodies, Monoclonal; Cancer Vaccines; Cost-Benefit Analysis; Cytokines; Humans; Immunotherapy; Neoplasms
PubMed: 25483656
DOI: 10.4161/hv.29407