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?? T cells for cancer immunotherapy: A systematic review of clinical trials.

ABSTRACT: ?? T cells contribute to the front line of lymphoid antitumor surveillance and bridge the gap between innate and adaptive immunity. They can be readily expanded to high numbers in vivo and in vitro, starting from the blood of cancer patients, and a number of Phase I trials have demonstrated that these cells can be employed in cancer immunotherapy. Sufficient patients have received ?? T cell-based immunotherapies in the context of clinical trials to evaluate their utility, and to inform the direction of new trials. A systematic approach was used to identify Phase I, Phase II, and feasibility studies testing ?? T cell-based immunotherapy in cancer patients. Studies were excluded from further analysis if they did not provide patient-specific data. Data were compiled to evaluate efficacy, with stratification by treatment approach. When possible, comparisons were made with the efficacy of second-line conventional therapeutic approaches for the same malignancy. Twelve eligible studies were identified, providing information on 157 patients who had received ?? T cell-based immunotherapy. The comparison of objective response data suggests that ?? T cell-based immunotherapy is superior to current second-line therapies for advanced renal cell carcinoma and prostate cancer, but not for non-small cell lung carcinoma. An evaluation of pooled data from 132 published in vitro experiments shows a consistent improvement in the cytotoxicity of ?? T cells in the presence of antitumor antibodies. Immunotherapy using ?? T cells alone shows promising clinical activity, but there is a strong preclinical rationale for combining this treatment modality with cancer-targeting antibodies to augment its efficacy.

SUBMITTER: Fisher JP

PROVIDER: S-EPMC3984269 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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γδ T cells for cancer immunotherapy: A systematic review of clinical trials.

Fisher Jonathan Ph JP Heuijerjans Jennifer J Yan Mengyong M Gustafsson Kenth K Anderson John J

Oncoimmunology 20140117 1

γδ T cells contribute to the front line of lymphoid antitumor surveillance and bridge the gap between innate and adaptive immunity. They can be readily expanded to high numbers in vivo and in vitro, starting from the blood of cancer patients, and a number of Phase I trials have demonstrated that these cells can be employed in cancer immunotherapy. Sufficient patients have received γδ T cell-based immunotherapies in the context of clinical trials to evaluate their utility, and to inform the direc ...[more]

PMID: 24734216

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Project description:The potential of gossypol and of its R-(-)-enantiomer (R-(-)-gossypol acetic acid, AT-101), has been evaluated for treatment of cancer as an independent agent and in combination with standard chemo-radiation-therapies, respectively. This review assesses the evidence for safety and clinical effectiveness of oral gossypol/AT-101 in treating various types of cancer. The databases PubMed, MEDLINE, Cochrane, and ClinicalTrials.gov were examined. Phase I and II trials as well as single arm and randomized trials were included in this review. Results were screened to determine if they met inclusion criteria and then summarized using a narrative approach. A total of 17 trials involving 759 patients met the inclusion criteria. Overall, orally applied gossypol/AT-101 at low doses (30 mg daily or lower) was determined as well tolerable either as monotherapy or in combination with chemo-radiation. Adverse events should be strictly monitored and were successfully managed by dose-reduction or treating symptoms. There are four randomized trials, two performed in patients with advanced non-small cell lung cancer, one in subjects with head and neck cancer, and one in patients with metastatic castration-resistant prostate cancer. Thereby, standard chemotherapy (either docetaxel (two trials) or docetaxel plus cisplatin or docetaxel plus prednisone) was tested with and without AT-101. Within these trials, a potential benefit was observed in high-risk patients or in some patients with prolongation in progression-free survival or in overall survival. Strikingly, the most recent clinical trial combined low dose AT-101 with docetaxel, fluorouracil, and radiation, achieving complete responses in 11 of 13 patients with gastroesophageal carcinoma (median duration of 12 months) and a median progression-free survival of 52 months. The promising results shown in subsets of patients supports the need of further specification of AT-101 sensitive cancers as well as for the establishment of effective AT-101-based therapy. In addition, the lowest recommended dose of gossypol and its precise toxicity profile need to be confirmed in further studies. Randomized placebo-controlled trials should be performed to validate these data in large cohorts.

Project description:Importance:Several reports have associated the placebo effect with objective response and improvement of a clinical condition in oncology, but only a few studies have analyzed the adverse events (AEs) in the placebo groups of the clinical trials. Objective:To determine the incidence of placebo AEs reported in randomized clinical trials of modern cancer drugs in the adjuvant setting. Data Sources:Based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, a systematic literature search of English-language publications from January 1, 2000, through April 15, 2018, was performed using MEDLINE (PubMed). The following search terms were used to retrieve all trials from the PubMed library: adjuvant, maintenance, consolidation, and placebo, in addition to specific cancer type-related keywords. Study Selection:A double-blind, randomized, placebo-controlled, phase 3 design was mandatory for study inclusion. Only studies enrolling patients who had undergone macroscopically complete resections were included. No other anticancer treatments in addition to placebo were allowed in the control group. Only trials involving a targeted therapy (tyrosine kinase, BRAF, or MEK inhibitors) or immunotherapy-related drugs were included. Trials using chemotherapy, interferon, and endocrine therapy were excluded. Two authors (D.H.E. and F.D.W.) independently reviewed the studies for inclusion. Data Extraction and Synthesis:Data were extracted by investigators, and random-effects meta-analysis was performed to estimate the proportion of grade 3 to 4 placebo AEs in the included studies. Main Outcomes and Measures:Incidence of grade 3 to 4 placebo AEs in the placebo groups. Results:Of 731 studies screened, 10 eligible trials were found including 4 tumor types (melanoma, non-small cell lung cancer, gastrointestinal stromal tumor, and renal cell carcinoma). Overall, 11?143 patients (6270 [56.3%] in the treatment group with mean [SD] age of 55.6 [4.2] years and 4873 patients [43.7%] in the placebo group with mean [SD] age of 55.9 [4.3] years) were included. The mean incidence of any-grade placebo AEs was 85.1% (95% CI, 79.2%-91.0%). The most frequent (mean [SD]) grade 3 to 4 placebo AEs in patients were hypertension (2.8% [2.2%]), fatigue (1.0% [0.9%]), and diarrhea (0.8% [0.6%]). The overall, random-effects pooled incidence of grade 3 to 4 placebo AEs was 18% (95% CI, 15%-21%), with a high level of heterogeneity (I2?=?86%). Frequency of grade 3 to 4 placebo AEs was found to be correlated in the treatment and placebo groups (??=?0.7; P?=?.03). Mean study drug discontinuation owing to placebo AEs was 3.9% (95% CI, 2.7%-5.2%). Conclusions and Relevance:Placebo administration was associated with a substantial incidence of grade 3 to 4 placebo AEs in modern cancer adjuvant trials. This finding should be considered by investigators, sponsors, regulatory authorities, and patient support groups.

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Dataset Information

?? T cells for cancer immunotherapy: A systematic review of clinical trials.

Publications

γδ T cells for cancer immunotherapy: A systematic review of clinical trials.

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