Abstract: We included 67 studies (representing 3632 women with epithelial ovarian cancer). The most striking observations of this review address the lack of uniformity in conduct and reporting of early-phase immunotherapy studies. Response definitions show substantial variation between trials, which makes comparison of trial results unreliable. Information on adverse events is frequently limited. Furthermore, reports of both RCTs and NRSs frequently lack the relevant information necessary for risk of bias assessment. Therefore, we cannot rule out serious biases in most of the included trials. However, selection, attrition, and selective reporting biases are likely to have affected the studies included in this review. GRADE ratings were high only for survival; for other primary outcomes, GRADE ratings were very low. The largest body of evidence is currently available for CA-125-targeted antibody therapy (17 studies, 2347 participants; very low-certainty evidence). Non-randomised studies of CA-125-targeted antibody therapy suggest improved survival among humoral and/or cellular responders, with only moderate adverse events. However, four large randomised placebo-controlled trials did not show any clinical benefit, despite induction of immune responses in approximately 60% of participants. Time to relapse with CA-125 monoclonal antibody versus placebo, respectively, ranged from 10.3 to 18.9 months versus 10.3 to 13 months (six RCTs, 1882 participants; high-certainty evidence). Only one RCT provided data on overall survival, reporting rates of 80% in both treatment and placebo groups (three RCTs, 1062 participants; high-certainty evidence). Other small studies targeting many different tumour antigens have presented promising immunological results. As these strategies have not yet been tested in RCTs, no reliable inferences about clinical efficacy can be made. Given the promising immunological results and the limited side effects and toxicity reported, exploration of clinical efficacy in large well-designed RCTs may be worthwhile. We conclude that despite promising immunological responses, no clinically effective antigen-specific active immunotherapy is yet available for ovarian cancer. Results should be interpreted cautiously, as review authors found a significant dearth of relevant information for assessment of risk of bias in both RCTs and NRSs.

Plain-language summary: We identified 67 studies, which included 3632 women with ovarian cancer and were published between 1966 and 2017. The most frequently described strategy was administration of antibodies targeting the tumour antigen CA-125 (2347 participants in 17 studies). Most of these studies primarily evaluated safety and immunological responses. Severe flu-like and gastrointestinal symptoms occurred in 7% to 30% of participants. Researchers frequently detected antibodies and immune cells recognising the tumour antigen CA-125, albeit response rates varied between studies. Despite these promising immunological responses, four large studies reported no survival advantage for participants treated with CA-125-directed antibody over those given placebo. For strategies not relying on antibody administration, similar conclusions cannot yet be drawn. Overall, study authors report that treatment was well tolerated and inflammatory side effects at the injection site were most frequently observed. Researchers observed responses of the immune system for most strategies studied, but the clinical benefit of these strategies remains to be evaluated in large trials. Because no high-certainty evidence of clinical benefit is currently available, antibody therapy targeting CA-125 should not be incorporated into standard treatment in its current form. Based on lack of uniformity in included studies, we strongly advocate universal adoption of response definitions, guidelines for adverse events reporting, and directives for trial conduct and reporting. Furthermore, results from ongoing randomised controlled trials (RCTs) are awaited, and further RCTs should be conducted.