Antigen-specific active immunotherapy for ovarian cancer

              " " Information on adverse events was frequently limited."

PLAIN LANGUAGE SUMMARY:


Epithelial ovarian cancer is the most frequently diagnosed ovarian malignancy and the leading cause of death from gynaecological cancers. Standard therapy consists of surgery followed by chemotherapy. Although initial response rates are high, the majority of patients with advanced disease relapse. No curative treatment is available for recurrent disease. The observation that the presence of certain immune cells in tumours is associated with improved survival, suggests that stimulation of anti-tumour immune responses, i.e. immunotherapy, might be a useful approach to improve prognosis of ovarian cancer. In this review, the feasibility of antigen-specific active immunotherapy is evaluated. Antigen-specific active immunotherapy aims at the induction of tumour-directed immune responses through the administration of a tumour-antigen, a molecule that is preferentially expressed by tumour cells and can induce immune responses. As immunotherapy is a novel (new) treatment strategy early phase studies were also included. Information on clinical and immunological responses, and adverse events was collected.

Thirty-six studies, which included 1780 ovarian cancer patients, were identified between 1966 and 2009. The most frequently described strategy (1505 patients in 15 studies) was administration of antibodies targeting CA-125. Most of these primarily evaluated safety and immunological responses. Five studies described severe flu-like and gastro-intestinal symptoms in 7 to 30% of patients. Antibodies and immune cells recognising CA-125 were frequently detected, albeit response rates varied between studies. Despite promising immunological responses, three large studies found equal survival rates for patients treated with placebo or CA-125 directed antibody. Because there is currently no high quality evidence of clinical benefit, antibody therapy targeting CA-125 should in its current form not be incorporated in standard treatment.

For strategies not relying on antibody administration, similar conclusions cannot be drawn as these have not yet been tested in large trials to evaluate clinical efficacy of treatment. These were generally small studies primarily investigating vaccine safety and immunogenicity. Overall, treatment was well-tolerated, with inflammatory side effects at injection site most frequently reported. Antibodies and immune cells were induced by most strategies studied, but their clinically efficacy still has to be evaluated in large trials.

Based on a 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 RCTs should be awaited and furhter RCTs should be conducted.

ABSTRACT:

Objectives

To assess feasibility of antigen-specific active immunotherapy for ovarian cancer. Primary outcomes are clinical efficacy and antigen-specific immunogenicity with carrier-specific immunogenicity and side-effects as secondary outcomes.

Main results

Thirty-six studies were included. Response definitions showed substantial variation between trials, which makes comparison of trial results unreliable. Information on adverse events was frequently limited. Furthermore, reports of both RCTs and non-RCTs frequently lacked information necessary to assess risk of bias. Serious biases in these trials can thus not be ruled out.

The largest body of evidence is currently available for CA-125 targeted antibody therapy (15 studies: 1505 patients). Non-RCTs of this CA-125 targeted antibody therapy suggest increased survival in humoral and/or cellular responders. However, three large randomised placebo-controlled trials did not show any clinical benefit despite induction of immune responses in approximately 60% of patients.

Other small studies targeting many different tumour antigens showed 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, limited side effects and toxicity exploration of clinical efficacy in large well-designed RCTs may be worthwhile.

Authors' conclusions

We conclude that despite promising immunological responses no clinically effective antigen-specific active immunotherapy is yet available for ovarian cancer. Furthermore, the adoption of guidelines to ensure uniformity in trial conduct, response definitions and trial reporting is recommended to improve quality and comparability of immunotherapy trials.