Although DC-based immunotherapy or vaccination has been widely explored for the treatment of many other malignancies, investigation of the potential for DC immunotherapy of ovarian cancer has been relatively limited. Schlienger and colleagues have shown that DC pulsed with killed autologous primary ovarian tumor cells induced antigen-specific T cells that secreted IFNγ upon stimulation with autologous tumor cells [3
], suggesting that antigen-pulsed DC may be a viable option for therapeutic vaccination against ovarian cancer. Various reports showing that DC loaded with tumor lysates, DC pulsed with acid-eluted peptides from ovarian cancer cells, DC fused with ovarian tumor cells, or DC loaded with ovarian tumor cells killed by oxidation could induce HLA class I-restricted CTL responses against autologous ovarian tumor cells [4
] support this position. A limitation of these approaches is that the identity of the tumor antigens recognized by DC-stimulated CTL is not well defined, and it is not clear that T cell responses retain specificity for the tumor. Therapeutic vaccination with DC loaded with defined ovarian tumor antigens of known tissue distribution would be preferable, both in terms of clinical benefit and limitation of autoimmune toxicity, particularly for long-term control of disease progression.
In the clinical setting, a phase I trial of autologous tumor antigen-loaded DC vaccination in 6 patients with ovarian cancer revealed no significant toxicity and 3 of 6 patients showed stable disease lasting 25 to 45 weeks [9
]. Lymphoproliferative responses to tumor antigen were detected in 2 patients. The most durable clinical response to DC vaccination was described in a case report of a patient with recurrent metastatic ovarian cancer, who received 10 vaccinations of autologous DC loaded with mRNA encoding folate receptor-α [10
]. Follow-up CT at 5 months after the last vaccination showed a partial response, and CT at 16 months showed greater than 50% remission of lymph node metastases. CA-125 levels were greatly reduced after the 1st
vaccination (from 640 U/mL to 60 U/mL) and remained at baseline 11 months after completion of vaccination. A clinical trial of MUC1 and HER2/neu peptide-pulsed DC vaccination in patients with advanced ovarian or breast cancer reported peptide-specific CTL responses in 5 of 10 patients [11
], and also showed evidence of epitope spreading. In one patient vaccinated with MUC1 peptides, carcinoembryonic antigen and MAGE3 peptide-specific T-cell responses were detected, and in a second patient, MUC1-specific T-cell responses were detected after seven vaccinations with HER2/neu peptide-pulsed DC [11
]. These results are interesting and encouraging, notwithstanding the limitations of HER2/neu as a target antigen for ovarian tumor immunotherapy, since this antigen is expressed in only about 10% of ovarian cancers.
Probably the best known ovarian tumor antigen is CA125, but it has received surprisingly little attention as a target for cellular immunotherapy. Possible reasons may have included a lack of information on the primary sequence, and the consequent difficulty of producing CA125 in recombinant form. However, the primary sequence and structure of CA125 has now been elucidated, revealing a core protein with a mass exceeding 2 million Da [12
]. Knowledge of the sequence has facilitated identification of HLA class I-restricted epitopes, resulting in DC-driven generation of CA-125-specific CD8+
CTL responses capable of killing ovarian tumors that express CA125 [13
Serine proteases represent a group of antigens with potential as targets for cellular immunotherapy of ovarian cancer [14
]. Of these antigens, stratum corneum chymotryptic enzyme (SCCE) in particular holds promise, based on a high frequency of expression by ovarian tumors and limited distribution in normal tissues. Quantitative RT-PCR analysis indicated that SCCE was overexpressed in >88% of serous ovarian tumors, and 100% of endometrioid and clear cell tumors, respectively [15
]. Using computer analysis of algorithms derived for estimation of epitope binding affinities to HLA DR molecules [16
], peptide sequences with multiple DR-binding motifs have been identified within SCCE. DC loaded with one such peptide, SCCE 110-139, were capable of stimulating CD4+
Th1 T cell responses from individuals of diverse HLA class II backgrounds, and were also capable of cross-priming CD8+
CTL responses restricted by HLA A2.1 and other class I molecules [17
]. This approach thus has the virtue of stimulating both CD4+
helper T cell responses and CD8+
CTL responses in a broad patient population, without suffering from the limitations of HLA type that are usually associated with peptide-based strategies.