Key words: tumour vaccines; helper T-cell responses; blastogenesis; anti-idiotypes; peptidesAnti-idiotypic antibodies that recognise paratopes of anti-tumour antibodies act as internal images of the tumour antigen and thus can be used as surrogate antigens. Although the majority of anti-idiotypic antibodies have been used to stimulate antibody responses, they can also stimulate T cells. Unprimed T cells are stimulated by antigen-presenting cells that take up antigen and present it on MHC molecules in combination with costimulatory signals. Uptake of antigen and expression of costimulatory molecules by antigen-presenting cells are therefore vital for T-cell activation. Antigen can be internalised by pincytosis or more actively by receptor-mediated endocytosis, the latter process being 1,000-fold more efficient. 1 Several scavenging receptors have been identified on antigen-presenting cells including the Fc receptor. 2 More recently, it has been shown that receptor-mediated Fc uptake of antigen/antibody complexes results in the priming of both CD4 and CD8 T-cell responses. 3 These results would suggest that anti-idiotypic antibodies may also be internalised by Fc receptormediated endocytosis and may therefore be very effective immunogens. Two anti-idiotypic antibodies, 105AD7 and 708, have been used to study the role of the Fc region in stimulating T-cell responses by anti-idiotypes.105AD7 is a human anti-idiotypic monoclonal antibody (MAb) that was cloned from a cancer patient receiving the anti-tumour antibody 791T/36 for diagnostic imaging. 4 The antigen recognised by the MAb 791T/36 has been identified as CD55, a complement regulatory protein. 5 CD55 is over-expressed by tumours to protect them from complement attack and thus acts as a tumour-associated antigen. 105AD7 mimics CD55 and can stimulate both T-cell and antibody responses that recognise tumour cells expressing CD55. [5][6][7][8] More recently, neoadjuvant colorectal cancer patients receiving 105AD7 therapy showed a 3-fold increase in tumour cell apoptosis that was associated with infiltration of CD56 and CD4 cells expressing the CD25 activation receptor. 9 -11 708 is a mouse anti-idiotypic antibody that recognises the paratope of the anti-CEA antibody NCRC23 and thus mimics CEA. 708 induces antibody responses that recognise CEA and can stimulate lymphocytes from colorectal cancer patients to respond to in vitro challenge with CEA. 12 This anti-idiotype has recently been cloned and sequenced and shows amino acid homology with CEA.Our study shows that the Fc region of antibodies is important in the presentation of T-cell epitopes. Furthermore, anti-idiotypes expressing human Fc regions are superior to mouse anti-idiotypes in stimulating both helper and cytotoxic T-cell responses and as a result has implications for all antibody-based vaccines.
8578 Background: Significant toxicity limits the systemic delivery of high-dose recombinant Interleukin-2 (IL-2). An alternative method for extended dosing of IL-2 that may reduce toxicity is by intratumoral injection of IL-2 plasmid DNA (pDNA) with electroporation (EP). Methods: A phase I dose-escalation trial is ongoing in subjects with metastatic melanoma to evaluate the safety of intratumoral delivery of IL-2 pDNA (VCL-IM01, Vical Inc., San Diego, CA) followed by EP (MedPulser DNA EPT System, Inovio, San Diego, CA). Eligible subjects have recurrent metastatic melanoma; an injectable lesion = 1 cm2 and < 25 cm2; ECOG 0 or 1; LDH = 1.5 × ULN, and no brain or liver metastases. In the dose-escalation stage of the trial, 3 subjects in each dose cohort received up to 2 cycles of treatment, each consisting of 4 weekly injections followed by a 4-week observation period. Dose levels included 0.5, 1.5, 5.0 mg/tumor, and 15.0 mg (5 mg in each of 3 tumors). A safety assessment was conducted for each cohort prior to enrollment of the next cohort. In the 2nd trial stage, 17 subjects are to be enrolled at the maximum tolerated dose (MTD). The observation period is shortened to 2 weeks between cycles. For all subjects, safety is assessed at every visit. Results: 12 subjects (7 male, 5 female) were enrolled in the dose escalation stage, 3 subjects at each dose. Ages range from 38 to 86 years. No Grade 3 or 4 adverse events (AEs) were reported related to study drug or procedures. All related AEs (12 reported) were Grade 1: 5 related to study drug, 4 to the EP procedure, and 3 to both. Injection site pain was the most common AE. No dose-limiting toxicities occurred; thus the MTD was defined as the 15 mg dose (5 mg/tumor in 3 tumors). To date, 6/17 subjects in Stage 2 of the trial (5 mg/tumor, up to 3 tumors injected) have been enrolled with no Grade 3 or 4 AEs related to study drug or injection/EP procedures. Physicians have observed responses in treated and untreated lesions. Overall response data will be presented. Conclusions: Intratumoral administration of IL-2 pDNA with EP appears safe and well tolerated in 18 patients with metastatic melanoma when given up to a 15 mg dose (5 mg/tumor). Preliminary indications of decreased tumor size suggest local and systemic activity of IL-2 pDNA with EP. No significant financial relationships to disclose.
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