1E10 anti-idiotype vaccine in non-small cell lung cancer: experience in stage IIIb/IV patients

Conventional treatment of non-small cell lung cancer (NSCLC) has apparently reached a plateau of effectiveness in improving the survival of the patients. For that reason the search for new therapeutic strategies in this type of tumor is justified. 1E10 is an anti-idiotype murine monoclonal antibody (Ab2 MAb) specific to P3 Ab1 MAb, which reacts with NeuGc-containing gangliosides, sulfatides and with antigens expressed in some tumors, including those from the lung. We report the treatment with aluminum hydroxide-precipitated 1E10 MAb of 34 stage IIIb and 37 stage IV NSCLC patients. These patients were treated with the anti-idiotype vaccine, after received standard chemotherapy and radiotherapy, in a compassionate-use basis study. Patients received five bi-weekly injections of 1 mg of 1E10/Alum, other 10 doses at 28-day intervals and later the patients who maintained a good performance status continued to be immunized at this same time interval. No evidence of unexpected or serious adverse effects was reported. The median survival time of the 56 patients who entered the study with partial response or disease stabilization and with a PS 1 after the first line of chemo/radiotherapy, was 11.50 months from starting vaccination. In contrast, the median survival time calculated for patients who started vaccination with progressive disease and/or a PS2 was 6.50 months.     

Clinical and immune responses in advanced melanoma patients immunized with an anti-idiotype antibody mimicking disialoganglioside GD2.

PURPOSE: To determine immune responses and toxicity to the anti-idiotype vaccine, as well as clinical responses and survival, we initiated a clinical trial for patients with advanced melanoma treated with an anti-idiotype antibody (TriGem) that mimics the disialoganglioside GD2. PATIENTS AND METHODS: Forty-seven patients with advanced melanoma received either 1-, 2-, 4-, or 8-mg doses of TriGem (Titan Pharmaceuticals Inc, South San Francisco, CA) mixed with QS-21 adjuvant (Aquila Biopharmaceuticals, Inc, Worcester, MA) 100 microg subcutaneously weekly for 4 weeks and then monthly until disease progression. Median age was 57 years, there were 32 men and 15 women, 43% of patients had undergone prior therapy for metastatic disease, 55% had disease confined to soft tissue, and 45% had visceral metastasis. RESULTS: Hyperimmune sera from 40 of 47 patients showed an anti-anti-idiotype (Ab3) response. Patient Ab3 was truly Ab1' because it specifically bound purified disialoganglioside GD2. The isotypic specificity of the Ab3 antibody consisted of predominantly immunoglobulin (Ig)G, and all IgG subclasses were represented. One patient had a complete response that persisted at 24 months, and 12 patients were stable from 14+ to 37+ months (median, 18+ months). Disease progression occurred in 32 patients on study from 1 to 17 months (median, 5.5 months), and 21 have died at 1 to 16 months (median, 6 months). The Kaplan-Meier-derived overall median survival has not been reached. Median survival has not been reached for the 26 patients with soft tissue disease only and was 13 months for 21 patients with visceral metastasis. Toxicity consisted of local reaction at the site of injection and mild fever and chills. CONCLUSION: TriGem has minimal toxicity and generates robust and specific IgG immune responses against GD2. Objective responses were minimal, but there may be a favorable impact on disease progression and survival that will require prospective randomized trials.     

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings

The aim of this study was to evaluate the clinical efficacy as determined by time to progression and response rate (RR) of autologous vitespen (formerly HSPPC-96; Oncophage, Antigenics Inc., New York, NY, USA) with and without interleukin-2 (IL-2; Proleukin: Chiron, Emoryville, CA, USA) in stage IV metastatic renal cell carcinoma (RCC) patients undergoing nephrectomy. Eighty-four patients were enrolled on study, and then underwent nephrectomy and harvest of tumour tissue for use in autologous vaccine manufacture. Initial treatment schedule started approximately 4 weeks after surgery and consisted of six injections: once weekly for 4 weeks, then two injections biweekly (vaccines administered at weeks 1, 2, 3, 4, 6, 8), followed by restaging at or around week 10. Patients who had stable or responsive disease continued to receive vaccine, with four more vaccinations biweekly (at weeks 10, 12, 14, 16). Patients who had progressive disease at week-10 evaluation received four consecutive 5-day-per-week courses of 11 x 10(6) U of IL-2 subcutaneously (weeks 10, 11, 12, 13), with four doses of vitespen at 2-week intervals (at weeks 10, 12, 14, 16). At the next evaluation (week 18), patients with a complete response received two further cycles of vitespen (with IL-2 if also received during prior cycle) or until vaccine supply was exhausted. Patients with stable disease or partial response repeated their prior cycle of therapy. Disease progressors who had not yet received IL-2 began IL-2 treatment, and progressors who had already received IL-2 came off study. Of 60 evaluable patients, 2 demonstrated complete response (CR), 2 showed partial response (PR), 7 showed stable disease, and 33 patients progressed. Sixteen patients had unconfirmed stable disease. Two patients who progressed on vaccine alone experienced disease stabilisation when IL-2 was added. Treatment with vitespen did not result in a discernable benefit in the majority of patients with metastatic RCC treated in this study. Use in combination with immunoregulatory agents may enhance the efficacy of vitespen.     

Chimeric anti-N-glycolyl-ganglioside and its anti-idiotypic MAbs: immunodominance of their variable regions

P3 monoclonal antibody (MAb) is a murine IgM that specifically recognizes N-glycolyl (NeuGc)-gangliosides and sulfatides. It also reacts with antigens expressed in human breast tumors and melanoma. In syngeneic model, P3 MAb is able to elicit a strong anti-idiotypic (Ab2) antibody response, even in the absence of adjuvants or carrier proteins. 1E10 MAb is an anti-idiotypic antibody specific for P3 MAb that has demonstrated anti-tumoral effects in syngeneic and allogeneic animals. Here we report the construction of the human IgG(1) chimeric P3 and 1E10 antibodies, and the evaluation of the maintenance of the main properties of the murine MAbs. Chimeric P3 antibody specifically reacted with GM3(NeuGc) and GM2(NeuGc) gangliosides, and not with their acetylated variants. Also, it strongly recognized the anti-idiotypic 1E10 MAb. Chimeric 1E10 antibody specifically reacted with P3 MAb. Upon immunization of Balb/c mice with both chimeric antibodies, we were able to demonstrate the immunodominance of their variable regions. The anti-idiotypic response induced by both antibodies was strong and in most of the mice was even significantly higher than the anti-isotypic response, despite the fact that 70% of the chimeric molecule is xenogenic with respect to the animal model.     

Generation and characterization of an anti-idiotype monoclonal antibody related to GM3(NeuGc) ganglioside

The 14F7 monoclonal antibody (MAb), IgG1 isotype, which reacts specifically to GM3(NeuGc) ganglioside induced a specific IgG anti-idiotypic antibody (Ab2) response in syngeneic mice when it was administered coupled with KLH and in the presence of Freund's adjuvant. Spleen cells from these mice were used in somatic-cell hybridization experiments using the murine myeloma cell line P3-X63-Ag8 653 as fusion partner. An IgG1 Ab2 MAb was selected. This Ab2 MAb, called 4G9, was able to block the binding of 14F7 MAb to GM3(NeuGc) ganglioside and developed a strong IgG anti-anti-idiotypic antibody (Ab3) response, when injected into syngeneic mice. These Ab3 antibodies were characterized to bear 14F7 MAb idiotopes, but did not have the same specificity as 14F7 MAb. In the other hand, a very specific anti-NeuGc-containing ganglioside response was generated in chickens immunized with this Ab2 MAb, thus behaving, in this species as an "internal image" antibody.     

Vaccine therapy for small cell lung cancer

One novel approach to the treatment of lethal residual disease in patients with small cell lung cancer (SCLC) relies on the induction of a host-immune response to attack chemoresistant tumor cells. Because of its neuroectodermal origin, SCLC has a number of specific antigens that could be capitalized on as immune targets. This article reviews two vaccine strategies currently in clinical study. The anti-idiotype vaccine to the GD3 ganglioside, BEC-2, has recently been tested in a phase III trial. In this trial, patients with SCLC who had completed initial chemotherapy were randomized to observation or vaccination with BEC-2 plus bacillus Calmette-Guerin adjuvant. A series of other trials have established the immunogenicity of several keyhole limpet hemocyanin conjugate vaccines relevant to SCLC, including GM2, Globo H, fucosyl GM1, and polysialic acid. To optimize an immune response against a broad range of tumor phenotypes, these components will be combined into a polyvalent vaccine. A randomized phase II trial of this polyvalent vaccine is planned to start in 2004.     

Phase I and imaging trial of indium 111-labeled anti-epidermal growth factor receptor monoclonal antibody 225 in patients with squamous cell lung carcinoma

Murine monoclonal antibody (MAb) 225 (IgG1) against the epidermal growth factor (EGF) receptor competitively blocks EGF binding and inhibits EGF-induced activation of receptor tyrosine kinase and cell proliferation. The effect of MAb 225 was studied in a phase I trial in patients with inoperable squamous cell carcinoma of the lung, which invariably expresses high levels of EGF receptors. Groups of three patients received total doses of MAb 225 ranging from 1 mg to 300 mg. Except at the lowest dose, each infusion included 4 mg of indium 111 (111In)-labeled MAb 225. No toxicity was observed. Tumors were imaged in all patients who received doses of 20 mg or greater. Presumed metastases greater than or equal to 1 cm in diameter were imaged with doses of 40 mg or greater. Single-photon-emission-computed tomography could be carried out at the 120-mg and 300-mg doses and significantly improved tumor visualization. All patients produced anti-murine antibodies. We conclude that treatment with an MAb that inhibits EGF receptor function is safe at the doses and schedule studied. 111In-labeled MAb images squamous cell lung carcinoma; tumor uptake of the labeled MAb is dose dependent. Further studies are warranted to explore the potential therapeutic efficacy of anti-EGF receptor MAbs and other agents that act in a comparable manner.     

Use of the anti-idiotype breast cancer vaccine 11D10 in conjunction with autologous stem cell transplantation in patients with metastatic breast cancer

The results of cytotoxic therapy, including dose-intensive therapy requiring autologous stem cell transplantation (ASCT), have been disappointing in patients with metastatic breast cancer, as almost all patients eventually experience disease progression. There has been a renewed interest in immunotherapeutic strategies in this disease, including evaluation of several breast cancer vaccines. In the current study, we describe the results of a program in which the anti-idiotype breast cancer vaccine 11D10 (TriAb) was administered before and after ASCT in patients with metastatic breast cancer chemosensitive to previous conventional therapy. The toxicity of this approach was acceptable, and idiotype-specific humoral and T-cell proliferative responses were observed in the majority of patients within a few weeks post-ASCT. The actuarial 3-year overall survival rate was 48% (95% CI, 32%-64%), while the progression-free survival rate was 32% (95% CI, 19%-45%). Multivariate analysis identified achievement of a strong antibody and cellular immune response to the vaccine as the only significant prognostic factors for outcome. The ability to reliably produce robust immune responses after ASCT is encouraging. Further studies are required to determine if the immune response mediates an antitumor benefit in these patients.     

The clinical use of monoclonal antibodies, MAb 17-1A, in the treatment of patients with metastatic colorectal carcinoma

Increasing doses of MAb 17-1A (mouse IgG2A) have been given for therapy of patients with metastatic colorectal carcinoma (n = 28). Serum half-life (T beta 1/2) of MAb 17-1A after a single infusion was about 24 h. A constant serum level of MAb 17-1A could be maintained for a long time period by infusions every 2-3 days. Patients received 500 mg 3 days a week for 12 weeks (total dose 12 g). Side effects were mild and dose related but never required medical intervention except for three times (out of 243 infusions) when allergic reactions appeared. All patients developed IgM and IgG antibodies. Two patients experienced immune complex-related symptoms. Six out of 22 evaluable patients (27%) had objective evidence of tumor cell regression/lysis. One of these achieved a complete remission. Median survival for all patients was 12 months, for responding patients 19 months and for non-responding 11 months. 5/17 patients were studied for the development of anti-anti-idiotypic antibodies (Ab3). The presence of Ab3 in serum correlated favourably to the clinical outcome of the disease.     

Therapy of colorectal carcinoma with monoclonal antibodies (MAb17-1A) alone and in combination with granulocyte monocyte-colony stimulating factor (GM-CSF).

A mouse monoclonal antibody (MAb17-1A) (IgG2A) against colorectal carcinoma cells was used to treat patients with metastatic disease. Major direct effector functions of MAb seem to be ADCC (antibody dependent cellular cytotoxicity), CDC (complement dependent cytolysis) and apoptosis ('programmed cell death'). Thus, a high tumor cell saturation of the MAb should be achieved. Increasing doses of MAb to the patients increased the total area under the concentration curve and thus the exposure of tumor cells to MAb. However, the response rate (with complete + partial + minor response + stable disease defined as response) was not augmented. In total, 10/52 (19%) patients responded and in fact lower doses (less than 2 g) might induce a higher response frequency (9/52) than higher doses (greater than 2 g) (1/52). During treatment, the numbers of cytotoxic cells (lymphocytes and monocytes) increases in the tumor lesion and complement components were deposited. As ADCC may be important, effector mechanism attempts were made to augment the cytolytic capability of the effector cells by simultaneously giving the patients GM-CSF. The combination of MAb17-1A + GM-CSF augmented the ADCC activity of blood mononuclear cells and a heavy infiltration of monocytes could be noted in the tumor. Out of 15 available patients 6 (40%) showed a response.     

Interim analysis of the use of the anti-idiotype breast cancer vaccine 11D10 (TriAb) in conjunction with autologous stem cell transplantation in patients with metastatic breast cancer

The anti-idiotype monoclonal antibody breast cancer vaccine 11D10 (TriAb) was administered before and after autologous stem cell transplantation (ASCT) in 45 patients with metastatic breast cancer whose disease was responsive to conventional chemotherapy. Evidence of a positive anti-anti-idiotype antibody (Ab3) humoral response was noted at a median of 1.76 months post-ASCT (range, before ASCT-6 months) with this strategy. Maximal Ab3 levels and idiotype-specific T-cell proliferative responses were observed at a median of 3 and 4 months, respectively, after ASCT. The achievement of rapid immune responses after ASCT, during a known period of decreased immunoresponsiveness, opens the possibility of an additional antitumor effect at a time when the tumor burden is relatively small. Moreover, in this interim analysis, patients with the most vigorous humoral and cellular immune responses had a significant improvement in progression-free survival. Further follow-up and evaluation of this approach is warranted.     

Different dose regimens of the mouse monoclonal-antibody 17-1a for therapy of patients with metastatic colorectal-carcinoma

Seventy-one patients with metastatic colorectal carcinoma(CRC) were treated with varying doses of the mouse monoclonal antibody (MAb) 17-1A. One patient achieved a partial remission (PR) (1%) with a survival duration of 114+ months. Further 10 patients showed a minor response (MR) or stable disease > 3 months (SD) (14%). In patients receiving a total dose of MAb17-1A < 2 g the overall response rate was 22% (10/45) (1 PR, 2 MR, 7 SD) while patients treated with a total dose > 2 g had a corresponding figure of 4% (1/26) (1 MR) (p < 0.05). Responding patients (n = 11) survived significantly longer than non-responding patients (n = 60) (median: 20 vs 10 months) (p < 0.0027). In the most intensive treatment group (total 12 g), 14 patients received 500 mg of MAb17-1A tiw for 8 weeks. The frequency and intensity of side-effects were mild and did not cause withdrawal or dose reduction of MAb17-1A, even in the 12 g dose schedule. Patients with a pretreatment ADCC (antibody dependent cellular cytotoxicity) activity above the median of all patients, survived significantly longer than those with a low value (p < 0.05).     

Phase I immunotherapeutic trial with long peptides spanning the E6 and E7 sequences of high-risk human papillomavirus 16 in end-stage cervical cancer patients shows low toxicity and robust immunogenicity.

PURPOSE: To determine the toxicity, safety, and immunogenicity of a human papillomavirus 16 (HPV16) E6 and E7 long peptide vaccine administered to end-stage cervical cancer patients. EXPERIMENTAL DESIGN: Three groups of end-stage cervical cancer patients (in total n = 35) were s.c. vaccinated with HPV16 E6 combined with or separated from HPV16 E7 overlapping long peptides in Montanide ISA-51 adjuvant, four times at 3-week intervals. Group 1 received 300 microg/peptide at a single site and group 2 received 100 microg/peptide of the E6 peptides in one limb and 300 microg/peptide of the E7 peptides in a second limb. Group 3 received separate injections of E6 and E7 peptides, each at a dose of 50 microg/peptide. The primary end point was to determine safety and toxicity of the HPV16 long peptides vaccine. In addition, the vaccine-induced T-cell response was assessed by IFN gamma enzyme-linked immunospot. RESULTS: No toxicity beyond grade 2 was observed during and after four vaccinations. In a few patients, transient flu-like symptoms were observed. Enzyme-linked immunospot analysis of the vaccine-induced immune response revealed that coinjection of the E6 and E7 peptides resulted in a strong and broad T-cell response dominated by immunity against E6. Injection of the E6 and E7 peptides at two different sites increased the E7 response but did not affect the magnitude of the E6-induced immune response. CONCLUSIONS: The HPV16 E6 and E7 long peptide-based vaccine is well tolerated and capable of inducing a broad IFN gamma-associated T-cell response even in end-stage cervical cancer patients.     

Network of idiotypic and anti-idiotypic antibodies related to the ovarian carcinoma-associated folate binding protein.

The present paper describes the generation and characterization of anti-idiotypic monoclonal antibodies (Ab2 MAbs) produced against the MOv19 MAb (Ab1 MAb), which shows a restricted reactivity with human ovarian carcinoma. The Ab2 MAbs were produced by immunizing mice with MOv19 conjugated to syngeneic mouse red blood cells (MRBC). After the somatic hybridization, five Ab2 MAbs, designated Id19.1, Id19.2, Id19.3, Id19.4 and Id19.5, were selected by a sandwich assay on the basis of their specific reactivity to the MOv19 MAb, but not to the isotype-matched MAb used as a control. A complete cross-inhibition between these 5 MAbs was observed, indicating that they recognize overlapping idiotopes on MOv19. The Ab2/antigen relationship of two Ab2 MAbs (Id19.1 and Id19.2) was investigated by competition experiments on a relevant tumor target cell line. We showed that both Ab2 MAbs were able to interfere with the antigen binding capacity of 125I-MOv19. Moreover, Id19.1 was able partially to inhibit the binding of the purified radiolabelled antigen recognized by the MOv19 MAb (125I-CaMOv19) on insolubilized MOv19. To investigate further whether the Ab2 MAb is the "internal image" of CaMOv19, Id19.1 was used as immunogen with the aim to induce an anti-CaMOv19 response. The antisera tested by indirect solid-phase radioimmunoassay (RIA) on the Ab2 MAb and the irrelevant isotype-matched control MAb revealed an anti-anti-idiotypic response (Ab3). However, no Ab3 antibodies with Ab1-like specificity (Ab1') were found in the immune sera, as assessed by testing the antisera both in indirect immunofluorescence (IF) and solid-phase RIA on CaMOv19-positive target cell lines.     

A transgenic mouse model for tumour immunotherapy: induction of an anti-idiotype response to human MUC1

MUC1 is a membrane bound, polymorphic epithelial mucin expressed at the luminal surface of glandular epithelium. It is highly expressed in an underglycosylated form on carcinomas and metastatic lesions and is, therefore, a potential target for immunotherapy of cancer. The monoclonal antibody HMFG1 binds the linear core protein sequence, PDTR, contained within the immunodominant domain of the tandem repeat of MUC1. The efficacy of murine and humanized HMFG1 (Ab1) used as an anti-idiotypic vaccine was examined in mice transgenic for human MUC1 (MUC1.Tg) challenged with murine epithelial tumour cells transfected with human MUC1. Humoral idiotypic cascade through Ab2 and Ab3 antibodies was observed in MUC1.Tg mice following multiple antibody inoculations in the presence of adjuvant. Impaired tumour growth at day 35 and highest Ab3 levels were found in mice that had received mHMFG1 with RAS adjuvant. However, comparison of Ab3 levels in individual mice with tumour size in all treatment groups did not show a correlation between smaller tumours and increased levels of anti-idiotype antibody. This suggests that the anti-tumour effects of anti-idiotype vaccination are not solely related to the induction of idiotypic antibody cascades and probably involve other mechanisms.     

Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines

PURPOSE: To identify prognostic factors associated with survival beyond 4 years and overall response in patients with metastatic melanoma treated with high-dose bolus i.v. interleukin-2 (IL-2) given either alone or in combination with a variety of melanoma vaccines. STUDY DESIGN: 684 consecutive patients with metastatic melanoma received high-dose bolus i.v. IL-2 either alone or in conjunction with a variety of melanoma vaccines. Treatments occurred between August 1, 1985 and January 1, 2006. RESULTS: The overall objective response rate was 13% for patients receiving IL-2 alone and 16% for patients who received IL-2 with vaccine. In patients treated with IL-2 alone (n=305) and IL-2 with vaccine (n=379), having an objective response was associated with survival beyond 4 years (P<0.0001). No pretreatment factors could be identified that were strongly associated with increased rate of objective response or long-term survival in patients receiving IL-2 alone. In patients receiving IL-2 with vaccines, there were increased response rates in patients with s.c. or cutaneous disease only and lower response rates with visceral disease only. Patients who received the gp100:209-217(210M) peptide plus IL-2 showed a strong trend to increased objective responses compared with IL-2 alone (22% versus 12.8%; P=0.01) and also compared with patients who received a variety of vaccines that did not include this immunogenic peptide (13.8%; P=0.009). CONCLUSION: IL-2 can produce a modest response rate in patients with metastatic melanoma including patients with durable complete responses. S.c. or cutaneous disease only and vaccination with gp100:209-217(210M) peptide was associated with significant increase in response rates.     

Phase I study of abagovomab in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer.

PURPOSE: This open-label study assessed the safety and immunogenicity of two doses and two routes of the anti-idiotypic monoclonal antibody abagovomab (formerly ACA125) in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. EXPERIMENTAL DESIGN: Eligible patients from the three participating institutions were any stage at diagnosis, had relapsed, and had complete or partial response to additional chemotherapy. Patients were randomized to receive abagovomab at 2.0 versus 0.2 mg and i.m. versus s.c. for four immunizations every 2 weeks and then monthly for two additional immunizations. Planned evaluation included interval physical examinations and laboratory assessments with immune assessment, including HLA typing, human anti-mouse antibody, ELISA, and enzyme-linked immunospot. Patients were required to remain on study until week 10 (the first post-baseline Ab3 determination) to be considered for immunologic assessment. The primary end points were safety and immunogenicity primarily determined by Ab3 response. RESULTS: Forty-two patients received at least one vaccination and were eligible for safety analysis. Thirty-three patients were available for Ab3 analysis (removed for progression of disease, 6; withdrawal of consent, 2; unrelated adverse event, 1). The most common adverse events were self-limited pain at injection site, myalgia, and fever. No hematologic or nonhematologic toxicity grade>2 related to immunization was seen. Ab3 was detectable in all patients (median, 236,794 ng/mL); none of route of administration (P=0.6268), dose (P=0.4602), or cohort (P=0.4944) was statistically significant in terms of effect on maximum post-baseline Ab3 titer. Human anti-mouse antibody was not detectable at baseline but was present in all patients at week 16 (range, 488-45,000 ng/mL). CONCLUSIONS: Immunization with abagovomab is well tolerated and induced robust Ab3 responses at the two doses and routes tested. A phase III randomized study with abagovomab (2.0 mg s.c.) is warranted.     

An idiotypic replica of carcinoembryonic antigen inducing cellular and humoral responses directed against human colorectal tumours.

A monoclonal anti-idiotypic antibody (anti-Id MAb) 708 (IgG2b), which inhibited the binding of NCRC23 (IgG1) MAb to CEA and prevented radiolabelled CEA from binding to MAb NCRC23, was produced. No recognition of 3 other anti-CEA antibodies, 3 other IgG1 or 2 IgM MAbs was observed with this anti-idiotypic antibody. When an immunoblotting technique was used, 708 anti-Id MAb failed to bind to isolated heavy or light chains of MAb NCRC23, whereas binding was observed with intact antibody. Mouse, rat and human lymphocytes (in vitro) were immunized with 708 anti-Id MAb and the resultant Ab3 antibodies all inhibited binding of labelled 708 anti-Id MAb to MAb NCRC23 and also reacted with CEA, showing that 708 anti-Id MAb induced anti-CEA antibody responses. Similarly, mice immunized with 708 anti-Id MAb could be restimulated in vitro with either CEA or tumour cells expressing CEA which induced specific T-cell proliferative responses. Human tumour-infiltrating lymphocytes isolated from colorectal tumours or peripheral blood T cells from cancer patients were stimulated in vitro with 708 anti-Id MAb or an irrelevant IgG2b antibody. Six days later both sets of lymphocytes were restimulated with CEA, and lymphocytes primed to 708 anti-Id MAb proliferated in response to CEA. These results suggest that 708 anti-Id MAb can act as an idiotypic replica of CEA and stimulate cellular and humoral anti-CEA immune responses. It is therefore of great interest as an idiotypic vaccine against colorectal cancer.     

A dose escalation study of topotecan in combination with epirubicin in pretreated patients with small-cell lung cancer

PURPOSE: To define the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTDs) of topotecan in combination with epirubicin in pretreated patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Twenty-seven SCLC patients with performance status (WHO) of 0-2 and adequate renal, hepatic, and bone marrow function who had failed EP-containing front-line chemotherapy entered the study. Patients received escalated doses of topotecan (starting dose 0.5 mg/m(2)) for 5 days and epirubicin (starting dose 40 mg/m(2)) on day 8, every 28 days. RESULTS: All patients were assessable for toxicity and 20 for response. The MTD was topotecan 0.90 mg/m(2) and epirubicin 40 mg/m(2) with neutropenia being the most common dose-limiting event. Seventy-three courses were administered. Grade 3-4 neutropenia occurred in 22 (30%) courses, grade 3-4 anemia in 7 (10%), and grade 3-4 thrombocytopenia in 11 (15%). Seven courses were complicated with fever and one patient died of neutropenic sepsis. Grade 3-4 non-hematologic toxicity was mild and infrequent with only grade 2-3 asthenia occurring in 16 (22%) courses. Among 20 patients who were evaluable for response, 16 (80%) were refractory to prior treatment. One patient with refractory disease (5%) achieved a complete response of 14 weeks duration and four experienced stabilization of the disease. CONCLUSIONS: The combination of topotecan 0.90 mg/m(2) on days 1-5, with epirubicin 40 mg/m(2) on day 8, administered every 28 days is a feasible outpatient regimen which merits further evaluation in patients with chemosensitive disease.     

Vaccination of patients with advanced ovarian carcinoma with the anti-idiotype ACA125: immunological response and survival (phase Ib/II).

PURPOSE: A Phase I/IIb multicenter study was conducted to evaluate the safety and immunogenicity of the anti-idiotypic antibody vaccine ACA125 that functionally imitates the tumor antigen CA125 in 119 patients with advanced ovarian carcinoma. A preliminary report on the initial 42 patients demonstrated safety and immunogenicity. EXPERIMENTAL DESIGN: Using the complete intention-to-treat population (n = 119) who received a mean of 9.7 ACA125 applications, survival was analyzed with respect to immunological responses. RESULTS: In 81 patients (68.1%), a specific anti-anti-idiotypic antibody (Ab3) response could be induced. Additionally, the development of CA125-specific antibodies (Ab1') and antibody-dependent cell-mediated cytotoxicity of CA125-positive tumor cells was observed in 50.4% and 26.9% of patients, respectively. The median survival of all patients was 19.4 months (range, 0.5-56.1 months). Ab3-positive patients showed a significantly longer survival (median, 23.4 months; P < 0.0001) as compared with Ab3-negative patients (median, 4.9 months). A positive Ab3 response remained associated with longer survival when controlling for other prognostic factors including FIGO (International Federation of Gynecologists and Obstetricians) stage, response to and type of first-line chemotherapy, number of previous treatments, or concomitant antitumor therapy. With regard to safety, repeated vaccination was well tolerated. No serious adverse events related to the application of ACA125 occurred. CONCLUSIONS: Although the uncontrolled design of this study prevents definitive conclusions with respect to subgroups, the data support a relationship between Ab3 response and survival time. Thus, the need for further randomized, controlled clinical trials to establish efficacy of the vaccine ACA125 seems to be indicated.