To evaluate the efficacy and toxicity of bortezomib +/- docetaxel as second-line therapy in patients with relapsed or refractory advanced non-small-cell lung cancer (NSCLC).
Patients were randomly ...assigned to bortezomib 1.5 mg/m2 (arm A) or bortezomib 1.3 mg/m2 plus docetaxel 75 mg/m2 (arm B). A treatment cycle of 21 days comprised four bortezomib doses on days 1, 4, 8, and 11, plus, in arm B, docetaxel on day 1. Patients could receive unlimited cycles. The primary end point was response rate.
A total of 155 patients were treated, 75 in arm A and 80 in arm B. Baseline characteristics were comparable. Investigator-assessed response rates were 8% in arm A and 9% in arm B. Disease control rates were 29% in arm A and 54% in arm B. Median time to progression was 1.5 months in arm A and 4.0 months in arm B. One-year survival was 39% and 33%, and median survival was 7.4 and 7.8 months in arms A and B, respectively. Adverse effect profiles were as expected in both arms, with no significant additivity. The most common grade > or = 3 adverse events were neutropenia, fatigue, and dyspnea (4% and 53%, 19% and 26%, and 17% and 14% of patients in arms A and B, respectively).
Bortezomib has modest single-agent activity in patients with relapsed or refractory advanced NSCLC using this schedule, with minor enhancement in combination with docetaxel. Additional investigation of bortezomib in NSCLC is warranted in combination with other drugs known to be active, or using different schedules.
To explore the biological activity of EMD 273063 (hu14.18-IL2), a humanized anti-GD2 monoclonal antibody fused to interleukin-2 (IL2), in patients with unresectable, stage IV cutaneous melanoma as ...measured by induction of immune activation at the tumor site and in peripheral blood.
Nine patients were treated with 4 mg/m2 per day of EMD 273063 given as a 4-h intravenous infusion on days 1, 2, and 3 every four weeks (one cycle). Peripheral blood was analyzed for T cell and natural killer cell phenotype and frequency, as well as levels of soluble IL2 receptor (sIL2R), IL10, IL6, tumor necrosis factor alpha and neopterin. Biopsies of tumor metastasis were performed prior to therapy and at day 10 of the first 2 cycles to study lymphocyte accumulation by immunohistochemistry.
Treatment was generally well tolerated and there were no study drug-related grade 4 adverse events. Grade 3 events were mainly those associated with IL2, most commonly rigors (3 patients) and pyrexia (2 patients). Best response on therapy was stable disease in 2 patients. There were no objective tumor regressions by standard response criteria. Systemic immune activation was demonstrated by increases in serum levels of sIL2R, IL10, and neopterin. There was evidence of increased tumor infiltration by T cells, but not NK cells, in most post-dosing biopsies, suggesting recruitment of immune cells to the tumor site.
EMD 273063 demonstrated biologic activity with increased immune-related cytokines and intratumoral changes in some patients consistent with the suspected mechanism of action of this immunocytokine.
We generated an anti-idiotype antibody, designated CeaVac, that is an internal image of the carcinoembryonic antigen (CEA). We previously demonstrated that the majority of patients with advanced ...colorectal cancer generate specific anti-CEA responses. The purpose of the current study was to treat patients with surgically resected colon cancer with CeaVac to determine the immune response and clinical outcome to treatment with vaccine. We also compared the immune responses between patients treated with fluorouracil (5-FU) chemotherapy regimens plus vaccine versus vaccine alone.
Thirty-two patients with resected Dukes' B, C, and D, and incompletely resected Dukes' D disease were treated with 2 mg of CeaVac every other week for four injections and then monthly until tumor recurrence or progression. Fourteen patients were treated concurrently with 5-FU chemotherapy regimens.
All 32 patients entered onto this trial generated high-titer immunoglobulin G and T-cell proliferative immune responses against CEA. The 5-FU regimens did not have a qualitative or quantitative effect on the immune response. Three of 15 patients with Dukes' B and C disease progressed at 19, 24, and 35 months. Seven of eight patients with completely resected Dukes' D disease remained on study from 12 to 33 months; one patient with resected Dukes' D disease relapsed at 9 months. One patient with incompletely resected Dukes' D disease remained on study at 14 months without evidence of progression; eight experienced disease progression at 6 to 31 months.
CeaVac consistently generated a potent anti-CEA humoral and cellular immune response in all 32 patients entered onto this trial. A number of very high-risk patients continue on study. 5-FU regimens, which are the standard of care for patients with Dukes' C disease, did not affect the immune response. These data warrant a phase III trial for patients with resected colon cancer.
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.
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.
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.
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.
We tested the clinical reactions to a synthetic,
Plasmodium falciparum, circumsporozoite multiple antigen peptide (MAP) vaccine in 39 volunteers immunized two to three times over 2–8 months using a ...dose escalation design. Immediate pain at the injection site was associated with the adjuvant QS-21 (
P<0.001), and delayed local inflammatory reactions were associated with high-titered circulating IgG anti-MAP antibody (
P=0.03). Because two volunteers developed acute, systemic urticaria after the third immunization associated with development of serum IgE MAP antibody, we employed immediate-type hypersensitivity skin tests (ITH-STs) using intradermal injections of diluted MAP vaccine to identify persons sensitized to the vaccine. ITH-STs were negative in seven volunteers tested 27 days after the first vaccination, but six of these individuals developed positive wheal and flare reactions when tested 14 or 83 days after the second vaccination; IgE MAP antibody was detected in only one of them. Another cohort of 16 volunteers, including the 2 allergic individuals, were ITH-ST negative when first tested late after their second or third vaccination at 6–7 months. Five of five non-immunized persons were also ITH-ST negative. ITH-STs may help identify individuals sensitized to malaria peptides and at potential risk of developing systemic allergic reactions after re-vaccination.
Development of antibody scaffolds to directly engage cytotoxic effector cells such as T-cells for therapeutic applications is limited by the scarcity of surface antigens which are expressed ...exclusively on tumor cells and show limited or no expression on non-malignant cells. We have therefore designed a novel antibody format to selectively retarget effector cell cytotoxicity to tumor cells co-expressing two surface antigens. NK-cells play an important role in the innate immune response to multiple myeloma (MM) and are known to contribute to the efficacy of novel therapeutics. We, therefore, utilized a MM-based model system to generate proof-of concept data demonstrating antibody-mediated NK-cell retargeting to cell lines co-expressing two MM-expressed surface antigens with increased selectivity ('dual-targeting').
B-cell maturation antigen (BCMA/CD269) is widely considered to be a promising target antigen for antibody-based therapies of MM due to its almost universal expression on patient myeloma cells and its restricted surface expression on cells outside of the haematological lineage. However, low levels of expression on healthy tissue, including skin, has been reported, which could account for potential side effects associated with BCMA-targeted antibody therapies due to effector cell activation in these organs.
To increase selectivity of antibody-induced, effector cell-mediated cytotoxicity towards malignant tissue, we developed a trispecific antibody format capable of selectively engaging NK-cells through bivalent binding to CD16A (FcγRIIIa) and monovalent binding to both BCMA and CD200, a second MM-expressed surface antigen found in the majority of MM patients. Using an in vitro model system, we demonstrated that binding to BCMA+/CD200+ cell lines and the resulting increase in avidity leads to preferential lysis of antigen double-positive cells compared with antigen single-positive cells. These data suggest that dual-targeting may increase the therapeutic window compared to approaches targeting only one antigen, thereby improving safety of BCMA-directed antibody therapeutics for MM. In addition to the MM-based model system used here, the novel trispecific antibody scaffolds we have developed may be adapted to alternative target combinations within MM or in other tumor indications. Moreover, they could be used to target phenotypically distinct tumor cell clones to induce deeper and more prolonged antitumor responses. Consequently, dual-targeting of effector cells to tumors using the described antibody technology could also be applied to increase safety of T-cell engaging antibodies in the absence of exclusively tumor-expressed target antigens.
Gantke:Affimed GmbH: Employment. Weichel:Affimed GmbH: Employment. Reusch:Affimed: Employment, Patents & Royalties: Patents. Ellwanger:Affimed GmbH: Employment. Fucek:Affimed GmbH: Employment. Griep:AbCheck s.r.o.: Employment. Molkenthin:AbCheck s.r.o.: Employment. Kashala:Affimed Inc.: Employment. Treder:Affimed: Employment.
SPf66 is a synthetic malaria peptide vaccine, which has been widely tested in combination with aluminium hydroxide (alum) as the adjuvant. Since this formulation is weakly immunogenic, we sought to ...improve its immunogenicity by using the saponin adjuvant QS-21. SPf66/QS-21 vaccines were evaluated for safety, tolerability and immunogenicity in healthy adults. The vaccines were found to be safe in 87/89 (97.8%) volunteers studied. However, two individuals developed severe vaccine allergy following the third dose of 1/3 SPf66/QS-21 formulations tested. Vaccine formulations containing QS-21 induced a 45- to over 200-fold increase in anti-SPf66 IgG titres over the alum formulation after the second and third doses, respectively. Anti-SPf66 antibody from some subjects reacted against asexual blood stage parasites, as demonstrated by immunofluorescence and immunoblotting. Antibody responses generated by the QS-21 formulations were of longer duration compared to those evoked by the alum formulation. While SPf66/alum has been found to induce only CD4+ T cell response, the QS-21 formulations exhibited the potential to also elicit SPf66-specific CD8+ responses. These observations demonstrate that the use of QS-21 can substantially enhance the immunogenicity of peptide vaccines, such as SPf66.
We initiated a clinical trial for patients with advanced malignant melanoma treated with an anti-idiotype antibody that mimics the disialoganglioside GD2. We report the clinical and immune responses ...of the first 12 patients entered into this trial. Patients received 1-, 2-, 4-, or 8-mg doses of the anti-idiotype antibody mixed with 100 microg of QS-21 adjuvant every other week, four times, and then monthly. Twelve patients have been on trial for 2-23 months, and all of them have generated immune responses. Patients were removed from the study if they demonstrated disease progression. Hyperimmune sera from all 12 patients revealed an anti-anti-idiotypic Ab3 response, as demonstrated by the inhibition of Ab2 binding to Ab1 by patients' immune sera. To further test the anti-anti-idiotypic response, patients' Ab3 antibodies were affinity purified on Sepharose 4B columns containing adsorbed immunizing anti-idiotype immunoglobulin. Purified Ab3 of all patients studied inhibited binding of Ab1 to a GD2-positive cell line. Purified Ab3 also inhibited binding of Ab1 to purified GD2, in a manner comparable to equal quantities of purified Ab1. The patient Ab3 was truly an Ab1' because it specifically bound to purified disialoganglioside GD2. The isotypic specificity of the Ab3 antibody was predominantly IgG, with only minimal IgM. The predominant IgG subclass was IgG1, with approximately equal quantities of IgG2, IgG3, and IgG4. These Ab3 antibodies reacted specifically with tumor cells expressing GD2 by immune flow cytometry and immunoperoxidase assays. Five patients' Ab3 antibodies studied for antibody-dependent cellular cytotoxicity were positive. One patient had a complete clinical response, with resolution of soft tissue disease, and six patients had stable disease, ranging from 9 to 23 months, and are being continued on vaccine therapy. Toxicity consisted of local reaction at the site of the injection, including induration and pain that generally resolved within a few days. Mild fever and chills were observed in 75% of the patients but rarely required acetaminophen. There was no additional toxicity, including abdominal pain that was previously seen with infusion of murine monoclonal anti-GD2 antibody. Current trials include patients with stage III melanoma and small cell lung cancer. Future trials will attempt to enhance the antitumor response by the addition of interleukin 2, granulocyte macrophage colony-stimulating factor, and other cytokines, together with the 1A7 vaccine.
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