Biomedical subjects
Publications and source records attributed to Lucie Heinzerling.
Postherpetic neuralgia is a chronic pain syndrome that is often difficult to treat and can lead to a disabling disease if it is resistant to therapy. Presented here is the case of a 46-year-old patient with human immunodeficiency virus infection and chronic, treatment-resistant neuralgia. Postherpetic pain resolved after treatment with 1 cycle of subcutaneous recombinant interleukin-2.
Measles virus (MV) has shown promise as an oncolytic virus in the treatment of different tumor models for human B-cell lymphoma, multiple myeloma, ovarian cancer, and glioma. We have shown that, in a phase I clinical trial, MV vaccine induces tumor regression in cutaneous T-cell lymphoma (CTCL) patients. Here, we investigated in detail, the effect of recombinant MV (rMV) vaccine strain in CTCL cell cultures, and in vivo in established CTCL xenografts in nude mice. The susceptibility of three CTCL cell lines, originating from patients, to rMV was tested by determination of cell surface expression of MV receptors. All cell lines expressed the receptors CD150 and CD46 and were easily infected by rMV and induced complete cell lysis. The cytoreductive activity was apparent in cells forming aggregates, indicating a cell-to-cell spread of MV and cytolysis owing to virus infection. Intratumoral (i.t.) injection of rMV, expressing enhanced green fluorescent protein induced complete regression of large established human CTCL tumors in nude mice, whereas tumors with control treatment progressed exponentially. Immunohistochemical analysis of tumor biopsies, after i.t. treatment, for MV-NP protein complex demonstrated replication of MV within the tumors. The data demonstrate the potential of MV as a therapeutic agent against CTCL.
Even though mistletoe extracts have been in clinical use for centuries their exact mode of action is still unknown. Currently, the application scheme for registered preparations is a dose-escalating scheme to thus reduce side effects. In this study, healthy controls and patients were evaluated for their immunologic response to treatment with a standardized mistletoe extract (Iscador). It shows a strong effect as adjuvant that induces TNF-alpha and IL-12, which was partly mediated via CD14. Desensitization of the TNF-alpha response could be shown after repeated application in vitro and in vivo. Furthermore, Iscador induces a specific lymphocyte sensitization upon multiple injections and production of IgG1- and IgG3 -mistletoe antibodies. Remarkably, a systemic bystander effect (heterologous immunity against other recall antigens) was observed after long-term treatment. In conclusion, dose-escalation reduces the monocyte-related clinical side effects. A T-lymphocyte sensitization stimulates mainly a specific Th1 response. The most interesting clinical long-term effect is the bystander stimulation of various memory T cells that might mediate in vivo antitumor and antiinfectious T-cell response under mistletoe-extract immunization.
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Since antigen-persistence plays a role for induction of immunity, we investigated the in vivo pharmacokinetic of a naked DNA vaccine at the site of its action, i.e., in the lymph node. After direct intralymphatic injection, naked DNA vaccine degraded within a few hours. In correlation with the short persistence of the DNA vaccine we found that the frequency of vaccination critically influenced the strength of the immune response. In mice vaccinated every 3 days, cytotoxic T-cell responses were enhanced compared to immunization in 6 or 9 days intervals. The results suggest that the so far disappointing efficiency of naked DNA vaccines in humans may be overcome by more frequent vaccination.
Some cutaneous T-cell lymphomas, (CTCLs) clonal T cells are deficient in interferon signaling, making them promising targets for viral oncolysis. We evaluated cytopathic effects of measles virus (MV) in CTCL. CTCL cell lines and infiltrating lymphocytes in CTCL expressed MV receptors CD150 and CD46. In a phase 1 dose escalation trial a total of 16 injections of live MV, Edmonston-Zagreb vaccine strain, were given intratumorally to 5 patients with CTCL. Patients had antimeasles-serum antibodies and were pretreated with interferon-alpha to prevent uncontrolled virus spread. The well-tolerated treatment with MV resulted in clinical responses. Evaluation of biopsies, before and at 11 days after injection, by immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated local viral activity with positive staining for MV nucleoprotein (NP), an increase of the interferon gamma (IFN-gamma)/CD4 and IFN-gamma/CD8 mRNA ratios and a reduced CD4/CD8 ratio. All patients demonstrated an increased antimeasles antibody titer after therapy. The data demonstrate that CTCLs are promising targets for an MV-based oncolytic therapy.
Plasmid DNA encoding human interleukin 12 (IL-12) was produced under GMP conditions and injected into lesions of nine patients with malignant melanoma (stage IV) previously treated with both standard and nonstandard therapies. The treatment was based on efficacy in preclinical studies with melanoma in mice and gray horses. The DNA was applied in cycles, three injections per cycle, for up to seven cycles. Three therapy arms comprised low (2 mg), medium (4 mg), and high (10 to 20 mg) amounts of total DNA. The therapy was well tolerated. Three of nine patients experienced a clinical response: two stable disease and one complete remission. One patient receiving a low dose of DNA experienced a long-lasting stabilization of the disease for more than 3 years, whereas the other two responders received high doses of DNA. All patients but one (patient 9) experienced a transient response at the intratumoral injection site. Immunohistochemical staining of responder sections showed local reduction of angiogenesis and lymphocyte infiltrations. All patients, in particular the clinical and local responders (patients 3, 7, and 8), exhibited an antigen-specific immune response against MAGE-1 and MART-1, which in some cases preexisted. Biopsies of responders showed some increase in IL-12, IP-10, and IFN-(). Serum levels revealed fluctuations. The results show that intratumoral injection of DNA produced some beneficial clinical effect. DNA encoding a cytokine may be useful as a therapeutic or adjuvant against various human cancers.
We report here that the interferon-induced protein of 10 kDa (IP-10 or CXCL10) elicits strong anti-tumor and anti-metastatic responses in mice when administered by plasmid DNA. Intratumoral but not intramuscular IP-10 DNA inoculation resulted in reduced tumor formation of malignant melanoma (B16F10) and Lewis lung carcinoma (LL/2) in C57BL/6 mice. In addition, plasmid DNA-encoding IP-10 substantially reduced the establishment of metastases when injected systemically by the intramuscular route. In contrast to the primary tumor model, the anti-metastatic effect of DNA-encoding IP-10 was primarily mediated by NK cells. Compared to DNA-encoding interleukin-12 (IL-12), therapy with DNA-encoding IP-10 exhibits lower efficacy against primary melanoma tumors but equivalent efficacy against primary Lewis lung tumors and against B16F10 lung metastasis formation. Co-administration of DNA-encoding IP-10 and IL-12 enhanced the anti-tumor activity of IL-12 in the lung metastasis model but had little effect in the local treatment of established subcutaneous tumors. Interestingly, treatment of nude mice lacking T lymphocytes with DNA-encoding IP-10 or IL-12 still resulted in a pronounced reduction of tumor growth or metastasis formation.
The first step of leukocyte extravasation, leukocyte rolling, is mediated by E-, P-, and L-selectins. Mice deficient for alpha-1,3-fucosyltransferase VII (FucTVII)(-/-) are characterized by deficiency of E-, P-, and L-selectin ligand activity. This model system was used to evaluate the role of the interactions of selectins with their ligands in T and B cell responses. In the present study, FucTVII(-/-) mice showed reduced CD4+ T cell-mediated contact hypersensitivity reactions of the ears to FITC as well as reduced CD8+ T cell-mediated delayed-type hypersensitivity reactions of the footpads against lymphocytic choriomeningitis virus infection. As Langerhans cell migration to local lymph nodes as well as CD4+ and CD8+ T cell induction were found to be normal, the afferent arm of these reactions was not impaired. The reduced inflammatory reactions of the skin were due to inefficient lymphocyte extravasation into the skin. In contrast, extravasation of CD4+ and CD8+ T cells into visceral organs, such as the ovaries or the brain, was not impaired in FucTVII(-/-) mice. Elimination of vaccinia virus and of lymphocytic choriomeningitis virus from ovaries and brain, as well as elimination of tumor cells from several visceral organs was normal. Thus, interactions of selectins with their ligands are important for lymphocyte homing into the skin, but not for lymphocyte extravasation into visceral organs.
DNA coding for murine interleukin 12 (IL-12) prevents the formation of B16-melanoma metastasis when administered intramuscularly. Here, the antitumor effect of IL-12-encoding DNA on established mouse B16 melanoma and human melanoma tumors was investigated in vivo using two animal models: B16 melanoma in C57B/6 mice and human melanoma in nude mice. In B16 melanoma, intratumoral injections of IL-12-encoding DNA resulted in highly significant growth retardation when compared with mice injected with control vector. In the case of the human melanoma model, treatment with DNA coding for IL-12 induced regression of tumors in all cases, with complete disappearance of the tumor in two out of five animals. DNA treatment did not induce systemic side-effects. In the animals injected with control vector the human melanoma tumors grew expansively. The therapeutic effect of the DNA injection was mediated in part by natural killer (NK) cells as shown by NK-depletion experiments. An antivascular effect of IL-12 treatment was evident in histological examination with endothelial thickening and abrupt changes in vessel diameters. These results suggest that intratumoral plasmid DNA coding for IL-12 holds some promise as a new therapeutic tool for accessible melanoma lesions and should be tested in clinical trial.
BACKGROUND: Systemic IL-2 has shown some activity in metastatic melanoma, but its use is severely limited by toxicity. TG2001 is a product in which the human IL-2 cDNA was incorporated into the genome of Vero cells, a monkey fibroblast cell line. The goal of this intratumorally applied therapy was to create an antitumor immune response stimulated by xeno-antigens and local production of IL-2 in the close vicinity of tumor-specific antigens. TG2001 was reported to have a good safety profile in two previous dose-escalating phase I studies performed in 18 patients with various solid tumors, with encouraging clinical responses in three patients. The objectives of this study were to evaluate the tolerance and incidence of tumor regression in patients with metastatic melanoma, following repeated administration of Vero-IL-2 cells. PATIENTS AND METHODS: This was on open-label, randomized phase II study comparing two doses of Vero-IL-2, 5x10(5) and 5x10(6) cells. Twenty-eight patients with metastatic melanoma were enrolled in the study, 14 in each treatment group. Patients received TG2001 by intratumoral injection on days 1, 3, and 5 every 4 weeks for four cycles, and every 8 weeks thereafter, until evidence of progressive disease (PD). Criteria for patient selection included histologically proven metastatic melanoma, with one tumor accessible for product administration, and at least another tumor site for response assessment. Evaluation included tumor measurements, humoral and T cell-mediated local and systemic immune response, humoral response to Vero cells, adverse events and standard laboratory parameters. RESULTS: None of the patients achieved a confirmed objective response. Stable disease (SD) was seen in six (43%) and eight patients (57%) at the 5x10(5) and the 5x10(6) dose level, respectively. Two patients, one in each group, died during the study (i.e., within 1 month after the last injection) due to PD. Three patients exhibited antibody responses to Vero cells. T-cell immunity, serum cytokine levels and cytokine mRNA expression in tumor biopsies did not show meaningful alterations after therapy, except for a trend toward an increase in intratumoral TH2 cytokine (IL-4 and/or IL-10) levels. The study drug was well tolerated at both dose levels and side effects mainly consisted of injection site pain and erythema, and pyrexia. CONCLUSION: The intratumoral administration of TG2001 was generally well tolerated in patients with metastatic melanoma, and transient disease stabilization was observed in 50% of patients.
BACKGROUND: Interferons are used in the immune therapy of multiple sclerosis, Kaposi's sarcoma, hepatitis and melanoma based on their antiviral, immunoregulatory and antitumor activities. We report a rare side effect observed during treatment of multiple sclerosis with subcutaneous interferon beta injections. OBSERVATIONS: A 44-year-old patient diagnosed with multiple sclerosis received immune therapy with 6 Mio IU recombinant interferon-beta (IFN-beta) every other day. After 4 years of subcutaneous interferon injections painful indurations appeared directly at and adjacent to the injection sites on the thighs, arms and abdomen. Pain in the thighs made walking almost impossible and required therapy with opiates. After changing to another interferon-beta medication the symptoms improved. Subsequent treatment with doxycycline for 3 weeks was of no additional benefit. CONCLUSIONS: Panniculitis at the injection sites is a rare event but has a significant impact on the quality of life during interferon therapy.