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PubMed2026

Genetic Profile, Treatment Response, and Outcomes of BCR::ABL1-Positive Mixed-Phenotype Acute Leukemia: A Study From the BCR::ABL1 Pathology Group.

Mixed-phenotype acute leukemia (MPAL) with BCR::ABL1 fusion is rare, and its clinicopathological features, genetic landscape, therapeutic response, and patient outcomes remain incompletely defined, as does its relationship to blast-phase chronic myeloid leukemia. In this multicenter study of 44 patients, 86.4% had B/myeloid MPAL, 72.7% showed lymphoid predominance, 40.9% had complex karyotypes, and 68.3% harbored somatic mutations, most commonly RUNX1 mutations (46.3%). RUNX1 mutations frequently co-occurred with acute myeloid leukemia (AML)-associated alterations, whereas DNMT3A, TET2, and BCORL1 mutations were restricted to RUNX1-mutated cases. In contrast, acute lymphoblastic leukemia (ALL)-associated alterations (IKZF1 mutation/deletion and ETV6 mutations) were confined to RUNX1-wild-type patients. TP53 and signaling pathway mutations (NRAS, KRAS, PTPN11, and FLT3) were not detected. Forty-two patients received induction chemotherapy and/or immunotherapy combined with tyrosine kinase inhibitors: 74.2% of lymphoid-predominant patients and 63.6% of myeloid-predominant patients received ALL- and AML-type therapies, respectively. Ten patients relapsed, and 2 had primary refractory disease; some exhibited a dynamic shift in predominant lineage immunophenotype, chromosomal alterations, and somatic mutations at the relapse or refractory stage. The overall remission rate was 86.8%, with no significant differences across ALL-, AML-, or hybrid-type regimens. After a median follow-up of 24.2 months, the median overall survival was 52.5 months. Complex karyotype was associated with inferior overall survival compared with cases lacking additional chromosomal alterations (P = .02), whereas RUNX1 mutations were not. No significant differences in genetic profiles, treatment response, or outcomes were observed between patients with and without chronic myeloid leukemia-like features. This study provides a comprehensive genomic and clinical characterization of BCR::ABL1-positive MPAL, supporting improved risk stratification and future therapeutic strategies.

Adolescent↗
PubMed1994

Role of antibodies against fibronectin-, collagen-binding proteins and alphatoxin in experimental Staphylococcus aureus peritonitis and septicaemia in neutropenic mice.

We have investigated the protective role of hyperimmune rabbit IgG against two surface structures of Staphylococcus aureus, i.e. fibronectin-, and collagen-binding proteins as well as alpha-toxin in experimental peritonitis and septicaemia in neutropenic mice pretreated with cyclophosphamide. This treatment markedly decreased clearance of bacteria from mouse organs. With combined immunotherapy given passively bacteria were eradicated more efficiently for all animals sampled, comparative to controls.

Adhesins, Bacterial↗
PubMed2002

Therapy of autoimmune diseases: clinical trials and new biologics.

Successful clinical efficacy trials have been recently completed for a growing array of new biologics. Prospects are improving for rational therapeutic interventions that potently interrupt adaptive immune response pathways. By contrast, disappointing results with antigen-based therapeutics highlight the difficulties of achieving tolerance in the context of active autoimmunity. Combination immunotherapy is probably necessary to sequentially or simultaneously inhibit inflammation, uncouple innate immune pathways, interrupt or ablate the adaptive memory response and promote antigen-specific tolerance in a suitable immunological context.

Antibodies, Monoclonal↗
PubMed2003

Immunodeficiency and cancer: prospects for correction.

Cellular immunodeficiency is associated with human cancer. Extensive reviews on cancer of the head and neck, lung, esophagus and breast convince the author that for these diseases the immunodeficiency is reasonably well established yet the mechanisms are poorly understood. Evidence indicates that other tumors are similarly associated with cellular immune deficiency. The advent of recombinant cytokines and of antitumor monoclonal antibodies has served to focus attention toward direct tumoricidal mechanisms. As tumor antigens relating to cellular and humoral immune mechanisms are being defined and vaccine strategies are increasingly being attempted, it is critical to confront issues of the mechanism of anergy and effective immunorestoration in order to maximize the potential of cellular immune response to address these tumor antigens. Intrinsic to this approach is the introduction of contrasuppressive therapy to alleviate the tumor-associated immune suppression. Encouraging attempts have been made with plasmapheresis, indomethacin, low-dose cyclophosphamide, anti CTLA-4, anti FAS ligand and, perhaps in the future, more judiciously applied chemotherapy. In contrast to the popular notion that thymic involution cannot be reversed in the adult, studies from the author's laboratory indicate that in aged hydrocortisone stressed mice, a natural Type 1-cytokine mixture (IRX-2) hastens the reversal of thymic involution and promotes T-cell responses to cytokines and mitogens. Recombinant IL-1 and IL-2 by themselves, and in combination, were inactive. Similar positive effects were observed with oral zinc, zinc-thymulin and thymosin alpha(1). The combination of a natural cytokine mixture (IRX-2) with thymosin alpha1 had a very large effect and increased the absolute number of peripheral T lymphocytes as measured in the spleen. In studies of combination immunotherapy in lymphocytopenic squamous cell head and neck cancer patients using IRX-2 (18 patients) and IRX-2 plus thymosin alpha(1) (IRX-3) in IRX-2-refractory patients (7 patients), marked increases in CD(45)RA(+) 'naïve' T cells (>250/mm(3)) were observed. These are among the first insights into how to generate T lymphocyte replacement in the adult. These and many other experimental efforts point to ways to achieve more effective immunotherapy of human cancer in the future, particularly if tumor-induced immune deficiency can be effectively addressed.

Adjuvants, Immunologic↗
PubMed2001

5-Fluorouracil induced Fas upregulation associated with apoptosis in liver metastases of colorectal cancer patients.

BACKGROUND: In vitro, thymidylate synthase (TS) inhibition by 5-fluorouracil (5-FU) induces thymineless apoptosis possibly via Fas receptor Fas ligand interactions and cell-cycle arrest. In colorectal cancer patients we evaluated whether 5-FU administration also resulted in apoptosis and cell-cycle arrest and which proteins might be involved. PATIENTS AND METHODS: Biopsy specimens were taken from 36 patients 2, 22 or 46 hours after administration of 500 mg/m2 5-FU, and from 12 control patients who did not receive 5-FU. In frozen tissue-sections from liver metastases immunohistochemistry was performed with antibodies directed against p53, p21, E2F2, Rb, Ki67 and TS (cell-cycle related) and bax, BCL-2, BCL-x, mcl-1, PARP, caspase-3, Fas receptor and Fas ligand (apoptosis related). Apoptosis was determined by M30 immunostaining, which recognises a cleavage product of cytokeratin 18. RESULTS: Fas receptor expression was 50% higher (P = 0.036) 46 hours after 5-FU administration compared to the control group. This was associated with a 12% increase (P < 0.02) in M30 positive tumour cells and with elevation of caspase-3 and PARP expression. The expression of Ki67 and E2F2 was 30% lower after 46 hours compared to the control group, whereas TS was 56% lower after 2 hours and 32% higher again after 46 hours. No differences in the expression of the other proteins were found. CONCLUSIONS: These results suggest that 5-FU decreases proliferation status and induces apoptosis possibly via the Fas pathway. Since Fas mediated cell killing is important for cytotoxic T cells this indicates that clinical studies combining immunotherapy for activation of T cells and chemotherapy using 5-FU might be very effective.

Adenocarcinoma↗
PubMed1998

Synergistic antitumor interaction of human monocyte chemotactant protein-1 gene transfer and modulator for tumor-infiltrating macrophages.

PURPOSE: In order to evaluate the possibility of synergistic antitumor gene therapy by the gene delivery of monocyte chemotactant protein-1 (MCP-1/MCAF/IE), the effect of a biological response modulater for macrophages on tumor progression of gene transfected tumor cells was studied. METHODS: Cachexia-inducing adenocarcinoma cells (cell line colon 26, clone 20) were transfected with either a control plasmid or MCP-1 cDNA. RESULTS: The production of MCP-1 reached 70-80 ng/ml in vitro when transfectant cells were cultured at a cell density of 1 x 10(5) cells/ml for 3 days. Transfection of MCP-1 cDNA did not affect the growth rate in vitro. Also, MCP-1-transfectants formed tumors after intra-footpad inoculation similar in size to the parental cells. The number of infiltrating macrophages in the primary tumor of the transfectant rapidly increased from the 3rd to 5th day after inoculation as revealed by immunohistochemical staining using an antibody against mouse macrophages. An earlier, greater, but no longer-lasting increase in tumor-infiltrating macrophages was induced in tumors by MCP-1 transfection was compared to that induced by the parent cells. On the 10th day after the inoculation, the tumor-infiltrating macrophages in mice inoculated MCP-1 transfectants were decreased to a level similar to that of the parent cells. Groups of mice were treated intraperitoneally with LPS at different times after the inoculation. Tumor cells producing high levels of MCP-1 were significantly lysed by macrophages treated with LPS, whereas parental or control transfected cells were not. Conclusions. Combination immunotherapy can provide a rationale for the application of MCP-1 treatment to increase immunological responses to cancer.

Adenocarcinoma↗
PubMed2001

Correlations between in vitro effects of preparations of interferon and its inducers on blood cells in patients with multiple sclerosis.

We studied in vitro production of interferon-alpha and interferon-gamma by peripheral blood leukocytes from 15 patients with multiple sclerosis. The priming effects of interferon preparations weakly correlated with interferon-alpha production by leukocytes from patients with multiple sclerosis, but negatively correlated with interferon-gamma production. The effects of interferon inducers in most cases positively correlated with its spontaneous production. We found a weak positive correlation between the priming effect of natural interferon-alpha and the effect of recombinant interferons. There were positive or strong positive correlations between the effects of recombinant interferons on leukocytes from patients with multiple sclerosis. The relationship between the effects of medicinal interferon inducers and interferon preparation varied from negative to strong positive correlations. These data suggest that correlation analysis can be used for dynamic control and elaboration of methods for combined immunotherapy of multiple sclerosis with various interferon preparations or interferon and its inducers.

Acridines↗
PubMed2000

Paraneoplastic syndromes: an unsolved murder.

With neuroimmunology playing an ever greater role in child neurology, paraneoplastic syndromes--uncommon but often devastating complications of cancer--are in the forefront. Abnormalities of both humoral and cellular immunity support the immunological theory of causation. Through co-complicity of host and tumor factors, targets of immunologically mediated injury remote from the tumor may be damaged or destroyed, giving rise to discrete neurological deficits. In the nervous system, the main targets are neuronal nuclei or cell bodies, structural constituents, surface receptors, synapses, and ion channels. The clinical syndromes and response to treatment differ substantially between children and adults. Current pharmacological and biological therapies, which are nonselective, include noncytotoxic and cytotoxic drugs, intravenous immunoglobulins, plasma exchange, and immunoadsorption, some chosen for induction and others for maintenance. Tumor resection and thymectomy are surgical treatments. Combination immunotherapies allow steroid sparing, targeting of more than one immunologic effector pathway, and deploy an advantageous mixture of early- and late-acting drugs. More selective and efficacious immunotherapies are needed.

Adult↗
PubMed1997

Interferon-alpha induced thyroid dysfunction: three clinical presentations and a review of the literature.

Three patients who developed symptomatic, autoimmune-mediated thyroid dysfunction during treatment with interferon-alpha (IFN-alpha) for chronic active hepatitis C with liver cirrhosis, age-related macular degeneration with foveal involvement, and chronic myelogenous leukemia, respectively, are described. The first two patients developed autoimmune hypothyroidism that required thyroxine replacement, and the third developed autoimmune thyroiditis with transient thyrotoxicosis. The clinical manifestations were protean, and required a high index of suspicion for diagnosis, the failure of which led to significant morbidity. A literature review revealed that the mean incidence of IFN-alpha induced thyroid dysfunction was 6%. Spontaneous resolution occurred in more than half with discontinuation of IFN-alpha treatment. Hypothyroidism was induced more frequently than hyperthyroidism. At least one positive thyroid autoantibody titer was found in 17% of patients receiving IFN-alpha. Risk factors for developing thyroid dysfunction with IFN-alpha treatment were female sex, underlying malignancy or hepatitis C, higher doses of IFN-alpha for longer durations, combination immunotherapy (especially with interleukin-2), and the presence of thyroid autoantibodies prior to or during treatment.

Adult↗
PubMed1994

Immunization of mice with allogeneic fibroblasts genetically modified for interleukin-2-secretion and expression of melanoma-associated antigens stimulate predetermined classes of anti-melanoma effector cells.

Immunization of C57BL/6 mice (H-2b) with a mouse fibroblast cell-line of C3H origin (H-2k) genetically modified for interleukin-2 (IL-2)-secretion and the expression of melanoma-associated antigens (MAAs) (RLBA-IL-2 cells) resulted in a systemic anti-melanoma cellular immune response that led to a prolongation of survival of mice with established melanoma. Here we report certain of the effector cell-types activated for anti-melanoma immunity in mice immunized with the modified cells and, for comparison, the anti-melanoma cell-types activated following immunization with IL-2-secreting, MAA-negative fibroblasts (LM-IL-2 cells) or with non-IL-2-secreting, MAA-positive fibroblasts (RLBA-ZipNeo cells). The data indicate that both Lyt-2.2+ (CD8+) and natural killer/lymphokine-activated killer (NK/LAK) cells with anti-melanoma cytotoxicity were predominant in mice immunized with RLBA-IL-2 cells. NK/LAK cells alone were predominant in mice immunized with LM-IL-2 cells, and Lyt-2.2+ cells were predominant in mice immunized with RLBA-ZipNeo cells. The involvement of L3T4+ (CD4+) cells in the effector phase of the response was not detected in mice immunized with the genetically modified cells. Immunization of mice with both LM-IL-2 cells and RLBA-ZipNeo cells resulted in an anti-melanoma response of greater magnitude than was present in mice immunized with either cell-construct alone. It was equivalent to the melanoma immunity in mice immunized with RLBA-IL-2 cells. These data indicate that the immunogenic properties of the modified cells determined the anti-melanoma effector cell-types and suggest that combination immunotherapy with cell-constructs that stimulate different classes of effector cells may be more effective in immune-mediated tumor regression than immunization with a construct that activates a single effector cell-type alone.

Animals↗
PubMed1996

Systemic interleukin-2 modulates the anti-idiotypic response to chimeric anti-GD2 antibody in patients with melanoma.

The induction of human antimouse antibodies (HAMA) and human anti-idiotypic (anti-Id) responses in cancer patients receiving therapeutic monoclonal antibody (mAb) may limit the effectiveness of the administered mAb. This report evaluates the influence of systemic interleukin-2 (IL-2) on the anti-Id response to anti-disialoganglioside (anti-GD2) antibody given as treatment for patients with melanoma. Twenty-eight patients with melanoma received combined immunotherapy with anti-GD2 antibody and IL-2 at 1.5 x 10(6) U/m2/day given 4 days/week. The anti-GD2 antibody [murine 14.G2a mAb; dose levels of 2-5 mg/m2/day (4 patients); or human-mouse chimeric 14.18 (ch14.18) antibody; dose levels of 2-10 mg/m2/day (24 patients)] was scheduled to be given for 5 days either before, during, or after initial systemic IL-2 treatment. All four patients who received murine 14.G2a developed HAMA anti-isotype antibodies (660-1,000 ng/ml) as well as measurable anti-Id antibodies. All three patients who received initial treatment with ch14.18 alone developed a strong anti-Id antibody response after IL-2 was started 1 week later. The serum level of anti-Id antibody decreased during subsequent ch14.18 infusions, suggesting that the anti-Id antibody may be binding the administered ch14.18. In contrast, measurable anti-Id antibody was detected in only 3 of 14 patients who received IL-2 before, during, and after initial ch14.18 administration. Two of four patients receiving systemic IL-2 before and during initial ch14.18 infusions, and two of three patients receiving systemic IL-2 concurrent with initial ch14.18 infusions developed anti-Id antibodies. These data suggest that the anti-Id response to chimeric anti-GD2 antibody is influenced by the timing of systemic IL-2 in relation to antibody administration and can be suppressed by systemic treatment with IL-2 given before, during, and after the antibody administration.

Adjuvants, Immunologic↗
PubMed1991

The role of tumor necrosis factor in allograft rejection. III. Evidence that anti-TNF antibody therapy prolongs allograft survival in rats with acute rejection.

We have previously demonstrated that TNF-alpha levels are elevated in liver transplant patients experiencing acute rejection. In addition, prophylactic administration of anti-TNF-alpha or anti-TNF-beta antibodies prolonged graft survival in a rat heterotopic cardiac transplant model. This experiment was designed to evaluate anti-TNF therapy in the treatment of acute allograft rejection. Heterotopic cardiac transplants were performed using Buffalo donors and Lewis recipients. Histologic sections of transplanted grafts from untreated animals revealed significant rejection at day 4 with terminal rejection occurring on day 10.8 +/- 0.4. Animals in the experimental groups received antirejection therapy from postoperative days 4-13. Treatment with cyclosporine at 2 mg/kg/day prolonged graft survival to 16.5 +/- 2.0 days (P = 0.01 versus controls). Administration of polyclonal anti-TNF-alpha in combination with polyclonal anti-TNF-beta increased graft survival to 14.6 +/- 0.4 days (P less than 0.001 versus controls). Use of a monoclonal anti-TNF-alpha antibody was even more effective, with graft survival of 17.4 +/- 0.7 days (P less than 0.001 versus controls). Combination immunotherapy with monoclonal anti-TNF-alpha in conjunction with CsA extended survival to greater than 30 days. In contrast, recombinant TNF-alpha (5 micrograms/day, i.p.) markedly accelerated the time to graft failure (7.4 +/- 0.2 days, P less than 0.001 versus controls). Examination of explanted graft tissue on postoperative day 9 from animals treated with anti-TNF showed decreased mononuclear cell infiltrate when compared to untreated animals. Treatment with TNF-alpha markedly increased the inflammatory process. These results suggest that TNF may play a role in the pathogenesis of acute rejection.

Animals↗
PubMed1979

Cell-mediated immunity in operable bronchial carcinoma: the effect of injecting irradiated autologous tumour cells and BCG.

In 52 patients undergoing tests of cell-mediated immunity before surgical resection of bronchial carcinoma a positive tuberculin test result was found in 71% compared with 68% of age- and sex-matched controls. Sensitisation to DNCB occurred in 52% of 37 patients but in 78% of controls. There was depression of lymphocyte transformation by PPD in 19 patients compared with controls (P=0.001), but there was no difference in lymphocyte transformation by PHA or pokeweed mitogen between 34 patients and controls. In a pilot study patients were randomly allocated to autograft (eight) or non-autograft (seven) groups. The autograft group were given an intradermal injection of a suspension of irradiated autologous tumour-cells mixed with intradermal BCG on the day of operation. Tests of cell-mediated immunity were repeated two weeks after operation. Five patients in each group received a course of radiotherapy to the mediastinum three weeks after operation. There was a rise in cutaneous tuberculin reactivity (P=0.08) and total leucocyte count (P=0.09) in the autograft group postoperatively with a fall in total lymphocyte and T lymphocyte counts in the non-autograft group (P less 0.05). These differences, however, were not followed by any difference in the frequency of tumour recurrence or the survival rate two years after operation. The results show that the immunological surveillance mechanism is impaired even in patients with early bronchial carcinoma and that it is possible to overcome postoperative immunological depression with specific immunotherapy combined with BCG. This treatment did not produce any clinical advantage in this small number of patients and the skin lesions caused the patients considerable discomfort.

Aged↗
PubMed2004

Kinase inhibition with BAY 43-9006 in renal cell carcinoma.

BAY 43-9006 is an oral inhibitor of CRAF, wild-type BRAF, mutant V599E BRAF, vascular endothelial growth factor receptor (VEGFR) 2, VEGFR3, mVEGFR2, FLT-3, platelet-derived growth factor receptor, p38, and c-kit among other kinases. A Phase I study of BAY 43-9006 identified 400 mg orally twice daily as the recommended Phase II dose. The Phase II results of a study of BAY 43-9006 at 400 mg orally twice daily were particularly interesting in patients with renal cell carcinoma. Data from the first 41 patients with renal cell carcinoma showed that 30% of patients had stable disease (defined as between 25% reduction and 25% growth), 40% had responded (defined as >25% reduction), and 30% had progressed. Disease could be stabilized for periods in excess of a year. Some lesions became cystic and could actually enlarge while developing a low attenuation core. This phenomenon is recognized in the treatment of gastrointestinal stromal tumors with imatinib mesylate. The toxic effects of BAY 43-9006 were manageable and included hypertension, edema, diarrhea, hand and foot syndrome, rash, and hair loss where the rash involved the scalp. There was an impression of tachyphylaxis such that patients who required a dose reduction could be restored to full dose after a few months. A Phase III randomized, placebo-controlled trial of BAY 43-9006 has started for patients whose renal cell carcinoma has progressed within 6 months of immunotherapy. Combination studies with interferon, interleukin 2, bevacizumab, and chemotherapy are under consideration. The therapeutic targets of BAY 43-9006 in renal cell carcinoma remain unclear. Unlike melanoma, BRAF mutations have not been found in renal cell carcinoma. Other candidate targets include VEGFR2 and VEGFR3.

Benzenesulfonates↗
PubMed1998

Granulocyte-macrophage colony-stimulating factor potentiates antitumor activity of interleukin-12 in melanoma model in mice.

To study the antitumor activity of the combination immunotherapy with interleukin-12 (IL-12) and granulocyte-macrophage colony-stimulating factor (GM-CSF), a murine MmB 16 melanoma tumor model was used. Seven days after inoculation of MmB 16 melanoma cells into the footpad of the right hind limb, mice were treated with IL-12 and/or GM-CSF administered intratumorally for 7 consecutive days. IL-12 used both at a high (1 microg) and at a low (0.01 microg) dose per day produced retardation of tumor growth, although neither treatment resulted in any significant prolongation of the survival of tumor-bearing mice. GM-CSF did not by itself exert antitumor activity in this model; however, it potentiated antitumor effects of IL-12. In particular, survival of tumor-bearing mice treated with IL-12 (0.01 microg per day) and GM-CSF was significantly prolonged compared with that in mice treated with either IL-12 or GM-CSF alone.

Animals↗
PubMed1995

[Generation and activation of tumor-infiltrating lymphocytes (TIL) within the scope of lymphokine activated killer cell therapy (LAK-TIL therapy) in patients with advanced breast and ovarian carcinoma].

In this study we examined a combined immunotherapy using lymphokine activated tumor infiltrating lymphocytes and active specific immunotherapy with virus-modified tumor cells in disseminated breast and ovarian cancer patients. During the therapy a significant increase in cytotoxicity could be observed, which nevertheless could not be maintained after the end of therapy. In an ongoing prospective randomized study we are using antigen specific stimulated cytotoxic T-lymphocytes to extend this effect.

Adult↗
PubMed2005

Unique toxicities and resistance mechanisms associated with monoclonal antibody therapy.

Anti-CD20 therapy has had a truly dramatic impact on treatment and outcome of patients with follicular lymphoma. Unfortunately, the majority of responses to single-agent rituximab are incomplete, and all patients with follicular lymphoma will experience disease progression at some point following rituximab therapy. Rituximab has multiple mechanisms of inducing in vivo cytotoxicity, including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, direct apoptotic signaling, and possible vaccinal effects. The cellular microenvironment within follicular lymphoma has a profound impact on which mechanism is dominant, and confers resistance in many situations. Both tumor-associated and host-associated factors also contribute to rituximab resistance. There are multiple potential approaches to overcoming rituximab resistance, including rational biologic combination immunotherapy, engineered antibodies, and radioimmunoconjugates. Improved ability to overcome resistance will require further elucidation of critical signaling pathways involved in rituximab induced cytotoxicity and a comprehensive understanding of interactions between its multiple mechanisms of action.

Antibodies, Monoclonal↗
PubMed2006

Investigating the combination of trastuzumab and HER2/neu peptide vaccines for the treatment of breast cancer.

BACKGROUND: Trastuzumab, an anti-HER2/neu monoclonal antibody, is thought to promote HER2/neu receptor internalization and/or turnover. This study was designed to investigate the kinetics of trastuzumab treatment on tumor cells with varying levels of HER2/neu expression and to determine the effect of trastuzumab on HER2/neu-specific cytotoxic T lymphocyte-mediated lysis. METHODS: Three cell lines with varying levels of HER2/neu expression were incubated with varying doses of trastuzumab at multiple time points. Trastuzumab binding and HER2/neu expression were determined. Peripheral blood mononuclear cells from three HLA-A2(+) healthy donors and four E75 peptide-vaccinated patients were stimulated with HER2/neu-derived peptides and tested in standard chromium release cytotoxicity assays with HER2/neu(+) tumor cells pretreated with trastuzumab. RESULTS: Treatment of tumor cells with 10 microg/mL of trastuzumab in an overnight incubation resulted in saturation of cell-surface HER2/neu receptors. At higher doses, trastuzumab staining and HER2/neu expression decreased in a time-dependent manner. Pretreatment of tumor cells with trastuzumab resulted in increases in specific cytotoxicity by peptide-stimulated cytotoxic T lymphocytes from HLA-A2(+) donors over untreated cells by an average of 5.6% and 15.3% (P = .0002) for doses of 10 and 50 microg/mL, respectively. In similar experiments involving peripheral blood mononuclear cells obtained from immunized patients, the average specific cytotoxicity for untreated cells was 34.2% +/- 1.3% vs. 40.6% +/- 2.5% (P = .035) and 40.7% +/- 1.6% (P = .0005) for those treated with 10 and 50 microg/mL, respectively. CONCLUSIONS: Our data suggest that pretreatment of breast cancer cells with trastuzumab induces turnover of the HER2/neu protein and enhanced killing by HER2/neu peptide-stimulated CTLs. This increased lysis occurs regardless of the degree of HER2/neu expression and seems more pronounced in vaccinated patients. These findings support further investigation into the use of combination immunotherapy with trastuzumab and HER2/neu peptide-based vaccines.

Antibodies, Monoclonal↗