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1.
Appl Ergon ; 43(2): 392-9, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21726854

ABSTRACT

Laptop computers may be used in a variety of postures not coupled to the office workstation. Using passive motion analysis, this study examined mean joint angles during a short typing/editing task in college students (n=20), in up to seven positions. Comfort was assessed after task execution through a body map. For three required postures, joint angles in a prone posture were different than those while seated at a couch with feet either on floor or on ottoman. Specifically, the prone posture was characterized by comparatively non-neutral shoulders, elbows and wrists, and pronounced neck extension. Significantly greater intensity and more regions of discomfort were marked for the prone posture than for the seated postures. It is recommended that the prone posture only be assumed briefly during laptop use. Exposure to laptops outside of the office setting should be assessed in future epidemiologic studies of musculoskeletal complaints and computer use.


Subject(s)
Microcomputers , Pain Measurement , Posture , User-Computer Interface , Adult , Anthropometry , Biomechanical Phenomena , Female , Humans , Male , Pain Measurement/methods , United States , Young Adult
2.
Appl Ergon ; 43(2): 408-12, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21764031

ABSTRACT

Mobile device text messaging and other typing is rapidly increasing worldwide. A checklist was utilized to characterize joint postures and typing styles in individuals appearing to be of college age (n = 859) while typing on their mobile devices in public. Gender differences were also ascertained. Almost universally, observed subjects had a flexed neck (91.0%, n = 782), and a non-neutral typing-side wrist (90.3%, n = 776). A greater proportion of males had protracted shoulders (p < 0.01, χ(2) test), while a greater proportion of females had a typing-side inner elbow angle of <90°, particularly while standing (p = 0.03, χ(2) test). 46.1% of subjects typed with both thumbs (two hands holding the mobile device). Just over one-third typed with their right thumb (right hand holding the mobile device). No difference in typing styles between genders was found. Future research should determine whether the non-neutral postures identified may be associated with musculoskeletal disorders.


Subject(s)
Computers, Handheld , Posture , Text Messaging , Adolescent , Checklist , Cross-Sectional Studies , Female , Humans , Male , Sex Factors , United States , Young Adult
3.
Ergonomics ; 48(1): 66-77, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15764307

ABSTRACT

Upper extremity musculoskeletal disorders (UEMSDs) comprise a large proportion of work-related illnesses in the USA. Physical risk factors including manual force and segmental vibration have been associated with UEMSDs. Reduced sensitivity to vibration in the fingertips (a function of nerve integrity) has been found in those exposed to segmental vibration, to hand force, and in office workers. The objective of this study was to determine whether an association exists between digital vibration thresholds (VTs) and exposure to ergonomic stressors in automobile manufacturing. Interviews and physical examinations were conducted in a cross-sectional survey of workers (n = 1174). In multivariable robust regression modelling, associations with workers' estimates of ergonomic stressors stratified on tool use were determined. VTs were separately associated with hand force, vibration as felt through the floor (whole body vibration), and with an index of multiple exposures in both tool users and non-tool users. Additional associations with contact stress and awkward upper extremity postures were found in tool users. Segmental vibration was not associated with VTs. Further epidemiologic and laboratory studies are needed to confirm the associations found. The association with self-reported whole body vibration exposure suggests a possible sympathetic nervous system effect, which remains to be explored.


Subject(s)
Automobiles , Ergonomics , Fingers , Stress, Physiological/etiology , Vibration , Adult , Age Factors , Cross-Sectional Studies , Female , Humans , Industry , Male , Middle Aged , Musculoskeletal Diseases/etiology , Occupational Diseases/etiology , Sex Factors
4.
New Solut ; 11(4): 397-402, 2001.
Article in English | MEDLINE | ID: mdl-17208756
5.
J Surg Res ; 59(2): 279-86, 1995 Aug.
Article in English | MEDLINE | ID: mdl-7543632

ABSTRACT

Autolymphocyte therapy (ALT) is adoptive cellular therapy of neoplastic disease based upon ex vivo activation of lymphocytes by either the supernatant derived from a previously prepared one-way mixed lymphocyte culture (MLC) or using low doses of the mitogenic monoclonal antibody OKT3 and a mixture of previously prepared cytokines (T3CS). We have previously demonstrated that nonspecific ex vivo activation of splenocytes from murine tumor-bearing hosts (TBH) using an MLC-supernatant or T3CS without the use of tumor antigen results in the expansion of the CD44+ (memory) T-cell subset. These CD44+ T-cells are the principal mediators of anti-tumor specificity in the ALT-cell population in advanced metastatic murine tumors and are able to protect against tumor challenge in healthy syngeneic mice (HSM). To determine if ALT is effective in an adjuvant setting, C57BL/6J splenocytes from HSM and TBH with B16 melanoma or Lewis lung (3LL) carcinoma were activated ex vivo using T3CS. Mice were implanted with either B16 melanoma or 3LL carcinoma and then underwent surgical excision of tumor. Tumor-excised mice (TEM) then received small numbers (10(6)) of ALT-cells derived from 3LL-TBH or B16-TBH splenocytes, HSM-derived ALT-cells, fresh splenocytes derived from 3LL-TBH or B16-TBH, or CD44-depleted ALT-cells. Significant anti-tumor activity as shown by prolonged survival (Day 100), cure of disease, and rejection of a local and systemic tumor rechallenge was demonstrated in 3LL-TEM that received B16-derived ALT-cells.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Carcinoma, Lewis Lung/therapy , Immunotherapy, Adoptive , Lymphocyte Activation/immunology , Melanoma/therapy , T-Lymphocyte Subsets/immunology , Animals , Antibodies, Monoclonal/therapeutic use , Carcinoma, Lewis Lung/immunology , Carcinoma, Lewis Lung/pathology , Carrier Proteins/analysis , Combined Modality Therapy , Cytokines/therapeutic use , Hyaluronan Receptors , Immunologic Memory , Immunophenotyping , Interleukin-2/therapeutic use , Killer Cells, Lymphokine-Activated/immunology , Killer Cells, Lymphokine-Activated/physiology , Melanoma/immunology , Melanoma/pathology , Mice , Mice, Inbred C57BL , Receptors, Cell Surface/analysis , Receptors, Lymphocyte Homing/analysis , Spleen/cytology , Spleen/immunology , T-Lymphocyte Subsets/pathology , Tumor Cells, Cultured
6.
Br J Urol ; 76(1): 115-22, 1995 Jul.
Article in English | MEDLINE | ID: mdl-7648042

ABSTRACT

OBJECTIVE: To determine if cis-diamminedichloroplatinum(II) (CDDP) enhances, by immunomodulation, ex vivo anti-tumour cytotoxicity of autolymphocyte therapy (ALT) against a chemotherapy-resistant tumour, and if lysis is mediated through T-cells, NK-cells, or both. MATERIALS AND METHODS: Human renal cell carcinoma (RCC) target cells were derived from surgical specimens and incubated in complete medium (CM) with CDDP, or in CM alone (control group). ALT-cells were prepared from autologous whole peripheral blood mononuclear cells (PBMC) or NK-cell (CD56)-depleted PBMC obtained before surgery. Tumour cells from each group were labelled with chromium-51(51Cr) and used as targets for ALT-cells and PBMC in a standard (4 h) and delayed (18 h) 51Cr-release assay at varying effector/target ratios (E:T). RESULTS: Tumour cells incubated in CDDP showed enhanced lysis, as measured by the 51Cr-release assay, at all E:T tested. This lysis was significantly greater during the 18 h assay and when ALT-cells were used as the effector cells rather than PBMC. Depletion of CD45RO+ (memory) T-cells from the ALT cell population precluded both the 4 and 18 h tumour cell lysis. Depletion of NK-cells (CD56+) diminished the ex vivo lysis of autologous targets during the 4 but not the 18 h assay. ALT-cells derived from two patients demonstrated ex vivo tumour-specificity against autologous and allogeneic RCC. CONCLUSIONS: These data suggest that: (i) ex vivo activated memory T-cells are the principal component demonstrating significant tumour-specific cytotoxicity of ALT-cells against RCC tumour targets; (ii) CDDP may alter the physical properties of tumour cells rendering them susceptible to immune-mediated attack; (iii) the combination of ALT and CDDP may lead to increased therapeutic efficacy in patients with metastatic RCC.


Subject(s)
Carcinoma, Renal Cell/therapy , Cisplatin/analogs & derivatives , Immunologic Memory/drug effects , Immunotherapy, Adoptive/methods , Kidney Neoplasms/therapy , T-Lymphocytes/drug effects , Cisplatin/therapeutic use , Female , Humans , Killer Cells, Natural/immunology , Lymphocyte Activation , Male , Middle Aged , T-Lymphocytes/immunology
7.
Cancer ; 75(12): 2875-8, 1995 Jun 15.
Article in English | MEDLINE | ID: mdl-7773936

ABSTRACT

BACKGROUND: Carcinoma of the breast infrequently presents initially as axillary adenopathy. In such cases, after biopsy proves the presence of metastatic carcinoma, the primary tumor generally is assumed to be in the ipsilateral breast, despite negative mammographic findings and the lack of a clinically palpable breast mass. METHODS: The authors recently studied a case of a 50-year-old woman in whom recurrent neuroendocrine carcinoma of the breast presented as a contralateral axillary lymph node metastasis. After mastectomy ipsilateral to the metastasis proved negative for tumor, a histologic comparison of the previous contralateral tumor with that in the lymph node was performed, followed by biopsy of the clinically and mammographically negative original lumpectomy site. RESULTS: Histologic and immunohistochemical studies proved that the original, metastatic, and locally recurrent tumors were identical, sharing unusual neuroendocrine features. The patient is currently disease free after chemotherapy. CONCLUSION: Contralateral mammary carcinoma should be considered in the workup of a patient who presents with evidence of an axillary lymph node metastasis. Locally recurrent breast carcinoma may be clinically and mammographically occult. Histologic review of prior biopsy material and comparison with current tissue is essential in proper patient management.


Subject(s)
Breast Neoplasms/pathology , Carcinoma, Neuroendocrine/pathology , Lymph Nodes/pathology , Lymphatic Metastasis/pathology , Axilla , Breast Neoplasms/surgery , Carcinoma, Neuroendocrine/surgery , Female , Functional Laterality , Humans , Mastectomy, Segmental , Middle Aged , Neoplasm Recurrence, Local
8.
Int J Cancer ; 61(4): 580-6, 1995 May 16.
Article in English | MEDLINE | ID: mdl-7759164

ABSTRACT

Autolymphocyte therapy (ALT) is adoptive cellular therapy of neoplastic disease using ex vivo activation of autologous (human) or syngeneic (murine) lymphocytes from tumor-bearing hosts (TBH) by low doses of anti-CD3 monoclonal antibody (MAb) and a mixture of previously prepared autologous cytokines (T3CS). Ex vivo activation by T3CS without tumor antigen results in expansion of CD44+ (memory) T cells. These memory T cells (ALT cells) mediate in vivo anti-tumor specificity and with cyclophosphamide (CY) are capable of curing metastatic disease in murine TBH. To determine whether CY could enhance the effectiveness of CD4+ or CD8+ subsets of ALT cells, C57BL/6J TBH with B16 melanoma or Lewis lung (3LL) carcinoma were treated with adoptive chemoimmunotherapy (ACIT) using CD4-depleted or CD8-depleted ALT cells and CY. ALT cells were derived from splenocytes of B16 or 3LL-TBH and activated ex vivo with T3CS. Depletion of CD4+ or CD8+ T cells was performed before or after activation with T3CS. B16-TBH or 3LL-TBH that received ACIT using CY with B16-derived or 3LL-derived CD8-depleted ALT cells, respectively, demonstrated cure of metastatic disease regardless of whether CD8+ T cells were depleted before or after T3CS activation. B16 or 3LL-TBH that received ACIT using CY with B16 or 3LL-derived CD4-depleted ALT cells also cured metastatic disease but only if CD4+ T cells were depleted after T3CS activation. Interleukin (IL)-2 added to pre-T3CS CD4-depleted ALT cells cultured with T3CS restored anti-tumor activity when combined with CY. TBH cured by ACIT using CY and ALT-cell subsets derived from syngeneic TBH with the identical tumor displayed tumor-specific immunity in rejecting a lethal challenge of identical but not reciprocal tumor. TBH given ACIT using CY and ALT-cell subsets derived from splenocytes of syngeneic TBH with reciprocal tumors rejected lethal challenges of both tumors. Tumor specificity measured by interferon (IFN)-gamma and 51Cr-release assays was demonstrated in pre- or post-T3CS/CD8-depleted, post-T3CS/CD4-depleted and pre-T3CS + IL-2/CD4-depleted ALT-cell subsets. Our data demonstrate that ACIT using CY combined with ex vivo T3CS-activated CD44+ memory T-cell subsets conveys long-term tumor-specific immunity.


Subject(s)
Carcinoma/therapy , Cyclophosphamide/pharmacology , Immunologic Memory , Immunotherapy, Adoptive , Lymphocyte Activation/immunology , Melanoma, Experimental/therapy , Neoplasms, Experimental/therapy , T-Lymphocyte Subsets/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Carcinoma/drug therapy , Carcinoma/immunology , Chromium/analysis , Chromium/metabolism , Chromium Radioisotopes , Combined Modality Therapy , Evaluation Studies as Topic , Immunophenotyping , Interferon-gamma/analysis , Interferon-gamma/metabolism , Lymphocyte Count , Melanoma, Experimental/drug therapy , Melanoma, Experimental/immunology , Mice , Mice, Inbred C57BL , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/immunology , Sensitivity and Specificity , T-Lymphocytes/metabolism
9.
J Surg Oncol ; 58(4): 212-21, 1995 Apr.
Article in English | MEDLINE | ID: mdl-7723363

ABSTRACT

Autolymphocyte therapy (ALT) is tumor-specific, adoptive cellular therapy of neoplastic disease using nonspecific ex vivo activation of autologous peripheral blood lymphocytes (PBL), which are composed primarily of memory T-cells (ALT-cells) and are active in patients with metastatic renal cell carcinoma and melanoma. Ex vivo pretreatment of tumor target cells with certain chemotherapeutic agents can enhance susceptibility to lysis by antitumor lymphocytes. To determine if cis-diamminedichloroplatinum(II) (CDDP) enhances ex vivo antitumor cytotoxicity of ALT-cells and if this lysis is mediated by T- and/or NK-cells and is human leukocyte antigen (HLA)-restricted, human soft tissue sarcoma (STS) target cells were derived from primary and metastatic surgical specimens and were incubated with and without CDDP. ALT-cells were prepared from autologous PBL obtained prior to surgery. Primary (PSTS) and metastatic (MSTS) target cells from each group were labelled with chromium 51 (51Cr) and used as targets for ALT-cells, CD45-depleted ALT-cells, CD56 (NK)-depleted ALT-cells, and PBL in a standard (4-hour) and delayed (18-hour) 51Cr release assay. Interferon-gamma (IFN-gamma) release was measured as an indication of antitumor effect and recognition by the noncytolytic lymphocytes in ALT-cells. Primary tumor target cells incubated in CDDP showed enhanced lysis as measured by the 51Cr release assay compared to non-CDDP-treated controls. Metastatic tumor target cells showed less lysis than the primary targets, although this was enhanced by pretreating metastatic tumor targets with CDDP. Lysis of all tumor targets was significantly greater when ALT-cells were used as the effector cells rather than PBL. Depletion of memory T-cells abrogated ex vivo lysis. Depletion of NK cells (CD56+) affected ex vivo lysis of autologous targets during the 4-hour but not the 18-hour assay. Ex vivo ALT-cell lysis and IFN-gamma release against only the autologous tumor targets confirmed tumor-specificity in one patient. Restriction of ALT-cell lysis and IFN-gamma release against HLA-A2+ autologous and one allogeneic HLA-A2+ STS tumor target, but not other non-STS targets, was demonstrated in another patient. These data suggest that CDDP may help render STS susceptible to tumor-specific, immune-mediated attack and that the combination of ALT and CDDP may lead to effective tumor-specific chemoimmunotherapy in patients with metastatic STS.


Subject(s)
Cisplatin/pharmacology , Immunologic Memory , Immunotherapy, Adoptive/methods , Lymphocyte Transfusion , Sarcoma/therapy , Soft Tissue Neoplasms/therapy , T-Lymphocytes/immunology , Blood Transfusion, Autologous , Female , Humans , Lymphocyte Activation , Male , Middle Aged
10.
Eur J Cancer ; 31A(5): 698-708, 1995.
Article in English | MEDLINE | ID: mdl-7640041

ABSTRACT

Autolymphocyte therapy (ALT) is the infusion of autologous peripheral blood mononuclear cells (PBMC) activated ex vivo by a cytokine-rich supernatant (T3CS) generated from a previous autologous lymphocyte culture using low doses of the anti-CD3 mitogenic monoclonal antibody. The mechanism of action is enhancement of a recall response by CD45RO+ (memory) T-cells (ALT cells) to host tumour without dependence on exogenous interleukin (IL)-2. The existence of anti-tumour-specific T-cells in melanoma patients has been well described, and efforts to utilise them therapeutically have achieved modest tumour response rates. However, few long-term survival data have been reported. From 1986 to 1992, we treated 36 patients with disseminated melanoma using ALT alone (26 patients) or adoptive chemoimmunotherapy using ALT and cyclophosphamide (CY) (10 patients). Over this time period, the cell activation method evolved from using cytokine supernatants derived from a one-way allogeneic mixed lymphocyte culture (MLCS), to the current practice of utilising anti-CD3 and autologous cytokines (T3CS). There were 21 men and 15 women, average age 57 years, range 30-82. 27 had failed prior therapies and 9 had no prior therapy. A total of 161 infusion of ALT cells were given: 65 with cells activated in MLCS and 96 with T3CS. There were no grade 3 adverse events, and an approximate 20% incidence of grades 1 and 2 reactions to ALT-cell infusions. Transient cytopenias were seen in patients receiving CY. Sixty-one per cent (22/36) of patients received the planned six ALT-cell infusions, while 39% did not due to progressive disease. In 33 evaluable patients, there were four complete responses, four partial responses and 6 patients with stable disease (SD). Responding patients and those with SD had prolonged survival compared to historical controls when matched for number of organ systems involved. Ex vivo depletion of CD45RO+ T-cells revealed preferential lysis of autologous and HLA-A-matched melanoma targets that was dependent on these memory T-cells. These data suggest that adoptive cellular therapy using ex vivo activated memory T-cells with and without CY is active, has low toxicity, is tumour-specific and can result in clinical benefit in patients with disseminated melanoma.


Subject(s)
Cyclophosphamide/therapeutic use , Immunologic Memory , Immunotherapy, Adoptive , Lymphocyte Activation , Melanoma/therapy , T-Lymphocytes/transplantation , Adult , Aged , Aged, 80 and over , Combined Modality Therapy , Female , Humans , Leukocyte Common Antigens/immunology , Male , Melanoma/secondary , Middle Aged , Survival Rate , T-Lymphocytes/immunology , Treatment Outcome
11.
Clin Immunol Immunopathol ; 73(1): 115-22, 1994 Oct.
Article in English | MEDLINE | ID: mdl-7923908

ABSTRACT

Autolymphocyte therapy (ALT) is adoptive cellular therapy of neoplastic disease based upon ex vivo activation of autologous peripheral blood mononuclear cells by either the supernatant derived from a previously prepared one-way mixed lymphocyte culture (MLC) or using low doses of the mitogenic monoclonal antibody anti-CD3 and a mixture of previously prepared autologous cytokines (T3CS). We have previously demonstrated that nonspecific ex vivo activation of splenocytes from murine tumor-bearing hosts (TBH) using an MLC supernatant or T3CS without the use of tumor antigen results in the expansion of the CD44+ (memory) T-cell subset. These memory T cells or autolymphocytes (ALT cells) mediate in vivo specificity when infused into murine TBH. To determine if cyclophosphamide (CY) could enhance the effectiveness of these ALT cells, C57BL/6J TBH with B16 melanoma or Lewis lung (3LL) carcinoma were treated with adoptive chemoimmunotherapy (ACIT) consisting of ALT cells and varying doses of CY. ALT cells were derived from the splenocytes of C57BL/6J TBH with B16 melanoma or 3LL carcinoma and activated ex vivo with T3CS. 3LL or B16 TBH received ALT cells derived from 3LL TBH splenocytes, B16 TBH splenocytes, CY alone, or ACIT with ALT cells and CY. Significantly greater antitumor activity as demonstrated by a decreased number of lung metastases (Day 21) and cure of primary and metastatic disease (Day 100) was seen in B16 or 3LL TBH that received ACIT using CY with B16-derived and 3LL-derived ALT cells, respectively, rather than ALT cells alone, CY alone, or ACIT with CY and reciprocal tumor-derived ALT cells. TBH cured by ACIT using CY and ALT cells derived from syngeneic TBH with the identical tumor displayed tumor-specific immunity as they were able to reject a lethal challenge of their previous B16 or 3LL tumor but not reciprocal tumors. TBH cured by ACIT using CY and ALT cells derived from splenocytes of syngeneic TBH with reciprocal tumors were able to reject lethal challenges of both tumors. These data demonstrate that effective ACIT using CY combined with ex vivo T3CS-activated CD44+ memory T cells from TBH conveys long-term tumor-specific immunity.


Subject(s)
Cyclophosphamide/therapeutic use , Immunotherapy, Adoptive , T-Lymphocytes/immunology , Animals , Antibodies, Neoplasm/immunology , Antibody Specificity , Antilymphocyte Serum/physiology , Carcinoma/drug therapy , Combined Modality Therapy , Immunity , Immunologic Memory , Melanoma, Experimental/drug therapy , Mice , Mice, Inbred C57BL , Neoplasms, Experimental/drug therapy , Phenotype , Spleen/cytology
12.
Clin Immunol Immunopathol ; 71(3): 325-32, 1994 Jun.
Article in English | MEDLINE | ID: mdl-7911078

ABSTRACT

Autolymphocyte therapy (ALT) is tumor-specific adoptive cellular therapy of neoplastic disease in human tumor-bearing hosts based upon nonspecific ex vivo activation of autologous peripheral blood lymphocytes. We have previously demonstrated that nonspecific ex vivo activation of splenocytes from murine tumor-bearing hosts using a mixed-lymphocyte culture supernatant without tumor antigen results in the expansion of the CD44+ (memory) T-cell subset and that depletion of these CD44+ T-cells results in the abrogation of all in vivo anti-tumor effects. To examine other means of generating anti-tumor-specific effectors, splenocytes of C57BL/6J healthy syngeneic mice and mice with B16 melanoma (B16 mice) or Lewis lung (3LL) carcinoma (3LL mice) were activated ex vivo using low doses of the mitogenic monoclonal antibody OKT3 and a mixture of previously prepared autologous cytokines (T3CS). Immunophenotypic studies of splenocytes pre- and postactivation by T3CS revealed preferential expansion of Thy-1.2+CD44+ (memory) T-cells. 3LL and B16 mice received ALT cells derived from splenocytes of 3LL mice, B16 mice, or healthy mice; fresh splenocytes from 3LL or B16 mice; or CD44-depleted ALT cells derived from splenocytes of 3LL or B16 mice. Significant anti-tumor activity as shown by a reduction in primary tumor size, decreased mean number of lung metastases (Day 21), and prolonged survival was demonstrated in 3LL mice that received 3LL-derived ALT cells and in B16 mice that received B16-derived ALT cells. To test long-term immunity, adoptive transfer of subtherapeutic numbers of ex vivo activated Thy-1.2+ memory T-cells were infused into healthy congenic B6.PL Thy-1a/CY (Thy-1.1+) mice. On rechallenge with 3LL or B16 tumor, long-term tumor-specific immunity was shown to be dependent on donor Thy-1.2+ memory T-cells. These data demonstrate that tumor-specific adoptive cellular therapy and long-term tumor immunity is possible using splenocytes from tumor-bearing mice that are activated ex vivo by T3CS and is dependent on the infusion of memory T-cells. These data are consistent with clinical results in patients with metastatic melanoma and renal cell carcinoma treated with T3CS-activated lymphocytes.


Subject(s)
Immunotherapy, Adoptive/methods , Lung Neoplasms/therapy , Lymphocyte Activation , T-Lymphocytes/immunology , Animals , Antigens, Surface/analysis , Humans , Immunologic Memory , Immunophenotyping , Melanoma, Experimental/therapy , Membrane Glycoproteins/analysis , Mice , Mice, Inbred C57BL , Neoplasms, Experimental/therapy , Spleen/cytology , Thy-1 Antigens , Time Factors , Tumor Cells, Cultured
13.
J Surg Oncol ; 55(4): 222-8, 1994 Apr.
Article in English | MEDLINE | ID: mdl-8159004

ABSTRACT

Autolymphocyte therapy (ALT) is adoptive cellular therapy of cancer using ex vivo activation of autologous peripheral blood lymphocytes (PBL). Memory T cells are the principal effector population in ALT, with in vivo activity in patients with metastatic renal cell carcinoma (RCC) and melanoma, and ex vivo cytotoxicity against autologous tumor targets. However, the noncytolytic lymphocyte portion of ex vivo-activated memory T cells (ALT cells) may also contribute as antitumor effectors. Pretreatment of murine and human tumor cells ex vivo with chemotherapeutic agents can enhance their susceptibility to antitumor lymphocytes ex vivo and in vivo. To determine whether cis-diamminedichloroplatinum(II) (DDP) could enhance ex vivo antitumor effects of ALT cells by immunomodulation, human breast and colorectal carcinoma target cells were derived from both primary and metastatic surgical specimens and incubated in complete medium (CM) with DDP or in CM alone (control group). Viability of each group was confirmed by trypan blue-dye exclusion test. ALT cells were prepared from autologous PBL at surgery. Primary and metastatic tumor cells from each group were used as targets for ALT cells and levels of interferon-gamma (IFN-gamma) release were measured as a determination of antitumor effect and recognition. Primary tumor target cells incubated in DDP showed enhanced antitumor effects and recognition by autologous ALT cells, as measured by the IFN-gamma assay compared to non-DDP-treated controls. Metastatic autologous tumor target cells demonstrated less IFN-gamma release than did the primary targets, although this was enhanced by pre-treating metastatic tumor targets with DDP. ALT cells demonstrated minimal IFN-gamma release when incubated with allogeneic tumor targets. These data suggest that autotumor recognition of metastatic tumor targets is comparable to that of primary lesions following ex vivo pretreatment of metastatic cells with nonlethal doses of certain chemotherapeutic agents. DDP may somehow alter the physical properties of target cells, rendering them susceptible to immune-mediated attack and the combination of ALT and DDP may lead to increased therapeutic efficacy in patients with metastatic breast and colon cancer.


Subject(s)
Breast Neoplasms/therapy , Cisplatin/therapeutic use , Colorectal Neoplasms/therapy , Immunotherapy, Adoptive , T-Lymphocytes/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/immunology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/immunology , Combined Modality Therapy , Drug Synergism , Female , Humans , Interferon-gamma/biosynthesis , Lymphocyte Activation , Male , Middle Aged , T-Lymphocytes/immunology
15.
Eur J Cancer ; 30A(12): 1871-82, 1994.
Article in English | MEDLINE | ID: mdl-7880620

ABSTRACT

Autolymphocyte therapy (ALT) is tumour-specific adoptive cellular therapy of neoplastic disease based upon non-specific ex vivo activation of autologous peripheral blood lymphocytes (PBL), using the supernatant derived from a previously prepared one-way mixed lymphocyte culture (MLC). To determine the requirement for tumour antigen during the activation process, splenocytes from C57BL/6J healthy syngeneic mice (HSM) and tumour-bearing mice (TBM) were activated ex vivo using a MLC-supernatant (MLCS). Ex vivo activation was performed both in the presence (HSM splenocytes) and absence (TBM splenocytes) of a 3M KC1 syngeneic tumour-antigen (STA) extract prepared from Lewis lung (3LL) carcinoma, B16 melanoma, or normal lung. Immunophenotyping of splenocytes pre- and post-activation by MLCS plus STA or MLCS only revealed expansion of activated CD44+ (memory) T-cells. Ex vivo tumour-specific cytotoxicity was demonstrated using MLCS-activated (TBM) or MLCS + STA-activated (HSM) splenocytes against 3LL or B16 target cells. CD44+ T-cells (ALT-cells) were then infused into synegeneic 3LL and B16 TBM. Significant antitumour activity was detected in 3LL and B16 TBM receiving cells from normal mice that were activated with MLCS in the presence of 3LL or B16 STA, respectively, and in 3LL and B16 TBM receiving splenocytes from 3LL-TBM and B16-TBM, respectively, activated by MLCS alone. Infusions of 3LL-derived or B16-derived ALT-cells into HSM provided specific immunity on tumour challenge. No antitumour activity was seen in 3LL and B16 TBM receiving fresh TBM splenocytes, ALT-cells derived from HSM which were activated ex vivo using MLCS without antigen, normal lung tissue as antigen, or using MLCS-activated splenocytes without STA derived from reciprocal TBM. Ex vivo depletion of CD44+ cells or Thy-1.2+ T-cells abrogated all antitumour activity in TBM and in HSM challenged with tumour. Depletion of NK-1.1+ natural killer (NK)-cells had no effect on antitumour efficacy. These data suggest that tumour-specific adoptive cellular therapy is possible using ex vivo activated HSM splenocytes with STA, or TBM splenocytes activated ex vivo without STA, and that these antitumour effects are dependent on CD44+ memory T-cells.


Subject(s)
Immunotherapy, Adoptive/methods , Lung Neoplasms/therapy , Lymphocyte Transfusion , Melanoma/therapy , Animals , Antigens, Neoplasm/immunology , Blood Transfusion, Autologous , Cytotoxicity, Immunologic , Immunophenotyping , Lung Neoplasms/immunology , Lymphocyte Activation , Lymphocyte Culture Test, Mixed , Melanoma/immunology , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Spleen/immunology , T-Lymphocytes/transplantation
16.
Am J Hematol ; 44(1): 42-7, 1993 Sep.
Article in English | MEDLINE | ID: mdl-8342564

ABSTRACT

Adoptively transferred immune cells in combination with chemotherapeutic agents form the basis for adoptive chemoimmunotherapy (ACIT) of neoplastic disease. Autolymphocytes (ALT-cells) are ex vivo activated peripheral blood lymphocytes (PBL) from tumor-bearing hosts (TBH) that consist primarily of tumor-specific CD45RO+ (memory) T-cells. These ALT-cells combined with cimetidine (CIM) as autolymphocyte therapy (ALT), have previously been demonstrated to be a safe and active form of outpatient adoptive immunotherapy (AIT) in human TBH with metastatic renal cell cancer (RCC). We have previously described an effective ACIT protocol using ALT and cyclophosphamide (CY) for patients with relapsed and refractory non-RCC solid tumors. We now report a case of a patient with a metastatic gastric leiomyosarcoma to the liver, who developed a clinical picture consistent with a tumor-lysis syndrome (TLS), following salvage therapy for his tumor with ACIT using ALT and CY. TLS is a well-known complication resulting from the treatment of rapidly proliferating hematopoietic tumors such as Burkitt's lymphoma and acute lymphocytic leukemia. TLS has also been rarely described in chronic lymphocytic leukemia, as well as certain solid tumors such as breast cancer, small cell lung cancer, and medulloblastoma. However, there have been no previous reports of TLS occurring either secondary to immunotherapy or in sarcomas. The nature of these unusual findings is discussed.


Subject(s)
Cyclophosphamide/adverse effects , Immunotherapy, Adoptive , Leiomyosarcoma/drug therapy , Leiomyosarcoma/therapy , Leukocyte Common Antigens/analysis , Lymphocyte Activation/physiology , Soft Tissue Neoplasms/drug therapy , Soft Tissue Neoplasms/therapy , Stomach Neoplasms/drug therapy , Stomach Neoplasms/therapy , T-Lymphocytes/physiology , Tumor Lysis Syndrome/etiology , Aged , Cimetidine/therapeutic use , Clinical Protocols , Cyclophosphamide/therapeutic use , Humans , Immunologic Memory , Liver Neoplasms/secondary , Male , Radiography, Abdominal , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Tomography, X-Ray Computed , Tumor Lysis Syndrome/diagnosis
19.
J Immunother Emphasis Tumor Immunol ; 13(3): 213-21, 1993 Apr.
Article in English | MEDLINE | ID: mdl-8471596

ABSTRACT

Autolymphocytes (ALT cells) are ex vivo activated peripheral blood lymphocytes (PBL) from tumor-bearing hosts (TBH) that consist primarily of tumor specific CD45RO+ (memory) T cells. These ALT cells combined with cimetidine as autolymphocyte therapy (ALT) have previously been demonstrated to be a safe and active form of outpatient adoptive immunotherapy (AIT) in human TBH with metastatic renal cell cancer (RCC). To determine activity of ALT in human TBH with therapy-resistant solid tumors other than RCC and whether it was feasible to combine ALT with chemotherapy, we studied 21 patients with relapsed or primary refractory solid tumors following a study protocol of adoptive chemoimmunotherapy (ACIT) using ALT and cyclophosphamide. Twenty patients were evaluable. Five responses were seen, including two complete responses (CRs) and three partial responses (PRs). ACIT activity was noted in relapsed TBH who had responded to their previous chemotherapy and/or radiation therapy. The toxic effects of this ACIT study were minimal with no treatment-related morbidity or mortality. It appears that in some relapsed but not primary refractory solid tumors, ACIT using ALT (CD45RO+ T cells and cimetidine) together with cyclophosphamide has definite antitumor activity associated with little or no toxic effects. Further studies of ACIT in solid tumors other than RCC are justified.


Subject(s)
Cyclophosphamide/administration & dosage , Immunotherapy, Adoptive/methods , Lymphocyte Activation , Neoplasm Recurrence, Local/therapy , Neoplasms/therapy , Adult , Aged , Combined Modality Therapy , Female , Humans , Immunophenotyping , Male , Middle Aged , Prognosis
20.
Cancer ; 70(1): 86-93, 1992 Jul 01.
Article in English | MEDLINE | ID: mdl-1606551

ABSTRACT

BACKGROUND: Lymphocytes that display a phenotype of mature B-cells, T-cells, natural killer (NK) cells, or a combination of T-cells and NK cells can be found in patients with lymphoproliferations that manifest as expansions of peripheral blood lymphocytes (PBL). If these PBL expansions exhibit clonality, they can be classified as chronic lymphocytic leukemia (CLL). METHODS/RESULTS: A patient who had two simultaneous, clonal lymphoproliferative disorders manifested as an unusual T-cell CLL in conjunction with systemic light chain amyloidosis is described. Gene rearrangement studies of the PBL of the patient showed clonal rearrangements of both the T-cell receptor beta (T beta) chain and the immunoglobulin genes. Additional immunologic and microscopic studies of the T-cells of the patient showed that they were large, agranular, CD4+ T-cells that also expressed the NK cell marker CD57. Cytogenetics disclosed an unusual karyotype in the PBL. CONCLUSIONS: The pathogenesis of this T-cell CLL and whether it truly represents a malignant disorder, as well as its relation to amyloidosis, is discussed.


Subject(s)
Amyloidosis/complications , Hypergammaglobulinemia/complications , Leukemia, Prolymphocytic, T-Cell/pathology , Aged , Amyloidosis/blood , Amyloidosis/genetics , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Enzyme-Linked Immunosorbent Assay , Humans , Hypergammaglobulinemia/blood , Hypergammaglobulinemia/genetics , Immunoglobulin Light Chains , Karyotyping , Leukemia, Prolymphocytic, T-Cell/blood , Leukemia, Prolymphocytic, T-Cell/genetics , Male , Microscopy, Electron , Phenotype , T-Lymphocytes/immunology , T-Lymphocytes/pathology
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