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Biomedical subjects

A E Chang

Publications and source records attributed to A E Chang.

At least 91 records · Page 5Linked to original sources
PubMed1993

Comparisons of dynamic infusion and delayed computed tomography, intraoperative ultrasound, and palpation in the diagnosis of liver metastases.

The purpose of this study was to determine whether delayed computed tomography (DCT) of the liver would more accurately detect hepatic malignancy when compared with bolus contrast-enhanced dynamic computed tomography (BCDCT). Fifty-one patients who required operation for intra-abdominal malignancy (92% with colorectal cancers) underwent preoperative BCDCT followed by DCT. At operation, palpation and intraoperative ultrasound (IOUS) examination of the liver were performed for localization and biopsy of tumor nodules. The standard for diagnosis was defined for this study as the combined results of IOUS, palpation, and biopsy. The sensitivities of BCDCT and DCT for hepatic metastases were 50% and 54%, respectively, with a corresponding specificity of 72% for each. DCT demonstrated no significant improvement over BCDCT in the detection of individual hepatic lesions. The sensitivity of palpation for the detection of metastases was 82%, equal to that of IOUS. Both palpation and IOUS were significantly superior to BCDCT or DCT in excluding false-positive and false-negative results (p < 0.001). IOUS failed to identify surface lesions less than 1.0 cm in diameter (sensitivity: 40%). Conversely, palpation was limited in the detection of subsurface tumors less than 1.0 cm in diameter (sensitivity: 33%). Combined IOUS and palpation were significantly more accurate in the detection of hepatic metastases than any single modality that was evaluated (p < 0.001).

Colorectal Neoplasms↗
PubMed1993

Generation of T-cells reactive to the poorly immunogenic B16-BL6 melanoma with efficacy in the treatment of spontaneous metastases.

The B16-BL6 (BL6) melanoma is a poorly immunogenic murine tumor that is highly invasive and spontaneously metastasizes from the primary site. Utilizing an established anti-CD3/interleukin-2 (IL-2) culture procedure, we have previously reported that lymph nodes (LNs) draining immunogenic murine sarcomas contained preeffector cells that could be activated to differentiate into therapeutic effector cells for adoptive immunotherapy. By contrast, LNs draining the poorly immunogenic BL6 melanoma were found not to be a reliable source of preeffector cells. Instead, sensitization of preeffector cells reactive to BL6 required the subcutaneous inoculation of tumor admixed with Corynebacterium parvum. LN cells draining these vaccination sites demonstrated therapeutic efficacy only after subsequent anti-CD3/IL-2 activation. The sensitization of preeffector cells was dependent on the presence of tumor antigen and an optimal dose of C. parvum (< or = 50 micrograms). Furthermore, kinetic analysis revealed that the preeffector response was transient after tumor vaccination. The therapeutic efficacy of anti-CD3/IL-2 activated LN cells was further evaluated in the treatment of spontaneous macroscopic BL6 visceral metastases. Spontaneous visceral metastases were induced in animals by inoculation with BL6 tumor in the footpad followed by amputation of the primary tumor 3 weeks later. The systemic transfer of 10(8) anti-CD3/IL-2 activated T-cells and the concomitant intraperitoneal administration of subtherapeutic doses of IL-2 1 week after amputation cured 50% of the animals and prolonged median survival time (MST) to > 140 days. All mice except one that received no treatment or was treated with IL-2 alone succumbed to visceral metastases with an MST of approximately 23 days. This study characterizes a model whereby the weak immune response to the BL6 melanoma can be positively or negatively modulated for the generation of antitumor reactive T-cells useful in adoptive immunotherapy.

Animals↗
PubMed1993

In vivo antitumor efficacy of tumor-draining lymph node cells activated with nonspecific T-cell reagents.

Progressive growth of immunogenic murine tumors elicits a tumor-specific but functionally deficient T-cell immune response in the draining lymph nodes. These T cells, referred to as "pre-effector" cells could be induced in vitro to differentiate into mature immune effector cells, capable of mediating the regression of established metastases. Initially, tumor cells were used to stimulate the in vitro maturation of pre-effector cells. Alternatively, we found that pre-effector cells could be activated by sequential stimulation with anti-CD3 and interleukin-2 in the absence of tumor cells. In adoptive immunotherapy, these activated cells mediated therapeutic effects that were exquisitely specific to the tumor that triggered the pre-effector cell response in vivo. Since the anti-CD3 interaction with T cells is polyclonal, the activated lymph node cell population must also contain a significant number of T cells that do not have tumor specificity. In an attempt to selectively activate tumor-sensitized pre-effector cells, we recently utilized superantigenic bacterial toxins as T-cell stimuli for effector cell generation. Superantigens combine with major histocompatibility class II molecules to form the ligands that stimulate T cells bearing distinct T-cell receptor V beta elements. Lymph node cells draining the MCA 205 sarcoma stimulated with staphylococcal enterotoxins A (SEA), B (SEB), or C2 (SEC2) resulted in selective expansions of V beta 3 and 11, V beta 3 and 8, or V beta 8.2 T cells, respectively. Adoptive immunotherapy experiments revealed that SEB- and SEC2-, but not SEA- stimulated cells, mediated tumor-specific eradication of pulmonary metastases.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Cellular interactions in effector cell generation and tumor regression mediated by anti-CD3/interleukin 2-activated tumor-draining lymph node cells.

Previous studies have demonstrated that progressive growth of the weakly immunogenic MCA 106 murine sarcoma stimulated, in the draining lymph nodes, the production of tumor-sensitized but not fully functional preeffector lymphocytes. These lymphocytes could develop into specific immune effector cells after sequential in vitro activation with anti-CD3 monoclonal antibody and interleukin 2 (IL-2). In this study, we analyzed cellular requirements for in vivo sensitization of preeffector cells, for generation of immune effector cells by the method of anti-CD3/IL-2 activation, and for adoptive immunotherapy mediated by activated cells. By selective depletion of T-cell subsets in vivo, we found that tumor regression after systemic adoptive immunotherapy required the collaboration of activated CD4+ and CD8+ cells. It was further demonstrated that CD8+ immune cells alone could mediate antitumor effects if exogenous IL-2 was provided in vivo. These results suggest that CD8+ cells served as immediate effector cells, whereas CD4+ immune cells provided a helper function via the secretion of IL-2. During in vitro anti-CD3/IL-2 activation, generation of effector cells depended on the collaborative interaction between previously sensitized CD4+ and CD8+ preeffector cells. At the stage of in vitro activation, the addition of IL-2 could not substitute the function of CD4+ cells. We next examined whether the sensitization of preeffector cells in the draining lymph nodes required cellular interactions between CD4+ and CD8+ T-cells. By in vivo depletion of T-cell subsets during tumor growth, we found that CD4+ cells were sensitized independently of CD8+ cells. More interestingly, in vivo sensitization of CD8+ preeffector cells also occurred independently in the absence of a CD4+ helper cell response. The lack of T-cell-T-cell interactions in vivo may explain the failure of effector cell generation during progressive tumor growth. Taken together, these results demonstrate that the anti-CD3/IL-2 activation defines an immune response distinct from many previously described mechanisms of antitumor immune responses.

Animals↗
PubMed1992

Rapid growth of leiomyoma in patient receiving tamoxifen.

A 49-year-old patient with breast cancer had a leiomyoma that rapidly enlarged shortly after she started therapy with tamoxifen. Exploratory laparotomy was necessary to confirm the diagnosis. The rapid growth may have resulted from the estrogen agonist properties of tamoxifen or alternatively by ovarian stimulation resulting in endogenous estrogen production.

Breast Neoplasms↗
PubMed1992

Divergent effects of TNF alpha in the adoptive immunotherapy of a murine sarcoma.

We have previously described an in vitro sensitization (IVS) procedure which enabled the generation of therapeutic T cells from tumor-bearing mice for adoptive immunotherapy. The procedure involved culture of tumor-draining lymph node (TDLN) cells with irradiated tumor in the presence of interleukin-2 (IL-2). The availability of many recombinant cytokines affords an opportunity to examine their effects on the immune response to tumor. In this study, we investigated the effect of tumor necrosis factor-alpha (TNF alpha) on the generation and function of IVS cells utilized in adoptive immunotherapy of the murine MCA 106 sarcoma. TNF alpha administered iv at nontherapeutic doses was found to enhance the antitumor efficacy mediated by IVS cells plus IL-2 in the treatment of pulmonary metastases. In contrast, TNF alpha administration to mice bearing progressive footpad tumors had inhibitory effects on the sensitization of tumor-reactive cells in TDLN since IVS cells generated from these animals displayed a diminished antitumor effect. This effect appeared to be due to a reduced number of tumor-reactive lymphoid cells in the TDLN since TNF alpha added to IVS cultures did not alter the antitumor efficacy of the resultant IVS effector cells. These findings indicate the divergent effects of TNF alpha on the immune response to tumor and adoptive immunotherapy with IVS cells.

Animals↗
PubMed1992

A novel role for autologous tumour cell vaccination in the immunotherapy of the poorly immunogenic B16-BL6 melanoma.

The growth of immunogenic tumours stimulates the generation of tumour-sensitized, but not functional, pre-effector T cells in the draining lymph nodes. These pre-effector cells can mature into effector cells upon in-vitro stimulation with anti-CD3 and IL-2. In the current study, using a defined, poorly immunogenic tumour, B16-BL6 melanoma, the pre-effector cell response was not evident during progressive tumour growth but was elicited by vaccination with irradiated tumour cells admixed with Corynebacterium parvum. After anti-CD3/IL-2 activation, these cells were capable of mediating the regression of established pulmonary metastases. The efficacy of the vaccine depended on the doses of both tumour cells and the adjuvant. While higher numbers of tumour cells were more effective, an optimal dose (12.5 micrograms) of C. parvum was required. The dose of irradiation was not a critical factor. After vaccination, kinetic studies revealed that the pre-effector cell response was evident 4 days later and declined after 14 days. These observations illustrate the potential role of active immunization in the cellular therapy of cancer.

Animals↗
PubMed1992

The role of fine-needle aspiration and pneumocystography in the treatment of impalpable breast cysts.

Prior studies have suggested that the recurrence rate is lower in breast cysts treated by pneumocystography (injection of air into cyst cavities after cyst aspiration) than in cysts treated by fine-needle aspiration alone. To determine if this is the case for impalpable breast cysts, we reviewed the hospital records and mammograms of 38 women with 41 impalpable cysts. Mammograms obtained immediately after aspiration show that pneumocystography was successful in 18 and unsuccessful in 20 of the 41 cysts. Four cysts were excluded from the study: one cyst that recurred after aspiration and was sampled by biopsy and three cysts for which immediate post-aspiration mammograms were unavailable but which had recurred or persisted 3 years after aspiration. Review of follow-up mammograms made 4 months to 3 years after the aspiration showed that three (17%) of 18 cysts in the group with successful pneumocystography recurred and 11 (58%) of 19 cysts in the unsuccessful group recurred (p = .02). No difference was found in the number of recurrent cysts in relation to estrogen therapy or menopausal status. Our results indicate that impalpable breast cysts treated by pneumocystography are less likely to recur than are cysts treated by aspiration alone.

Adult↗
PubMed1991

Specific adoptive immunotherapy mediated by tumor-draining lymph node cells sequentially activated with anti-CD3 and IL-2.

Lymph nodes (LN) draining progressively growing tumors contain tumor-sensitized but not fully functional preeffector lymphocytes. These cells could acquire therapeutic efficacy and be expanded upon sequential culture with anti-CD3 mAb for 2 days followed by incubation in IL-2 for 3 days. Using the weakly immunogenic MCA 106 and MCA 205 murine sarcomas, we have further defined conditions of this anti-CD3/IL-2 activation with which preeffector cells differentiated into immune effector cells. In vitro activation and expansion of effector cells required sequential but independent stimulation with anti-CD3 and IL-2 because the simultaneous presence of both anti-CD3 and IL-2 at either stage did not enhance the efficacy of activation. Generation of effector cells by this two-stage activation was critically dependent on the optimal concentrations of anti-CD3 (1.0 microgram/ml) and IL-2 (2-10 U/ml). However, these conditions were not optimal for inducing the greatest cellular proliferation. In adoptive immunotherapy experiments, although the transfer of anti-CD3/IL-2-activated cells alone could mediate the regression of established metastases, the concomitant administration of IL-2 enhanced the in vivo activity of these cells. More importantly, tumor regression mediated by the anti-CD3/IL-2-activated cells was found to be immunologically specific. The specificity was determined by the tumor that stimulated the preeffector cell response. In spite of their in vivo antitumor effects, the anti-CD3/IL-2-activated tumor-draining LN cells did not exhibit detectable in vitro cytotoxicity against the tumor target in the 4-h 51Cr-release assay. In mice bearing progressive tumor, draining LN contained most preeffector cells. Some preeffector cells were also detected in the spleen whereas mesenteric LN did not demonstrate any reactivity. In kinetics studies, sensitization of preeffector cells in the draining LN occurred between 4 to 6 days after tumor inoculation. As the tumor progressed, the presence of preeffector cells declined gradually suggesting a tumor-induced suppression. These results define the conditions whereby tumor-draining LN cells could be stimulated, in the absence of tumor Ag, to develop into specific therapeutic effector cells. Our findings also raise the possibility of using similar approaches for isolating immune effector cells from cancer patients for adoptive immunotherapy.

Animals↗
PubMed1991

Enhanced antitumor reactivity of tumor-sensitized T cells by interferon alfa.

Tumor-draining lymph node cells from mice bearing the methylcholanthrene-induced MCA 106 tumors can be sensitized in vitro to acquire antitumor reactivity. We examined the effect of interferon alfa on the function of cells that underwent in vitro sensitization in adoptive immunotherapy. Interferon alfa increased the antitumor reactivity of in vitro sensitized cells in the treatment of MCA 106 pulmonary metastases. This effect was evident in irradiated mice, indicating that a host response to the interferon alfa was not required. Interferon alfa treatment increased class I major histocompatibility complex antigen expression on tumor cells and increased their susceptibility to lysis by in vitro sensitized cells. These results suggest that interferon alfa enhancement of adoptive immunotherapy was mediated by its effect on tumor cells. Interferon alfa may be a useful adjunct to the adoptive immunotherapy of human cancer.

Animals↗
PubMed1991

Suppressive effects of visceral tumor on the generation of antitumor T cells for adoptive immunotherapy.

Antitumor reactive cells can be generated from lymphoid organs of mice bearing subcutaneous (SC), but not liver or lung, tumors by in vitro sensitization with irradiated tumor and interleukin 2. To examine whether visceral tumors mediated tumor-induced suppression, in vitro sensitization cells were generated from mice bearing SC tumors with and without concomitant liver or lung tumors. Antitumor efficacy of these cells was assessed in adoptive immunotherapy experiments. The presence of visceral tumors suppressed the ability to generate therapeutic in vitro sensitization cells from mice with SC tumors. By establishing visceral tumors at different intervals in relationship to SC tumor inoculation, we found that visceral tumor appeared to suppress directly the development of a host immune response to SC tumor, rather than inhibit function of established immune cells. Our model affords a means to study mechanisms of tumor-induced immunosuppression.

Animals↗
PubMed1991

Enhancing effect of interleukin 1 alpha administration on antitumor effector T-cell development.

Antitumor effector T cells can be generated from tumor-draining lymph node cells by activation with anti-CD3 monoclonal antibody and interleukin 2. Fresh tumor-draining lymph node cells do not have antitumor activity, but after anti-CD3 monoclonal antibody-interleukin 2 activation, these cells mediate immunologically specific tumor regression in vivo. We examined the effect of interleukin 1 alpha administration on the development of effector T cells derived from tumor-draining lymph nodes. Mice were inoculated with tumor cells, and interleukin 1 alpha (180 to 720 ng) was administered on days 0, 2, and 4. Tumor-draining lymph nodes harvested 10 to 14 days later were activated in anti-CD3 monoclonal antibody for 2 days followed by expansion in interleukin 2 for 3 days. Antitumor efficacy of the activated cells was assessed in the adoptive immunotherapy of lung micrometastases. Administration of interleukin 1 alpha enhanced the antitumor reactivity of effector cells derived from tumor-draining lymph nodes without changing the immunologic specificity of the cells. Administration of interleukin 1 alpha did not alter the phenotype of fresh or activated tumor-draining lymph node cells. Interleukin 1 alpha deserves further investigation as an immune adjuvant in adoptive immunotherapy.

Animals↗
PubMed1991

Activation by anti-CD3 of tumor-draining lymph node cells for specific adoptive immunotherapy.

Lymph nodes draining progressive tumors contain tumor-sensitized but not functional preeffector T lymphocytes. These cells can acquire antitumor reactivity after stimulation with tumor cells and interleukin-2 (IL-2). We demonstrated here that, in the absence of tumor cells, preeffector cells could be stimulated and expanded by sequential culture with anti-CD3 monoclonal antibody and IL-2. The adoptive transfer of such activated cells mediated immunologically specific reductions of established pulmonary metastases. The therapeutic effects could be enhanced by the administration of IL-2. This activation represents a secondary immune response because effector cells could be generated only from tumor-draining but not from normal or adjuvant-stimulated lymph nodes. Furthermore, treatment of advanced metastases with these cells resulted in prolongation of survival and cure of the disease. Thus, anti-CD3 may serve as a universal reagent for activating tumor-sensitized T lymphocytes for cancer therapy.

Animals↗
PubMed1990

Phenotype analyses and cellular mechanisms of the pre-effector T-lymphocyte response to a progressive syngeneic murine sarcoma.

Lymph nodes draining the progressively growing, weakly immunogenic, MCA 105 sarcoma contained tumor-sensitized but not fully functional pre-effector T-cells. These cells could further differentiate to acquire full antitumor effector function for adoptive therapy in an established in vitro sensitization (IVS) procedure. In this study, we utilized selective depletion with antibodies of lymphocyte subsets bearing the L3T4 (CD4) or Lyt-2 (CD8) antigen and of cells bearing the asialo-GM1 (ASGM-1) glycosphingolipid to identify the phenotype of pre-effector cells elicited during progressive tumor growth. Cells from lymph nodes draining a progressive MCA 105 tumor in the footpad were treated with antibodies plus complement prior to IVS. The antitumor efficacy of resulting IVS cells was assessed in adoptive therapy of 3-day established pulmonary MCA 105 metastases. Depletion of Lyt-2+ cells eliminated in vivo antitumor reactivity with concurrent elimination of in vitro cytotoxic activity against the MCA 105 tumor, whereas depletion of L3T4+ cells did not have an impact on either in vivo or in vitro antitumor reactivities. Treatment with ASGM-1 antiserum plus complement was also found to abrogate therapeutic efficacy. However, the in vitro cytotoxic activity was not affected. These results indicate that the pre-effector cells were Lyt-2+, L3T4-, and ASGM-1+. We next examined whether the sensitization of pre-effector cells in vivo required the participation of L3T4+ helper cells. To approach this, mice were depleted of L3T4+, Lyt-2+, or ASGM-1+ cells by antibody injections before tumor inoculation. Treatment with Lyt-2 monoclonal antibody abrogated the pre-effector cell response in the draining lymph nodes, as evidenced by failure to generate therapeutically effective cells following IVS. On the other hand, neither L3T4 nor ASGM-1 antibody treatment affected the generation of pre-effector cells. Thus, sensitization of Lyt-2+ pre-effector cells in response to progressive tumor occurred in the absence of L3T4+ helper cells.

Animals↗
PubMed1990

Effector phenotype and immunologic specificity of T-cell-mediated adoptive therapy for a murine tumor that lacks intrinsic immunogenicity.

The MCA 102 sarcoma has been defined by a variety of immunologic studies as a tumor lacking intrinsic immunogenicity. Nevertheless, we have recently demonstrated the feasibility of generating therapeutically effective lymphocytes for adoptive immunotherapy of this tumor. Procedures to achieve this required in vivo priming of syngeneic mice to elicit preeffector cells followed by in vitro sensitization (IVS) with tumor cells in the presence of IL-2. By selective depletion of T cell subsets in vivo, we identified the involvement of both CD4+ (L3T4+) and CD8+ (Lyt-2+) T cells in mediating tumor regression. The CD4+ cells exerted their helper function via the secretion of IL-2 because antitumor effects abrogated by depletion of CD4+ cells could be reconstituted by exogenous IL-2. In order to elicit preeffector cells with reactivity against the MCA 102 tumor, we found that in vivo sensitization could be accomplished with either the MCA 102 or MCA 106 tumor but not with the MCA 101 or MCA 105 tumor. Analysis of specificity of tumor stimulation during IVS of MCA 102 tumor-primed preeffector cells demonstrated cross-reactivity between not only the MCA 102 and MCA 106 tumors but also the MCA 105 tumor whereas the MCA 101 tumor was ineffective. In adoptive immunotherapy, transfer of IVS cells generated from MCA 102 tumor-primed and stimulated lymph node cells was able to mediate reductions of pulmonary metastases established from the MCA 102, MCA 105, and MCA 106 tumors but not from the MCA 101 tumor. We conclude that regression of the MCA 102 tumor is probably mediated through T cell recognition of a set of common tumor-associated Ag shared by several other syngeneic tumors. Immunologically, the tumor-associated Ag are characteristically different from classical tumor-specific transplantation Ag (TSTA) because immunity to TSTA on the MCA 105 or MCA 106 tumor does not cross-react with the MCA 102 tumor. Thus, this study demonstrates that Ag other than TSTA on chemically induced tumors can serve as target molecules for T cell-mediated adoptive immunotherapy.

Adjuvants, Immunologic↗
PubMed1990

Repeat hepatic resections for colorectal metastases.

We identified 106 patients who had undergone complete resection of isolated colorectal hepatic metastases. Nine of these patients subsequently underwent repeat liver resections for isolated hepatic recurrences. The median follow-up for these patients was 21 months. One postoperative death was related to the second hepatectomy. At the time of last follow-up, five patients were alive and free of recurrent disease at 9, 19, 31, 50, and 67 months after their second hepatic resection. The remaining three patients were alive, but disease had recurred 11 months after resection in the first patient, 12 months after resection in the second, and 18 months after resection in the third. Among these three patients, two had solitary pulmonary nodules, which were resected, and one had unresectable liver disease. Our experience and a review of the literature suggest that repeat hepatic resection for isolated colorectal metastases can result in long-term survival in selected patients.

Colonic Neoplasms↗