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Biomedical subjects

M A Cheever

Publications and source records attributed to M A Cheever.

At least 91 records · Page 5Linked to original sources
PubMed1984

Interleukin 2 administered in vivo induces the growth of cultured T cells in vivo.

The capacity of exogenous IL 2 to induce the growth of antigen-activated T lymphocytes in vivo was evaluated. The in vivo growth of adoptively transferred T lymphocytes that had been previously cultured long-term with IL 2 was initially examined, because in vitro such T cells are exquisitely dependent upon exogenous IL 2 for proliferation and survival. Daily administration of IL 2 in vivo, beginning on the day of cell transfer, induced these IL 2-dependent long-term cultured T lymphocytes to proliferate in vivo, and the magnitude of in vivo growth was proportional to the dose of IL 2 administered. The capacity of IL 2 to induce the in vivo growth of antigen-activated T cells not previously exposed in vitro to exogenous IL 2 was similarly studied. T lymphocytes from the spleens of immune mice, activated by 5-day culture with tumor antigen before transfer, survived poorly in vivo when injected with antigen alone, but demonstrated marked proliferation in vivo in response to antigen and exogenous IL 2. By contrast, immune spleen cells transferred with antigen, but without prior culture, proliferated without supplementary exogenous IL 2. Moreover, the growth of noncultured donor T cells was not augmented by the administration of exogenous IL 2, implying that noncultured spleen cells immune to tumor antigens can produce sufficient amounts of endogenous IL 2 in vivo to sustain maximal T cell growth over the time period examined. Importantly, the ability of exogenous IL 2 to induce donor T cell growth in vivo correlated with its ability to function in vivo to augment the anti-tumor efficacy of specifically immune donor T cells in models for the adoptive therapy of disseminated antigenic murine leukemia. Thus, the current studies highlight the potential of exogenous IL 2 to induce T cell growth in vivo and suggest that the administration of IL 2 in vivo may be useful for augmenting T cell responses that are relatively deficient in the production of endogenous IL 2.

Animals↗
PubMed1983

Intensification therapy for acute nonlymphoblastic leukemia in adults.

Thirty-nine adults with acute nonlymphoblastic leukemia (ANL) in complete remission (CR) for six months were considered for intensification therapy. All patients had received a high dose chemotherapeutic remission-induction regimen consisting of daunorubicin, cytosine arabinoside, 6-thioguanine, prednisone, and vincristine, followed by one consolidation course of the same drugs at reduced doses and then monthly maintenance course of low-dose chemotherapy. The intensification therapy consisted of the same intensive chemotherapy regimen utilized for remission induction in place of the sixth and 12th monthly courses of postremission induction chemotherapy. Twenty-three of the 39 patients received intensification therapy, whereas 16 patients refused or were not offered such therapy for medical reasons and, therefore, received only monthly therapy. The median remission duration of the 23 patients who received intensification therapy was 157 weeks, and 9 remain in continuous first remission at 176-285 weeks. The remission duration of the 16 patients who did not receive intensification therapy was 73 weeks (P = 0.03). Kaplan-Meier estimates of remission duration and survival from time of remission computed by including the patients who either relapsed or received bone marrow transplantation before the time of intensification (6 months) revealed a median remission duration and survival of 100 and 172 weeks for patients receiving intensification compared to 37 and 72 weeks, respectively, for patients not receiving intensification therapy. Since results in patients not receiving intensification therapy are consistent with our previous results in patients receiving the same induction and consolidation regimens without intensification, this nonrandomized study suggests that intensification therapy prolongs remission duration and survival in adults with ANL.

Acute Disease↗
PubMed1982

Augmentation of the anti-tumor therapeutic efficacy of long-term cultured T lymphocytes by in vivo administration of purified interleukin 2.

Spleen cells from C57BL/6 mice immunized in vivo with a syngeneic Friend virus-induced leukemia, FBL-3, were specifically activated by culture for 7 d with FBL-3, then nonspecifically induced to proliferate in vitro for 12 d by addition of supernatants from concanavalin A-stimulated lymphocytes containing interleukin 2 (IL-2). Such long-term cultured T lymphocytes have previously been shown to specifically lyse FBL-3 and to mediate specific adoptive therapy of advanced disseminated FBL-3 when used as an adjunct to cyclophosphamide (CY) in adoptive chemoimmunotherapy. Because the cultured cells are dependent upon IL-2 for proliferation and survival in vitro, their efficacy in vivo is potentially limited by the availability of endogenous IL-2. Thus, the aim of the current study was to determine whether exogenously administered purified IL-2 could augment the in vivo efficacy of long-term cultured T lymphocytes. Purified IL-2 alone or as an adjunct to CY as ineffective in tumor therapy. However, IL-2 was extremely effective in augmenting the efficacy of IL-2-dependent long-term cultured T lymphocytes in adoptive chemoimmunotherapy. The mechanism by which IL-2 functions in vivo is presumably by promoting in vivo growth and/or survival of adoptively transferred cells. This assumption was supported by the findings that IL-2 did not enhance the modest therapeutic efficacy of irradiated long-term cultured cells that were incapable of proliferating in the host and was ineffective in augmenting the in vivo efficacy of noncultured immune cells that are not immediately dependent upon exogenous IL-2 for survival.

Animals↗
PubMed1982

Treatment of chronic granulocytic leukemia with chemoradiotherapy and transplantation of marrow from identical twins.

Twelve patients in the chronic phase of Ph1 (Philadelphia)-positive chronic granulocytic leukemia (CGL) received chemoradiotherapy and marrow from their normal, identical twins. All had a complete remission, with disappearance of all Ph1-positive cells. One patient died of pneumonitis while in remission. Three had a cytogenetic relapse 22 to 30 months after grafting; only one of these three entered blast crisis and died. Eight remain in complete remission 21 to 65 months (median, 30) after transplantation. Thus, the Ph1-positive clone can be ablated and blast crisis delayed or prevented. Of 10 patients with CGL who received transplants during the terminal phase, eight died soon after, one is in complete remission 11 months after receiving a second graft, and one remains in complete remission 71 months after transplantation. This experience suggests to us that every patient with CGL and an identical twin should receive a marrow graft, preferably in the chronic phase. On the basis of our results, trials of allogeneic-marrow transplantation for CGL seem justified.

Adolescent↗
PubMed1982

Nonbacterial nonfungal pneumonia following marrow transplantation in 100 identical twins.

Pneumonia attributable to causes other than bacterial or fungal infection is a major complication of allogeneic marrow transplantation. In this study, the incidence, mortality, and possible risk factors for the development of nonbacterial, nonfungal pneumonia after 100 syngeneic marrow transplants for hematological malignancy are reviewed and compared with the results found in 351 allogeneic marrow transplants performed during the same time period. Both the incidence and mortality of pneumonia were far lower among syngeneic patients, especially for pneumonia associated with cytomegalovirus. Idiopathic pneumonia, however, occurred with about equal frequency in the two populations. Among twins, an increased incidence of pneumonia was seen in older patients and in those who received chemotherapy in addition to cyclophosphamide and total body irradiation as part of the preparative regimen for transplantation.

Adolescent↗
PubMed1982

Treatment of refractory acute nonlymphocytic leukemia with a combination of pyrazofurin and cytarabine.

Six patients with refractory acute nonlymphocytic leukemia were treated with pyrazofurin (15 mg/m2) followed by cytarabine (100 mg/m2) every 12 hours for 6--21 days. All patients cleared their peripheral blood of blast cells but no complete remissions were achieved. Excessive toxicity to skin and mucous membranes was observed. In the doses used, this combination is too toxic for further use. Alternate treatment schedules should be explored.

Acute Disease↗
PubMed1981

High-dose combination chemotherapy for acute nonlymphoblastic leukemia in adults.

One hundred thirty-nine consecutive unselected adults with acute nonlymphoblastic leukemia were treated with a high-dose chemotherapeutic remission-induction regimen consisting of daunomycin (70 mg/m2 IV on days 1, 2, 3), cytosine arabinoside (100 mg/m2 IV every 12 hours), 6-thioguanine (100 mg/m2 orally every 12 hours), prednisone (40 mg/m2 daily), all given on days 1 through 7, and vincristine (1 mg/m2 IV on days 1 and 7). Supportive care consisted of broad spectrum antibiotics for fever in the presence of granulocytopenia and prophylactic platelet transfusions. The complete remission (CR) rate was 60%. The median number of days to CR was 30. Fifty-eight of 77 (75%) patients under age 50 and 26 of 62 (42%) patients over age 50 attained CR. Despite the use of a relatively large dose of daunomycin and monthly maintenance chemotherapy, the median remission duration was only 39 weeks and the medial survival 64 weeks. Most patients who failed to achieve CR died early-77% of deaths occurred within the first six weeks. Infections accounted for the increase mortality in patients over age 50. Thirty-seven percent of patients over age 50 died of infections whereas only 10% under age 50 did so (P less than 0.001). Seven percent of the patients died of fungal infection during attempted remission induction. The incidence of resistance of the leukemia to the remission-induction regimen was low (8%).

Acute Disease↗
PubMed1981

Eradication of disseminated murine leukemia by chemoimmunotherapy with cyclophosphamide and adoptively transferred immune syngeneic Lyt-1+2- lymphocytes.

The phenotype of T cells therapeutically effective in immunotherapy of advanced Friend virus-induced (FBL) leukemia in vivo and cytotoxic to FBL in vitro was determined. Mice bearing disseminated FBL leukemia were successfully treated by a combination of cyclophosphamide and adoptive transfer of syngeneic immune lymphocytes. Therapeutic efficacy was largely dependent on the presence of Lyt-1+2- T cells in the transferred cells, whereas cells cytotoxic to FBL tumor in vitro were derived from the Lyt-1+2+ and Lyt-1-2+ subsets. Thus, the predominate cell required to eradicate tumor in adoptive chemoimmunotherapy was not cytolytic to tumor in vitro. Potentially, the Lyt-1+2- cell may operate in vivo as an amplifier cell rather than by a direct anti-tumor effect. Elimination of the Lyt-1+ population with alpha-Lyt-1 and complement prevented the generation of significant cytotoxic responses during both primary in vitro sensitization to alloantigens and in vitro sensitization of tumour-primed cells. The capacity of Lyt-1+ cell-depleted population to generate cytotoxic responses was partially reconstituted by addition, at the initiation of culture, of interluekin 2, a T cell growth factor derived from Lyt-1+2- cells, which contain the CTL and CTL precursors, were nearly as effective in vitro as unseparated immune cells. If the remaining effector cells (i.e., Lyt-1+2- T cells) function in vivo predominantly as amplifier cells, than the tumour-bearing host must be capable of making a positive contribution to the outcome of therapy.

Animals↗
PubMed1981

Definition of alien H-2 determinants on a Friend leukaemia by analysis of alloreactivity of CTL from primary MLC.

A Friend virus-induced tumour of BALB/c (H-2d) origin, HFL/d, was examined for the expression of alien H-2 antigens. The alloantigens on HFL/d were typed by generating CTL in primary MLC with HFL/d as stimulator and measuring reactivity to targets with known H-2 antigens, and confirmed by assessing recognition of HFL/d targets by CTL generated in primary MLC with stimulators expressing known H-2 antigens. Potential cross-reactivities between alloantigens were analysed by cold-target inhibition experiments. BALB/c cells stimulated with HFL/d lysed H-2b targets, and BALB/c anti-H-2b CTL lysed HFL/d; analysis with recombinant haplotypes demonstrated both H-2Kb and H-2Db alien antigens antigens on HFL/d. C57BL/6 (H-2b) cells stimulated with HFL/D recognized H-2Kd, H-2Dd, and an additional determinant unique to HFL/d. (BALB/c x B6)F1 cells also recognised a unique HFL/d determinant not of H-2b or H-2d origin. These unique determinants, which induced a strong cytotoxic response in primary MLC, were not shared by BALB/c or B6 tumours induced by cross-reactive FMR viruses. Thus, HFL/d expressed the K and D antigens of its strain of origin, two typed alien H-2 antigens, and at lest one other untyped antigen which may represent an additional H-2 determinant. These studies further demonstrate the utility of examining the reactivity of CTL generated in primary MLC to probe for the presence of alien H-2 antigens.

Animals↗
PubMed1981

Distinct phenotypic expression of immunogenicity and immunosensitivity in sublines of a tumor.

Continuous in vitro or in vivo passage of a BALB/c leukemia has resulted in generation of 2 immunologically distinct sublines. The subline maintained by in vitro passage failed to stimulate an allogeneic response but was susceptible to lysis by alloreactive cytotoxic cells. Conversely, the subline maintained by in vivo passage induced an allogeneic response but was resistant to lysis by cytotoxic T lymphocytes (CTL) reactive to H-2d antigens. Resistance to lysis occurred despite expression of H-2d antigens in a form recognizable by differentiated alloreactive CTL, as determined by cold-target inhibition experiments. Moreover, resistance was immunologically specific, in that the subline was susceptible to immune lysis mediated through recognition of other determinants. The results imply that the display and/or orientation of antigen in the cell membrane of these sublines that is required for a lytic event is distinct from the antigen expression necessary for immunologic recognition.

Animals↗
PubMed1981

Chemoimmunotherapy of a Friend leukemia with cells secondarily sensitized in vitro: effect of culture duration on therapeutic efficacy.

Although in vivo-primed cells are known to be rendered more effective in adoptive tumor therapy by secondary sensitization in vitro, they were tested only at the time of maximum in vitro cytolytic reactivity. Since the requirements for in vitro cytotoxicity and tumor therapy differ, the present study was designed to evaluate and compare the influence of culture duration on these two effector functions. Spleen cells from inbred C57BL/6 mice primed in vivo with the Friend virus-induced leukemia FBL-3 were secondarily sensitized in vitro by culture with tumor and tested for cytotoxicity in vitro in a 4-hour 51Cr release assay and for therapeutic efficacy in vivo against established tumor. In vivo-primed cells tested directly without prior culture were effective in therapy but were not cytotoxic in vitro. Culture of primed cells for 3 days rendered them cytotoxic as measured in vitro. This cytotoxicity increased through day 5, then it plateaued. Cultured duration modified the in vivo efficacy of primed cells differently. Cells cultured for 3 days with secondary sensitization by tumor became more effective in tumor therapy than noncultured primed cells. Increasing the duration of in vitro sensitization from 3 to 5 days did not enhance in vivo therapeutic efficacy, despite a concurrent increase in in vitro cytotoxicity. However, further lengthening of the culture duration to 7 days rendered cells more effective in vivo. These discrepancies presumably reflect different effector cell requirements and/or regulation operative for tumor lysis during a short-term in vitro assay and for tumor eradication following adoptive transfer of immune cells in vivo.

Animals↗
PubMed1981

Bone marrow transplantation for refractory acute leukemia in 34 patients with identical twins.

Thirty-four patients aged 4-67 yr (median 17) with acute lymphocytic leukemia (ALL) (18 patients) or acute nonlymphocytic leukemia (ANL) (16 patients) who failed to enter complete remission (CR) or relapsed on conventional chemotherapy were treated with cyclophosphamide (CY), 60 mg/kg/day for 2 days, 1000 rad total body irradiation, and a marrow transplant from a genotypically identical normal twin. Sixteen of the patients received additional chemotherapy within the week before CY. After the transplant, 23 patients received immunotherapy consisting of killed autologous leukemic cells and/or normal twin peripheral blood lymphocytes, 16 as part of a prospectively randomized study. One moribund patient died before engraftment. Nine patients (6 ALL, 3 ANL) continued to have detectable leukemic cells. Twenty-four patients (70%) achieved CR. One of them died of viral hepatitis at 1 mo and another of viral interstitial pneumonitis at 4 mo in CR. Fourteen patients (7 ALL, 7 ANL) relapsed 2-16 mo (median 4) after transplantation. However, 8 patients (24%) (3 ALL, 5 ANL) remain in CR without any maintenance chemotherapy at 29-103 mo (median 80) after the transplant. The end results were not signficantly influenced by the type of leukemia, the immediated pre-CY chemotherapy, or the immunotherapy. The results show that this approach, even when applied to endstage patients with acute leukemia in relapse, causes tolerable morbidity, rare nonleukemic deaths, and frequent remissions, some of which represent cures.

Acute Disease↗
PubMed1981

Adoptive therapy of established syngeneic leukemia by cells primarily sensitized in vitro.

The aim of the current studies was to determine whether cells primarily sensitized in vitro are effective in adoptive therapy of established tumors. Spleen cells from normal BALB/c mice were cultured for 5 days at variable responder:stimulator ratios with an X-irradiated syngeneic Moloney virus-induced leukemia (LSTRA), denoted as BALB/c.(LSTRA)x, or with X-irradiated normal BALB/c spleen cells, denoted as BALB/c. (BALB/C)x, and tested for ability to eradicate an established lethal inoculum of LSTRA in adaptive chemoimmunotherapy. BALB/c mice inoculated with 2 X 10(3) LSTRA i.p. on Day 0 were treated on Day 5 with cyclophosphamide (180 mg/kg) plus 1 X 10(7) cultured cells. Treatment with cyclophosphamide alone cured only 3% of mice. As an adjunct to cyclophosphamide, therapy with BALB/c.(BALB/c)x cultured at responder:stimulator ratios of 8:1, 32:1, and 128:1 cured 29%, 37%, and 33% of mice, respectively; and BALB/c.(LSTRA)x cultured at the same responder:stimulator ratios cured 54, 83, and 29% of mice, respectively. Furthermore, the therapeutic efficacy of BALB/c.(LSTRA)x was abrogated by treatment with anti-Thy 1.2 + complement. Thus, culture of normal lymphoid cells with tumor at optimal responder:stimulator ratios substantially enhanced their ability to eradicate established tumor, and the enhanced therapeutic efficacy was mediated by a T-cell generated during culture. The specificity of primary in vitro sensitization in generating cells effective in the therapy of established tumors was confirmed by treating BALB/CH-2d X C57BL/6H-2b F1 (hereafter called B6F1) mice bearing either LSTRAH-2d or an antigenically distinct chemically induced leukemia, EL-4(G-)H-2b, with CB6F1 spleen cells sensitized in vitro to either of the parental tumors.

Animals↗