PubMed Health⌕ Search

Biomedical subjects

M A Cheever

Publications and source records attributed to M A Cheever.

At least 73 records · Page 4Linked to original sources
PubMed1986

Antigen-driven long term-cultured T cells proliferate in vivo, distribute widely, mediate specific tumor therapy, and persist long-term as functional memory T cells.

Mice bearing disseminated syngeneic FBL-3 leukemia were treated with cyclophosphamide plus long term-cultured T cells immune to FBL-3. The cultured T cells for therapy had been induced to grow in vitro for 62 d by intermittent stimulation with irradiated FBL-3. At the time of therapy, such antigen-driven long term-cultured T cells were greatly expanded in number, proliferated in vitro in response to FBL-3, and were specifically cytotoxic. Following adoptive transfer, donor T cells persisting in the host were identified and counted using donor and host mice congenic for the T cell marker Thy-1. The results show that antigen-driven long term-cultured T cells proliferated rapidly in vivo, distributed widely in host lymphoid organs, and were effective in tumor therapy. Moreover, the already rapid in vivo growth rate of donor T cells could be augmented by administration of exogenous IL-2. When cured mice were examined 120 d after therapy, donor L3T4+ T cells and donor Lyt-2+ T cells could be found in large numbers in host ascites, spleen, and mesenteric and axillary lymph nodes. The persisting donor T cells proliferated in vitro, and became specifically cytotoxic in response to FBL-3, demonstrating that antigen-driven long term-cultured T cells can persist long term in vivo and provide immunologic memory.

Animals↗
PubMed1986

Potential uses of interleukin 2 in cancer therapy.

Interleukin 2 (IL 2) has several potential uses in cancer therapy including: the augmentation of specific T cell mediated anti-tumor immunity and the activation of non-specific cytolytic effector cells, termed lymphokine-activated killer (LAK) cells. The current review will present data from our laboratory demonstrating in animal models the feasibility of both potential approaches. Studies to be reviewed show that: IL 2 can induce the proliferation and expansion in number of tumor-reactive T cells in vitro; T cells grown in culture in IL 2 can be effective reagents in vivo for specific tumor therapy; the administration of exogenous IL 2 can induce the growth and augment the function of cultured T cells in vivo; however, as a corollary, T cells cultured long-term in vivo with IL 2 are functionally limited in vivo without the administration of exogenous IL 2 in vivo; by contrast, T cells grown in vitro with specific antigen, as opposed to IL 2, as the major stimulus for proliferation are able to proliferate rapidly in vivo, distribute widely in host lymphoid organs, and mediate therapy of disseminated murine leukemia; importantly, such antigen-driven long-term cultured T cells can survive long-term in vivo and provide specific immunologic memory, and, the administration of low-dose IL 2 in vivo can induce the growth of antigen-driven long-term cultured T cells in vivo and thereby increase the number of functional memory T cells; the culture of lymphoid cells in high concentrations of IL 2 can induce LAK cells in vitro capable of lysing leukemia in vitro; LAK cells generated in vitro can mediate a small but detectable anti-tumor effect in vivo against disseminated leukemia as an adjunct to chemotherapy; and, high-dose IL 2 administered in vivo can activate LAK cells in vivo and cure disseminated murine leukemia. Therefore, it is highly likely that IL 2 can become an effective reagent for the therapy of human cancer.

Animals↗
PubMed1986

Marrow transplantation for the treatment of chronic myelogenous leukemia.

One hundred ninety-eight patients with chronic myelogenous leukemia received marrow transplants after intensive chemotherapy and total body irradiation. Multivariate analysis showed disease status at time of transplantation to be the most powerful predictor of survival. The probability of long-term survival for allogeneic graft recipients was 49% for 67 patients in the first chronic phase, 58% for 12 in the second chronic phase, 15% for 46 in the accelerated phase, and 14% for 42 in the blastic phase. The major cause of death was interstitial pneumonia for patients in the chronic phase, and relapse for those in the blastic or accelerated phases. Factors favoring survival were early transplantation, age less than 30 years, and absence of severe graft-versus-host disease. Splenectomy or spleen size did not influence survival. For recipients of syngeneic grafts survival probability was 87% for 16 patients in the chronic phase, 27% for 7 in the accelerated phase, and 12% for 8 in the blastic phase. Of the 198 patients, 71 are alive without Philadelphia chromosomes 1 to 9 years after receiving their graft. All but 4 long-term disease-free survivors have Karnofsky performance scores of 80% or better.

Adult↗
PubMed1986

Bone marrow transplantation in patients aged 45 years and older.

Increasing age has been reported to be a poor prognostic factor for survival after bone marrow transplantation. We evaluated causes of death and frequency and type of complications after marrow grafting in 24 syngeneic and 39 allogeneic recipients who were 45 to 68 years old at the time of transplant. Most patients were in an advanced stage of hematologic malignancy. Among patients given syngeneic transplants, actuarial disease-free survival at 7 years is 20%. The major causes of death were relapse of leukemia and idiopathic interstitial pneumonia. Among allogeneic recipients, 9 (23%) are currently alive, and actuarial disease-free survival at 7 years is 11%. Cytomegalovirus pneumonia and septicemia were the most frequent causes of death. Patients over 50 years of age had the poorest survival rate (1/13), but many of these were transplanted in an advanced stage of their disease. However, among 12 patients transplanted while in remission or at an early stage of their disease, 5 are surviving 65 to 1,160 days after transplantation, with an actuarial survival rate of 22% at 3 years. This is in contrast to those who received their transplant in relapse: 2 out of 20 patients (10%) became long-term survivors, with a probability of survival of 15% at 3 years. The actuarial incidence of grade II through IV acute graft-v-host disease (GVHD) was 30% for allogeneic recipients 45 to 50 years of age. This was not significantly different from the incidence in younger patients. In patients 51 to 62 years of age, the actuarial incidence of acute GVHD was 79%; however, this group included three partially HLA-mismatched transplants. Ten of 15 patients surviving at least 3 months developed chronic GVHD. These results suggest that marrow transplantation is feasible and should be considered in patients over 45 years, especially if recipients are in good clinical condition and are at an early stage of their disease, such as the chronic phase of chronic myelogenous leukemia and preleukemia. For patients more than 50 years of age, allogeneic marrow grafting cannot presently be considered first-line therapy.

Adult↗
PubMed1986

Identical-twin (syngeneic) marrow transplantation for hematologic cancers.

The Seattle Marrow Transplant Team treated about 130 patients (age 4-68 yr) for hematologic cancer with supralethal chemoradiotherapy and bone marrow transplantation (BMT) from the normal genetically identical twin. The procedure was well tolerated. The principal problem was tumor resistance. Nevertheless, BMT for acute leukemia in relapse still cured about 20% of the patients. Moreover, BMT performed while in complete remission cured about 50% of patients with acute lymphocytic leukemia or acute nonlymphocytic leukemia. Sixteen patients received transplantation in the chronic phase of Ph1+ chronic granulocytic leukemia (CGL). All showed disappearance of all Ph1+ cells. Two died of pneumonitis. Of the 14 who are alive, 3 continue to have CGL 37-76 months after BMT and 11 remain in complete hematologic and cytogenetic remission without any Ph1+ metaphases at 31-108 months (median = 68) after BMT. Thus the Ph1-positive clone can be ablated and blast crisis prevented. BMT in the accelerated or blastic phase was far less effective. Syngeneic BMT also benefited or cured patients with lymphoma, hairy-cell leukemia, and multiple myeloma. Therefore, BMT should be considered for every patient who has a hematologic cancer and an identical twin.

Acute Disease↗
PubMed1985

Therapy of disseminated murine leukemia with cyclophosphamide and immune Lyt-1+,2- T cells. Tumor eradication does not require participation of cytotoxic T cells.

The ability of noncytolytic Lyt-1+,2- T cells immune to FBL-3 leukemia to effect eradication of disseminated FBL-3 was studied. Adult thymectomized, irradiated, and T-depleted bone marrow-reconstituted (ATXBM) B6 hosts were cured of disseminated FBL-3 by treatment with 180 mg/kg cyclophosphamide (CY) and adoptively transferred Lyt-1+,2- T cells obtained from congenic B6/Thy-1.1 donors immune to FBL-3. Analysis of the T cell compartment of ATXBM hosts treated and rendered tumor-free by this therapy revealed that the only T cells present in the mice were donor-derived Lyt-1+,2- T cells. In vitro stimulation of these T cells with FBL-3 tumor cells, which express class I but no class II major histocompatibility complex antigens, induced lymphokine secretion, but did not result in the generation of cytotoxic T lymphocytes (CTL). Thus, in a setting in which mice lack Lyt-2+ T cells, and in which no CTL of either host or donor origin could be detected, immune Lyt-1+,2- T cells, in conjunction with CY, mediated eradication of a disseminated leukemia. The results suggest that delayed-type hypersensitivity responses induced by immune T cells represent a potentially useful effector mechanism for in vivo elimination of disseminated tumor cells.

Animals↗
PubMed1985

Adoptive immunotherapy of metastatic B16 melanoma with allogeneic immune cells sensitized to minor histocompatibility antigens.

Host mice bearing pulmonary metastases of B16 melanoma were treated by adoptive immunotherapy with allogeneic donor lymphocytes. Rejection of the allogeneic donor cells by the host was delayed by pretreatment immunosuppression of the host with cyclophosphamide and selection of donors that were matched at the major histocompatibility complex (MHC) but disparate for background minor histocompatibility genes. Adoptively transferred normal nonimmune donor cells exhibited no therapeutic activity. However, allogeneic MHC-matched donor cells that were primed in vivo and secondarily sensitized in vitro to host minor histocompatibility antigens expressed on normal lymphocytes were cytotoxic to B16 tumor cells in vitro and mediated a dose-dependent antitumor effect in vivo following i.v. infusion. The therapeutic activity of sensitized allogeneic cells, which presumably reflected recognition of minor histocompatibility antigens expressed both on normal host tissues and on malignant B16 tumor cells, was not associated with any detectable toxicity to these transiently immunosuppressed tumor-bearing hosts.

Animals↗
PubMed1985

Marrow transplantation for chronic myelocytic leukemia: a controlled trial of cyclosporine versus methotrexate for prophylaxis of graft-versus-host disease.

Forty-eight patients with chronic myelocytic leukemia, aged 11 to 47, were treated with high-dose cyclophosphamide and fractionated total body irradiation, followed by infusion of marrow from HLA-identical siblings. They were randomized to receive either methotrexate (MTX) (n = 23) or cyclosporine (CSP) (n = 25) as postgrafting prophylaxis for graft-v-host disease (GVHD). All patients had evidence of sustained hematopoietic engraftment. Seventeen of the 25 patients receiving CSP and 17 of the 23 patients receiving MTX are alive between one and almost four (median, 1.7) years, with an actuarial survival rate at three years of 62% and 66%, respectively (P = .60). Also, with respect to most other parameters studied, the two drugs were identical. The probability of acute GVHD was .42 and .46, respectively (P = .70), that of chronic GVHD, .50 and .63 (P = .44), and that of death from transplant-related causes, .30 and .24 (P = .51). There were no differences in the speed of granulocyte and platelet engraftment (P = .82 and .94, respectively), and the duration of hospitalization was comparable (P = .58). Patients receiving MTX required red cell transfusions for a shorter period of time (P = .02), but had a slightly increased morbidity from early oral mucositis. The leukemia recurrence rates were comparable (P = .60). With the regimens used in this study, we conclude that CSP failed to reduce the incidence of GVHD and improve the survival of patients with chronic myelocytic leukemia when compared to results with standard MTX.

Adolescent↗
PubMed1985

Interleukin 2 (IL 2) administered in vivo: influence of IL 2 route and timing on T cell growth.

The influence of the route and the frequency of IL 2 administration on the ability of IL 2 to induce the growth of activated T cells in vivo was evaluated. Initial pharmacokinetic studies confirmed that i.v. injection of IL 2 results in a relatively high peak serum concentration, but a short serum half-life. By contrast, i.p. or subcutaneous (s.c.) injection of IL 2 results in a lower peak concentration but a prolonged serum half-life. The bioavailability of IL 2 administered by these routes was assessed by measuring the in vivo growth of adoptively transferred T cells that had been previously cultured long-term with IL 2, because the growth of such cells in vivo has been shown to be proportional to the dose of IL 2 administered. The results demonstrated that i.p., s.c., or i.v. administration of IL 2 each resulted in marked donor T cell growth in vivo. Thus, IL 2 can function in vivo at sites distant to the sites of injection. In addition, the magnitude of T cell growth in vivo varied dependent on the route of IL 2 administration and correlated with the length of time IL 2 was detectable in serum, rather than the peak level achieved (i.e., IL 2 inoculated i.v. had the highest peak concentration but was least effective). As suggested by these findings, dividing the total dose of IL 2 into frequent low-dose injections was more effective in inducing T cell growth in vivo than was dividing the total dose of IL 2 into less frequent higher-dose injections. These studies confirm the great potential for IL 2 to induce the growth of activated of T cells in vivo and demonstrate that the rate of T cell growth reflects not only the dose but also the route and timing of IL 2 administration.

Animals↗
PubMed1985

Recurrence of aplastic anemia following cyclophosphamide and syngeneic bone marrow transplantation: evidence for two mechanisms of graft failure.

Two patients with aplastic anemia were treated with high-dose cyclophosphamide and marrow transplantation from their normal, genetically identical twin. Both patients rapidly recovered normal marrow function, but marrow failure recurred 13 and 18 months later. Because donor and host pairs were identical twins, these cases of graft failure could not have resulted from the usual cause of graft failure, ie, immunological reactivity of host cells against unshared minor histocompatibility antigens of the donor. These results imply that there are at least two mechanisms responsible for graft failure after marrow transplantation for severe aplastic anemia.

Adult↗
PubMed1984

Bone marrow transplantation or chemotherapy after remission induction for adults with acute nonlymphoblastic leukemia. A prospective comparison.

We compared the outcome of marrow transplantation with that of continued chemotherapy for adults with acute nonlymphoblastic leukemia who achieve a first remission. From May 1977 to July 1982, 111 consecutive adults (ages 17 to 50) with newly diagnosed acute nonlymphoblastic leukemia were treated with induction chemotherapy. Ninety patients (81%) had a complete remission. Forty-four remission patients had available donors: 33 received a transplant and 11 did not. Forty-six patients in remission without matched donors were treated with continued chemotherapy. Kaplan-Meier estimates of 5-year, disease-free survival from complete remission are 49% +/- 18% for the transplant group and 20% +/- 13% for the chemotherapy group. When compared to the chemotherapy group, patients undergoing transplantation had a higher risk of dying during the first 6 months after remission induction but a lower risk of dying thereafter. Within the transplant group, only age influenced survival. Within the chemotherapy group, a leukocyte count of greater than 10 000 mm3 at diagnosis, a French-American-British (FAB) Cooperative Group morphologic status of M-4, M-5, or M-6, and the presence of infection at diagnosis were all associated with shorter survival.

Acute Disease↗
PubMed1984

Treatment of disseminated leukemia with cyclophosphamide and immune cells: tumor immunity reflects long-term persistence of tumor-specific donor T cells.

B6 mice bearing disseminated syngeneic FBL leukemia can be cured by treatment on day 5 with 180 mg/kg cyclophosphamide and 2 x 10(7) adoptively transferred syngeneic immune spleen cells. Complete tumor eradication in this model requires more than 30 days and is dependent upon the transfer of specifically immune T cells. To evaluate the relative contributions of host and donor T cells to tumor elimination and the maintenance of tumor immunity, donor cells obtained from Thy congenic mice were used for adoptive transfer. Thus, host and donor T cells could be readily distinguished by the expression of either Thy-1.2 or Thy-1.1 antigen. The results demonstrated that the majority of immunologically competent T cells present in hosts cured by adoptive therapy were of host origin. A small population of donor T cells, however, persisted long after transfer. At day 60, a time point shortly after tumor eradication had been completed, 5% of splenic T cells were of donor origin, and by day 120 this percentage had decreased to less than 2%. Functional studies performed at both time points revealed that this small number of residual donor T cells contained the subpopulation of tumor-reactive T cells present in the host. Thus, host T cells did not make a substantial contribution to the expression of the anti-tumor response and presumably have little role in either tumor eradication or the long-term maintenance of tumor immunity.

Animals↗
PubMed1984

Potential for specific cancer therapy with immune T lymphocytes.

In animal models, advanced disseminated tumors can be specifically eradicated by infusions of T lymphocytes immune to tumor. The most successful regimens require a relatively small tumor burden and immunosuppression of the host to augment the transfer of immunity. Since chemotherapeutic agents administered to tumor-bearing hosts can achieve both requirements, models that combine chemotherapy and immune cells have been developed and have been shown to be effective for the therapy of advanced syngeneic malignancies. Surprisingly, tumor eradication in these and similar models does not require the transfer of cytotoxic T lymphocytes. Rather, noncytotoxic T cells of the helper/inducer subset alone are sufficient, presumably mediating tumor elimination by a delayed-type hypersensitivity mechanism involving induction of host inflammatory cells. Since donor T cells must persist in the host to provide maximum benefit in therapy, the outcome of therapy is subject to both positive and negative influences within the host for a prolonged period of time. Interleukin-2 (IL-2), a T cell replication-inducing lymphokine, promotes the in vitro growth of antigen-activated T lymphocytes. T lymphocytes immune to tumor can be grown long-term in vitro in response to IL-2 and are able to mediate a specific, cell dose-dependent effect in therapy when inoculated into tumor-bearing hosts. In vitro such long-term cultured T lymphocytes are exquisitely dependent upon exogenous IL-2 for the induction of proliferation and survival. In vivo the administration of IL-2 induces the growth of similar long-term cultured T lymphocytes and, as a consequence, increases their therapeutic efficacy. Therefore, IL-2 can be utilized both in vitro and in vivo to augment specific T cell responses for the therapy of established tumors.

Animals↗
PubMed1984

Effector mechanisms operative in adoptive therapy of tumor-bearing animals: implications for the use of interleukin-2.

Disseminated tumors growing progressively in syngeneic hosts can be eradicated by combination therapy with cyclophosphamide and adoptive transfer of specifically immune T cells. Interleukin-2 (IL-2), which induces proliferation of T cells specifically activated by antigen, has substantial therapeutic potential as a reagent for increasing the magnitude of tumor-specific T cell responses. The purpose of the present studies was to determine the effector mechanisms operative in tumor-bearing hosts by which subpopulations of immune T cells can mediate tumor eradication, and to determine if the in vivo administration of exogenous IL-2 can augment these T cell effector functions. Disseminated leukemia was eradicated by adoptive therapy with the immune Lyt 1+2- noncytolytic T cell subpopulation, under experimental conditions in which cytolytic T lymphocytes could not participate. The Lyt 1+2- subset contains helper/amplifier cells that produce endogenous IL-2 in response to tumor and effector cells that mediate delayed-type hypersensitivity reactions. The administration of exogenous IL-2 following transfer of immune T cells containing this noncytolytic subset failed to augment their therapeutic activity, implying that the amount of IL-2 being produced endogenously did not limit the antitumor response. Adoptive therapy with purified cytolytic Lyt 1-2+ T cells produced a demonstrable but limited antitumor effect. Since this cytolytic subpopulation lacked helper T cells, the limited activity observed presumably reflected a requirement for an IL-2-producing cell. Administration of exogenous IL-2 following cell transfer satisfied this requirement and markedly augmented the efficacy of adoptive therapy with Lyt 1-2+ T cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Interleukin-2 administered in vivo induces the growth and augments the function of cultured T cells in vivo.

The purpose of the studies being described was to determine if interleukin-2 (IL-2) administered in vivo can induce the growth and increase the number of antigen-activated T cells, and thereby augment specific T cell function in vivo. Initial experiments examined the in vivo growth of adoptively transferred T cells previously cultured long term with IL-2, since in vitro such long-term cultured T cells are exquisitely dependent on exogenous IL-2 for proliferation and survival. To identify and quantify donor T cells in vivo, experiments were performed with donor and host mice congenic for the T cell marker Thy 1. Host mice receiving congenic long-term cultured immune T cells were inoculated daily with purified IL-2 beginning on the day of cell transfer, and donor T cells within host ascites, spleen, and lymph nodes were enumerated at selected points in time. The experiments demonstrated that exogenous IL-2 induced in vivo growth of long-term cultured T cells proportional to the dose of IL-2 administered. Similar IL-2 regimens induced the in vivo growth and augmented the function of donor T cells that had been activated to express IL-2 receptors in vitro by 5-day culture with antigen but had not been cultured with exogenous IL-2. Thus, prior adaptation to growth with exogenous IL-2 in vitro is not necessary to render T cells responsive to IL-2 in vivo. In contrast to long-term cultured T cells in vivo (which died rapidly in vivo without exogenous IL-2), noncultured donor T cells proliferated in vivo in response to antigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗