Biomedical subjects

Sagar Lonial

Publications and source records attributed to Sagar Lonial.

25 records · Page 2Linked to original sources

PubMed2003

Pharmacokinetics and pharmacodynamics of anti-thymocyte globulin in recipients of partially HLA-matched blood hematopoietic progenitor cell transplantation.

Polyclonal anti-thymocyte globulin (ATG) administered before allogeneic blood hematopoietic progenitor cell transplantation reduces the risks of graft rejection and graft-versus-host disease, but may delay posttransplant immune reconstitution caused by delayed clearance of ATG from the blood. We studied graft-versus-host disease, infections, and the kinetics of immune reconstitution in 28 patients with very poor-risk hematologic malignancies who received lymphocyte-depleted, CD34(+) cell-enriched hematopoietic progenitor cell grafts from partially HLA-matched related donors (PMRD). The incidence of these clinical events was correlated with blood ATG levels in 19 transplant recipients who received rabbit ATG (r-ATG, thymoglobulin) during conditioning. Total r-ATG and the fraction of ATG antibodies that bind human cells (active ATG) were measured for up to 45 days posttransplantation using enzyme-linked immunosorbent assay and flow cytometry assays. Three patients received equine ATG (e-ATG; total dose of 60 mg/kg/day), 3 patients received 10 mg/kg r-ATG, and 22 patients received 6 mg/kg r-ATG during conditioning. All evaluable patients engrafted. Median numbers of blood CD4(+) and CD8(+) T cells at 100 days posttransplantation were 15 and 8 cells/microL, respectively. Acute graft-versus-host disease developed in 3 of 3 recipients of e-ATG and 1 of 25 recipients of r-ATG. Rapid T-cell reconstitution was seen only in younger patients. Overall mortality was 93% (26/28 patients) with poor immune reconstitution contributing to death in 21 of 28 patients. Recipients of 6 mg/kg r-ATG had peak levels of total and active r-ATG of 64+/-20 microg/mL and 9.2+/-5.8 microg/mL, respectively, with clearance of active r-ATG (t(1/2)6 days) to sub-therapeutic levels (<1 microg/mL) by a median of 15 days posttransplantation (range, 8-38 days). Delayed immune reconstitution is likely a consequence of ex vivo and in vivo purging of donor T cells in the graft coupled with inadequate thymic function rather than persistence of active r-ATG in the blood for months posttransplantation.

Adult↗

PubMed2003

Ex vivo fludarabine exposure inhibits graft-versus-host activity of allogeneic T cells while preserving graft-versus-leukemia effects.

Allogeneic donor T cells in bone marrow transplantation (BMT) can contribute to beneficial graft-versus-leukemia (GVL) effects but can also cause detrimental graft-versus-host disease (GVHD). A successful method for the ex vivo treatment of donor T cells to limit their GVHD potential while retaining GVL activity would have broad clinical applications for patients undergoing allogeneic hematopoietic cell transplantation for malignant diseases. We hypothesized that donor lymphocyte infusions treated with fludarabine, an immunosuppressive nucleoside analog, would have reduced GVHD potential in a fully major histocompatibility complex-mismatched C57BL/6 --> B10.BR mouse BMT model. Recipients of fludarabine-treated donor lymphocyte infusions (F-DLI) had significantly reduced GVHD mortality, reduced histopathologic evidence of GVHD, and lower inflammatory serum cytokine levels than recipients of untreated DLI. Combined comparisons of GVHD incidence and donor-derived hematopoietic chimerism indicated that F-DLI had a therapeutic index superior to that of untreated DLI. Furthermore, adoptive immunotherapy of lymphoblastic lymphoma using F-DLI in the C57BL/6 --> B10.BR model demonstrated a broad therapeutic index with markedly reduced GVHD activity and preservation of GVL activity compared with untreated allogeneic T cells. Fludarabine exposure markedly reduced the CD4+CD44(low)-naive donor T-cell population within 48 hours of transplantation and altered the relative representation of cytokine-producing CD4+ T cells, consistent with T-helper type 2 polarization. However, proliferation of fludarabine-treated T cells in allogeneic recipient spleens was equivalent to that of untreated T cells. The results suggest that fludarabine reduces the GVHD potential of donor lymphocytes through effects on a CD4+CD44(low) T-cell population, with less effect on alloreactive T cells and CD4+CD44(high) memory T cells that are able to mediate GVL effects. Thus, F-DLI represents a novel method of immune modulation that may be useful to enhance immune reconstitution among allograft recipients with reduced risk of GVHD while retaining beneficial GVL effects.

Animals↗

PubMed2003

Breakthroughs in the management of multiple myeloma.

Although multiple myeloma remains a terminal illness, the past four decades have seen a dramatic change in the outlook for a newly diagnosed patient in terms of therapies available, supportive care and insight into the pathogenesis of this disease. Among the newer agents available for treatment, thalidomide has been resurrected and discovered to be a valuable therapy for myeloma. Thalidomide appears to work, at least in part, through its anti-angiogenic properties, but much remains to be learned about its mechanism of action as well as optimal administration regimens. With the development of increasingly more potent bisphosphonates it has become possible to diminish the painful skeletal complications of myeloma, one of the most devastating problems of this disease. The most recent generation of bisphosphonates, pamidronic acid and zoledronic acid, have provided a statistically significant decrease in the skeletal complications of myeloma when used in a prophylactic manner. These agents appear to work by inhibiting osteoclast function. Progressive improvement in cytogenetic techniques has now demonstrated that almost all patients with myeloma have chromosomal abnormalities, some of which appear to confer varying degrees of prognostic significance. In particular, the changes in chromosome 13 are associated with an unusually poor outcome. These findings are serving as a guide toward learning more about the pathogenesis of myeloma as well as in identifying potential targets for therapy. Stem cell transplantation has emerged as the standard treatment for the large majority of patients with myeloma following the demonstration of superior complete remission and survival, both disease-free and overall, in a French randomised trial. Unfortunately, virtually all patients will eventually relapse following autologous stem cell transplantation, prompting continuing efforts such as tandem transplants, CD34+ selection, as well as modifications in the conditioning regimen to improve outcomes. Allogeneic bone marrow transplants appear to offer a better chance for a possible cure of myeloma but have been associated with an unusually high mortality. However, this approach is being revived with the advent of the less toxic non-myeloablative transplant that has provided an 81% short-term survival in a trial combining this approach with an initial conventional autologous bone marrow transplant. Immunotherapy with dendritic cells appears now to be a feasible way to enhance innate or acquired immunity to help eliminate minimal residual disease following autologous bone marrow transplant. Unfortunately, a cure for myeloma remains elusive but the continuing advances in management may significantly prolong survival in affected patients.

Bone Marrow Transplantation↗

PubMed2002

A randomized, placebo-controlled trial of subcutaneous administration of GM-CSF as a vaccine adjuvant: effect on cellular and humoral immune responses.

Thirty healthy volunteers were randomly assigned to receive either a single subcutaneous injection of GM-CSF or placebo at the time of vaccination with tetanus and diptheria toxoid (Td), influenza and hepatitis A vaccines. Humoral response was measured by weekly serum samples assayed for antibodies to tetanus toxoid (TT), influenza and hepatitis A; while cellular response to TT was determined by measuring IL-2 expression in T-cells following in vitro exposure to TT antigen using a flow cytometric assay. It was hypothesized that (1). GM-CSF would augment immune response and (2). that the frequencies of TT responsive T-cells in the blood would predict humoral responses. The administration of subcutaneous GM-CSF as an adjuvant at the time of vaccination did not augment the antibody responses to influenza or hepatitis A in normal volunteers when compared to placebo. Subjects who received GM-CSF had statistically significant lower increases in anti-tetanus antibodies than placebo recipients. Immunization with TT resulted in an increase in the frequency of antigen responsive T-cells in the blood over time. The frequencies of TT responsive T-cells in baseline blood samples were correlated with baseline anti-tetanus antibody titers, but humoral and cellular responses were not correlated following vaccination. Recipients of GM-CSF did not develop significantly higher numbers of TT responsive T-cells after vaccination compared to recipients who received placebo.

Adjuvants, Immunologic↗

PubMed2002

Development of drug-resistant herpes simplex virus infection after haploidentical hematopoietic progenitor cell transplantation.

An unusually high incidence of acyclovir- and foscarnet-resistant herpes simplex virus (HSV) infection was noted after lymphocyte-depleted blood hematopoietic progenitor cell (HPC) transplantation from HLA-haploidentical family donors. Fourteen adults with hematologic malignancies underwent blood HPC transplantation from haploidentical family donors. Pheresis products were stringently depleted of T and B cells by immunomagnetic adsorption, and patients received no immunosuppression after transplantation. HSV reactivation occurred in all 7 evaluable HSV-1- or HSV-2-seropositive patients, at a median of 40 days after transplantation. Susceptibility testing of clinically resistant viral isolates demonstrated acyclovir resistance in all 5 cases tested. Second-line therapy produced only partial responses, and in vitro evidence of foscarnet resistance developed rapidly in all 3 patients treated with foscarnet. Healing of lesions coincided with T-cell recovery. The prolonged immunodeficiency associated with stringent lymphocyte depletion of the graft appears to strongly predispose to emergence of drug-resistant HSV. Furthermore, immune reconstitution is necessary for eradication of infection.

Acyclovir↗

PubMedDate not supplied

Facilitating T-cell immune reconstitution after haploidentical transplantation in adults.

Delayed reconstitution of cellular immunity following T-cell-depleted, CD34-enriched, allogeneic hematopoietic progenitor cell transplantation (HPCT) is the major cause of morbidity and mortality following haploidentical transplantation in adults. This is illustrated in our recent study of 28 high-risk adult patients (median age 31) who were treated with conditioning regimens containing antithymocyte globulin (ATG) before T-cell-depleted, CD34-enriched allogeneic HPCT. Overall mortality was 93% (26/28 patients) with a median survival of 4 months posttransplant. Poor cellular immune reconstitution contributed to death of 21/28 patients, with eight deaths due to opportunistic infections and seven deaths due to relapse. While recovery of normal numbers of circulating NK cells and B-cells occurred within the first 1-2 months posttransplant, recovery of normal numbers of blood T-cells was suppressed for more than 1 year. The mean half-life of active ATG levels in serum was 6 days; rapid clearance suggested that residual ATG did not contribute to the delay of posttransplant T-cell reconstitution. Rapid T-cell reconstitution was seen only in younger patients, indicating that poor thymic function and the absence of T-cells in the graft are the major causes of delayed recovery of cellular immunity. Improved cellular immunity after T-cell-depleted haploidentical HPCT will thus require novel strategies to adoptively transfer antigen specific donor T-cells without inducing lethal graft-versus-host disease (GvHD). This problem has been addressed in a preclinical murine model of MHC-mismatched bone marrow transplantation. Donor T-cells treated ex vivo with fludarabine or a UVA light-activated psoralen compound (amotosalen) have a markedly reduced ability to induce GvHD, yet the treated T-cells confer protection against murine cytomegalovirus and an infused leukemic cell line. Polyclonal donor T-cells reconstituted the blood and lymphoid compartments posttransplant and expanded in vivo. Derivatives of ex-vivo-treated donor T-cells retained the ability to produce cytokines and proliferate in response to antigen challenge. The mechanism of reduced GvHD potential of ex-vivo-treated T-cells appears to be selection of a subset of memory donor T-cells that do not initially home to secondary lymphoid organs and have reduced capacity for producing inflammation in the immediate posttransplant period. Direct selection of the memory subset by high-speed FACS confirmed the improved therapeutic index in the murine model system. Preclinical data indicate the feasibility of treating human T-cells with fludarabine, psoralen, or direct selection based upon the memory phenotype to efficiently produce a population of polyclonal donor T-cells with reduced GvHD activity. A planned clinical phase 1 trial of adoptive therapy utilizing ex vivo psoralen-treated donor T-cells in recipients of T-cell-depleted haploidentical HPCT is presented.

Adult↗

PubMedDate not supplied

Signal transduction and myeloma: new targets, new hope.

Multiple Myeloma is a hematologic malignancy characterized by the abnormal proliferation of plasma cells. Therapy for this disease has largely been palliative, and chances for long term survival after initiation of treatment have been quite limited. In the era of molecular therapies, a better understanding of the molecular biology resulting in the development of myeloma have shed light on a number of novel and potentially exciting therapeutic options for this disease which previously had limited options. This review will discuss some of the basic mechanisms of current therapy such as corticosteroids and alkylating agents, as well as developing such as the proteasome inhibitors, thalidomide and its analogs, arsenic trioxide, anti-sense technology, and others. The final section will assess the potential for new targeted approaches to treatment for mechanisms which have yet to be fully explored, and for agents which are in early phase I development

Antineoplastic Agents↗