charles hesdorffer - Academia.edu (original) (raw)

Papers by charles hesdorffer

Bone Marrow Transplantation, 2010

The New England Journal of Medicine, Oct 22, 2015

Blood, Dec 15, 1997

MHC class II molecules. In addition to a peptide derived of Medicine and the Division of Immunoge... more MHC class II molecules. In addition to a peptide derived of Medicine and the Division of Immunogenetics, Department of from the carboxy-terminal of the bcr protein, we have identi-Pathology, College of Physicians and Surgeons of Columbia Univerfied several differentiation stage-and tissue-specific selfsity, New York, NY.

Blood, Nov 16, 2005

Autologous stem cell transplant has been used with variable success rates in the treatment of dif... more Autologous stem cell transplant has been used with variable success rates in the treatment of different malignancies. One of the potential causes of relapse is contamination of the stem cell collection by neoplastic cells. Purging the stem cells by CD34+ selection has been used to reduce such contamination. In this study two different devices were compared in their efficiency to achieve CD34+ selection of peripheral blood stem cells collected in individuals undergoing autologous transplant for breast cancer, neuroblastoma, plasma cell dyscrasia, lymphoma (both Hodgkin and non Hodgkin), rhabdomyosarcoma and amyloidosis. A total of 28 patients were randomized to CD34 selection on the Nexell Isolex 300i® system (NIS) or the Miltenyi Biotec CliniMACS® (MCMS) system. The prevalence of plasma cell dyscrasia was higher in the MCMS group (57%) than in the NIS group (22%). On the other hand, there were 2 cases of Hodgkin lymphoma and 2 cases of breast cancer in the NIS group, in comparison to none in the MCMS group. Average values for parameters of selection efficacy for the 19 patients transplanted are shown in table 1 (recovery = number of cells post / number of cells pre-selection X 100, viability measured with the trypan blue exclusion test). Transplant was done as per local protocols according to the type of malignancy. CD34+ cell dose was determined by institutional guidelines. Average values for engraftment are shown in table 2 (two patients who died before engraftment in the MCMS group were excluded from calculation of the mean values). One patient died of graft failure in the MCMS group in contrast to none in the NIS group. Although the numbers of patients are relatively low, this is the first randomized study in which the selection efficiency of the NIS and MCMS devices have been compared in patients receiving CD34-selected autografts. CFU-GM recovery and cell viability were lower, while neutrophil engraftment was slower in the MCMS group, but these differences were not statistically significant. Our data do not show any clinically significant advantage for either the NIS or MCMS selection device. Table 1 Device CD34+ recovery (%,range) CFU-GEMM recovery (%,range) CFU-GM recovery (%,range) Viability pre (%,range) Viability post (%,range) P-value calculated with Student’s t-Test. NIS 52 (16–76) 5 (1–14) 9 (0–42) 95 (91–99) 95 (90–99) MCMS 66 (48–75) 4 (1–5) 5 (0–9) 94 (80–99) 88 (60–100) P 0.17 0.71 0.57 0.69 0.16 Table 2 Device CD34+ infused (X 106/kg, range) Time to ANC ≥500 (days, range) Time to plt ≥20 (days, range) # Units plt P-value calculated with Student’s t-Test. NIS 3.6 (2.0–5.2) 12.2 (9–20) 15.9 (11–38) 19.4 (0–30) MCMS 3.6 (1.5–5.1) 15.1 (11- ∞) 16.8 (9-∞) 40.2 (6–150) P - 0.22 0.79 0.23

Bone Marrow Transplantation, Jul 25, 2005

In an effort to improve the outcome of poor-risk lymphoma patients, we evaluated a novel regimen ... more In an effort to improve the outcome of poor-risk lymphoma patients, we evaluated a novel regimen of tandem high-dose chemotherapy (THDC) with autologous stem cell transplantation. A total of 41 patients (median age 40 years, range 15-68 years) with poor-risk non-Hodgkin's lymphoma and Hodgkin's disease were enrolled. THDC consisted of melphalan (180 mg/m 2) and escalating dose mitoxantrone (30-50 mg/m 2) (MMt) for the first conditioning regimen, and thiotepa (500 mg/m 2), carboplatin (800 mg/m 2), and escalating dose etoposide phosphate (400-850 mg/m 2), (ETCb) as the second regimen. In all, 31 patients (76%) completed both transplants, with a median time between transplants of 55 days (range 26-120). The maximum tolerated dose was determined as 40 mg/m 2 for mitoxantrone and 550 mg/m 2 for etoposide phosphate. The overall toxic death rate was 12%. Following high-dose chemotherapy, 10 of 24 evaluable patients (42%) were in CR. The two-year overall survival and event-free survival is 67% (95% CI, 52-81%) and 45%, (95% CI, 29-61%) for the 41 patients enrolled; and 69% (95% CI, 525-586%) and 48% (95% CI, 30-67%) for the 31 patients completing both transplants. This THDC regimen is feasible but with notable toxicity in heavily pretreated patients; its role in the current treatment of high-risk lymphoma remains to be determined.

Journal of Clinical Investigation, Apr 15, 2004

Ectopic gene expression in tumors versus normal somatic tissues provides opportunities for the sp... more Ectopic gene expression in tumors versus normal somatic tissues provides opportunities for the specific immunotargeting of cancer cells. SSX gene products are expressed in tumors of different histological types and can be recognized by tumor-reactive CTLs from cancer patients. Here, we report the identification of an SSX-2derived immunodominant T cell epitope recognized by CD4 + T cells from melanoma patients in association with HLA-DR. The epitope maps to the 37-58 region of the protein, encompassing the sequence of the previously defined HLA-A2-restricted immunodominant epitope SSX-2 41-49. SSX-2 37-58-specific CD4 + T cells were detected among circulating lymphocytes from the majority of melanoma patients analyzed and among tumorinfiltrating lymphocytes, but not in healthy donors. Together, our data suggest a dominant role of the 37-58 sequence in the induction of cellular CD4 + T cell responses against SSX antigens and will be instrumental for both the onset and the monitoring of upcoming cancer-vaccine trials using SSX-derived immunogens. Nonstandard abbreviations used: American Society for Histocompatibility and Immunogenetics (ASHI); cancer/testis antigen (CTA); National Marrow Donor Program (NMDP); recombinant human (rh); tumor-infiltrated lymph nodes (TILN).

Cytotechnology, 1995

The human multiple drug resistance (MDR) gene has been used as a model for human gene transfer wh... more The human multiple drug resistance (MDR) gene has been used as a model for human gene transfer which could lead to human gene therapy. MDR is a transmembrane protein which pumps a number of toxic substances out of cells including several drugs used in cancer chemotherapy. Normal bone marrow cells express low levels of MDR and are particularly sensitive to the toxic effects of these drugs. There are two general applications of MDR gene therapy: (1) to provide drug-resistance to the marrow of cancer patients receiving chemotherapy, and (2) as a selectable marker which when co-transferred with a non-selectable gene such as the human beta globin gene can be used to enrich the marrow for cells containing both genes. We demonstrate efficient transfer and expression of the human MDR gene in a retroviral vector into live mice and human marrow cells including CD34(+) cells isolated from marrow and containing the bulk of human hematopoietic progenitors. MDR gene transduction corrects the sensitivity of CD34(+) cells to taxol, an MDR drug substrate, and enriches the marrow for MDR-transduced cells. The MDR gene-containing retroviral supernatant used has been shown to be safe and free of replication-competent retrovirus. Because of the safety of the MDR retroviral supernatant, and efficient gene transfer into mouse and human marrow cells, a phase 1 clinical protocol for MDR gene transfer into cancer patients has been approved to evaluate MDR gene transfer and expression in human marrow.

Blood, Sep 1, 1994

The human multiple-drug resistance (MDRI) gene has been transferred into human hematopoietic prog... more The human multiple-drug resistance (MDRI) gene has been transferred into human hematopoietic progenitors using retroviral gene transfer. Human bone marrow cells and isolated CD34+ cells isolated from marrow were exposed to growth factors interleukin-3 (IL-3), IL-6, and stem cell factor for 48 hours and then to two changes of MDR retroviral supernatants over the next 24 hours. Progenitor assays in methylcellulose at this time showed that 18% to 70% of BFU-E and 30% to 6096 of CFU-GM contain the transferred MDR gene by polymerase chain reaction analysis. Up to 11.2% of the progeny of these cells express increased amounts of MDR glycoprotein on their surface by fluorescence-activated cell sorter (FACS) analysis. In addition, transduced cells are HE HUMAN MDRI (MDR) gene expression encodes a transmembrane protein (p-glycoprotein) that functions as an efflux pump for many natural substances.' The expression of MDR in different normal and tumor tissues varies greatly, but is consistently low in bone marrow (BM) cells. Because of this, hematopoietic cells are particularly sensitive to certain naturally occurring anticancer drugs. These drugs (MDR-type drugs) include the anthracyclines, vinca alkaloids, etoposide, and taxol (Bristol-Myers Squibb. Princeton, NJ), all of which are effective against a variety of human cancers. Transgenic mice expressing an MDR cDNA transgene at high levels in BM cells are resistant to the marrow-toxic effects of the anthracycline, doxorubicin.'.3 Similarly, mouse BM cells transduced with retroviruses containing MDR cDNA can be shown to express increased amounts of MDR RNA4 and protein.' In addition, the marrow cells containing the gene are enriched by exposure to taxol?' indicating that the increased MDR expression is accompanied by functional drug resistance in vivo in murine marrow.

Hematology-oncology Clinics of North America, Jun 1, 1991

Many problems obviously continue to exist in gene transfer using retroviruses as a means of inser... more Many problems obviously continue to exist in gene transfer using retroviruses as a means of inserting foreign DNA into hematopoietic stem cells, especially with regulated genes such as the human beta globin genes. First, it is unclear whether the available retroviral vectors will infect enough stem cells for gene transfer to be successful over the long term. Second, there may be sequences necessary for normal beta globin gene expression that may also inhibit the normal retroviral life cycle, thus decreasing the efficiency of gene transfer or gene expression. It seems clear that in order to optimize the success of gene transfer, the highest possible titer of viral production is necessary. New approaches are aimed at increasing viral titer. The transfect/infect method appears useful. Growth factors may also be useful by increasing stem cell proliferation. Single growth factors may not be sufficient to optimize stem cell cycling. To date, interleukin-3 seems to be the single most useful growth factor, although interleukin-3 with interleukin-6 or other combinations of growth factors including interleukin-1 and granulocyte-macrophage colony-stimulating factor (GM-CSF) appear to have potential. Future work also is required to optimize the number of marrow stem cells needed for successful transplantation. Long-term bone marrow culture and stromal cell cultures may provide new and improved marrow culture conditions for achieving this goal. Improvements in the efficiency of both gene transfer and gene expression are necessary before we can consider the concept of gene transfer for the treatment of various hematologic genetic diseases in humans.

Journal of Clinical Oncology, 1998

PURPOSE Normal bone marrow cells have little or no expression of the MDR p-glycoprotein product a... more PURPOSE Normal bone marrow cells have little or no expression of the MDR p-glycoprotein product and, therefore, are particularly susceptible to killing by MDR-sensitive drugs, such as vinca alkaloids, anthracyclines, podophyllins, and paclitaxel and its congeners. Here we report the results of a phase I clinical trial that tested the safety and efficacy of transfer of the human multiple drug resistance (MDR1, MDR) gene into hematopoietic stem cells and progenitors in bone marrow as a means of providing resistance of these cells to the toxic effects of cancer chemotherapy. PATIENTS AND METHODS Up to one third of the harvested cells of patients who were undergoing autologous bone marrow transplantation as part of a high-dose chemotherapy treatment for advanced cancer were transduced with an MDR cDNA-containing retrovirus; these transduced cells were reinfused together with unmanipulated cells after chemotherapy. RESULTS High-level MDR transduction of erythroid burst-forming unit (BFU-...

Journal of Clinical Oncology, 2005

7551 Background: Vaccination of melanoma (M) patients (pts) with a combination of cancer-testis a... more 7551 Background: Vaccination of melanoma (M) patients (pts) with a combination of cancer-testis and M associated peptides may circumvent tumor escape due to antigen loss. GM-CSF may promote T-cell ...

South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, Jan 3, 1987

A case of carcinoma of the prostate metastasising to the breast and mimicking breast cancer in a ... more A case of carcinoma of the prostate metastasising to the breast and mimicking breast cancer in a male is presented. The possibility of this diagnosis should always be considered. The usefulness of cytochemical staining for prostate-specific acid phosphatase is illustrated.

Journal of Hematotherapy, 1997

The use of CFU-GM and CD34+ cell enumeration for assessing harvest quality and factors affecting ... more The use of CFU-GM and CD34+ cell enumeration for assessing harvest quality and factors affecting peripheral blood progenitor cell (PBPC) harvest and engraftment were investigated in 45 women with high-risk and metastatic breast cancer scheduled for dose-intensive cyclophosphamide, thiotepa, and carboplatin (CTCb). PBPC were mobilized with standard breast cancer regimens or cyclophosphamide (1.5 g/m2) and 5 micrograms/kg/day G-CSF and used together with G-CSF for hematopoietic support post-CTCb. There was a significant correlation between peripheral blood CD34+ cells/microliter and harvest CD34+/kg (r = 0.73, p < 0.0001) and between harvest CFU-GM and CD34+ cells/kg (r = 0.5, p < 0.0001). CFU-GM clonogenic assays were of no clinical use beyond that of CD34+ cell enumeration, with the latter allowing for real-time decisions regarding harvesting. Multiple stepwise regression identified the number of prior chemotherapy cycles as the only significant clinical predictor of CD34+ cell yield. For 34 patients proceeding to CTCb with PBPC support, multiple stepwise regression identified as the best predictors for engraftment CFU-GM and CD34+ cells/kg for neutrophils and CFU-GM, CD34+ cells/kg, and the number of prior cycles of chemotherapy for platelets, respectively. A threshold dose of 1 x 10(6) CD34+ cells/kg, obtained in 87% of these heavily pretreated breast cancer patients, was adequate to ensure engraftment within 15 days. There was no significant difference in length of hospital stay or blood product use between patients receiving 1-2.5 x 10(6) CD34+ cells/kg and greater than 2.5 x 10(6) CD34+ cells/kg, although median time to engraftment of neutrophils (9 days versus 8 days, p = 0.007) and platelets (12 days versus 9 days, p = 0.006) was significantly longer. The established threshold of > or = 1 x 10(6) CD34+ cells/kg will allow for more confident consideration of using aliquots of this threshold dose for hematopoietic support in sequential high-dose regimens inclusive of CTCb.

Clinical Nuclear Medicine, 1987

Clinical cancer research : an official journal of the American Association for Cancer Research, 1996

The multiple drug resistance (MDR) gene P-glycoprotein product is a transmembrane efflux pump tha... more The multiple drug resistance (MDR) gene P-glycoprotein product is a transmembrane efflux pump that prevents toxicity of a variety of chemotherapeutic agents, including the anthracyclines, Vinca alkaloids, podophyllins, and taxol. The bone marrow toxicity of these drugs is due to the low or absent expression of MDR in marrow cells. Transfer and expression of the human MDR gene into bone marrow progenitors should prevent this toxicity. We report here the efficient transfer and expression of the MDR gene by retroviral-mediated gene transfer into CD34(+) cells isolated from peripheral blood progenitor cells (PBPCs), comparable to that obtained using bone marrow-derived progenitors. Optimal MDR transduction of these PBPC-derived cells requires exposure to growth factors and a period of preincubation. In addition, we demonstrate that we can transduce up to 100% of progenitor cells derived from PBPCs and can protect up to 25% of these progenitors from a dose of taxol toxic to untransduced ...

American Journal of Clinical Oncology, 1989

Leukemia & Lymphoma, 2003

As both fludarabine and rituximab are active against indolent lymphoproliferative disorders, we h... more As both fludarabine and rituximab are active against indolent lymphoproliferative disorders, we have studied the combination of fludarabine and rituximab in patients with low-grade lymphoma and chronic lymphocytic leukemia (CLL) in phase I/II fashion. Of 33 patients enrolled, 21(63.6%) had low-grade lymphoma and 12 (36.4%) had CLL. They received fludarabine 30 mg/m2 on days 1-4 and rituximab 125, 250 or 375 mg/m2 on day 5 at intervals of 28 days to a maximum of 8 cycles. Three patients were removed from the study because of rituximab-associated anaphylaxis and four because of prolonged hematopoietic toxicity. Toxicity and responsiveness did not differ at the different dose levels of rituximab. For 29 evaluable patients, responses were seen in 82.8% and complete responses in 34.5%. Of 7 responding patients not referred for stem cell transplantation, 6 remain in complete remission at a median follow-up of 16 months (range 4-30 months). Of 13 previously untreated patients, all responded and 46.2% had a complete response. Of 16 previously treated patients, 68.5% responded and 25% had a complete response. The combination of fludarabine and rituximab has major activity and acceptable toxicity in patients with low-grade lymphoma and CLL.