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James J Mulé

Publications and source records attributed to James J Mulé.

13 recordsLinked to original sources
PubMed2006

Allogeneic and autologous melanoma vaccines: where have we been and where are we going?

The past three decades have seen substantial research on vaccines for the treatment of metastatic melanoma and the prevention of recurrence following resection. Despite their enormous promise, the actual results have been disappointing, with several high-profile vaccine clinical trials failing to show a benefit. Nonetheless, enthusiasm for melanoma vaccines remains and has increased with our expanding understanding of the immune response to tumor. Cellular vaccines can be divided into autologous, derived from the patient's own tumor and allogeneic vaccines. Autologous vaccines have the advantage of containing all potentially relevant tumor-associated antigens for that particular patient. However, autologous vaccines are difficult to obtain from most patients with advanced disease and impossible to obtain from patients who present after resection of all clinically evident disease. No consensus exists for how tumors should be processed, preserved, modified, and delivered to serve as an effective vaccine. The amount of autologous tumor available is rarely enough to produce more than two or three vaccination doses, and the time between initial tumor harvest and ultimate availability of the vaccine may result in interval tumor progression that diminishes the likelihood of vaccine efficacy. All these drawbacks of autologous tumor vaccination limit its applicability and also limit the ability to test autologous vaccines in prospective trials. Allogeneic vaccines avoid many of these problems, but may not contain all of the tumor-associated antigens present on the patient's own tumor. In particular, neoantigens created by mutations in the patient's tumor would be unlikely to be represented in an allogeneic vaccine. Although allogeneic vaccines can be manufactured in sufficient quantities to allow large-scale trials, there remain significant limiting issues in the manufacture and standardization of the vaccine product.

Animals↗
PubMed2006

Early vaccination with tumor-lysate-pulsed dendritic cells after allogeneic bone marrow transplantation has antitumor effects.

Allogeneic bone marrow transplantation (BMT) remains the primary treatment for many hematologic malignancies but has had limited success against solid tumors. The antitumor activity of this treatment approach involves the tumoricidal activity of chemoradiation and the additive graft-versus-tumor activity of donor T cells. However, even with current protocols, some tumors develop resistance and become unresponsive to current therapeutic regimens. To address the problem of resistance and lack of solid tumor activity in allogeneic BMT, we undertook experiments to determine whether the graft-versus-tumor activity of donor T cells could be enhanced in the period immediately after allogeneic BMT with tumor lysate-pulsed dendritic cell (DC) vaccines. Using the B16 melanoma model, we found that the treatment of 6-day tumors with allogeneic BMT and 3 weekly vaccinations of tumor lysate-pulsed DCs starting 3 days after BMT had a significant effect on the growth of murine flank melanomas. This effect was tumor specific and occurred in the absence of full immune reconstitution as measured by donor T cell engraftment and cytotoxic T lymphocyte activity. In addition, DC vaccinations did not appear to exacerbate graft-versus-host disease. These experiments support the feasibility of DC vaccine strategies in the setting of allogeneic BMT.

Animals↗
PubMed2005

Induction of anti-tumor immunity by vaccination with dendritic cells pulsed with anti-CD44 IgG opsonized tumor cells.

Due to the pivotal role that dendritic cells (DC) play in eliciting and maintaining functional anti-tumor T cell responses, these APC have been exploited against tumors. DC express several receptors for the Fc portion of IgG (Fcgamma receptors) that mediate the internalization of antigen-IgG complexes and promote efficient MHC class I and II restricted antigen presentation. In this study, the efficacy of vaccination with DC pulsed with apoptotic B16 melanoma cells opsonized with an anti-CD44 IgG (B16-CD44) was explored. Immature bone marrow derived DC grown in vitro with IL-4 and GM-CSF were pulsed with B16-CD44. After 48 h of pulsing, maturation of DC was demonstrated by production of IL-12 and upregulation of CD80 and CD40 expression. To test the efficacy of vaccination with DC+B16-CD44, mice were vaccinated subcutaneously Lymphocytes from mice vaccinated with DC+B16-CD44 produced IFN-gamma in response to B16 melanoma lysates as well as an MHC class I restricted B16 melanoma-associated peptide, indicating B16 specific CD8 T cell activation. Upon challenge with viable B16 cells, all mice vaccinated with DC alone developed tumor compared to 40% of mice vaccinated with DC+B16-CD44; 60% of the latter mice remained tumor free for at least 8 months. In addition, established lung tumors and distant metastases were significantly reduced in mice treated with DC+B16-CD44. Lastly, delayed growth of established subcutaneous tumors was induced by combination therapy with anti-CD44 antibodies followed by DC injection. This study demonstrates the efficacy of targeting tumor antigens to DC via Fcgamma receptors.

Animals↗
PubMed2004

Current developments of immunotherapy in the clinic.

The clinical application of immunotherapy for cancer is rapidly moving forward in multiple areas, including the adoptive transfer of anti-tumor-reactive T cells and the use of 'therapeutic' vaccines. Recently, both clinical and immunological endpoints have shown improvement. Novel strategies designed in the laboratory and proven in preclinical animal tumor models are now entering the clinic, with the intent of enhancing current therapeutic efficacy. These novel strategies involve breaking tolerance to tumor self-antigens by inhibiting regulatory cells, boosting T-cell co-stimulation and using combinations of recombinant cytokines and other defined molecules with 'immuno-enhancing' activities.

Antigens, Neoplasm↗
PubMed2004

Chemokine gene modification of human dendritic cell-based tumor vaccines using a recombinant adenoviral vector.

Previous animal studies conducted in our laboratory have shown that tumor antigen-pulsed dendritic cells (TP-DC) can mediate antitumor effects in vivo. However, durable and complete regression of established tumors has been difficult to achieve through the administration of TP-DC alone. To better augment immune priming to tumors in vivo, we have hypothesized that it is necessary to achieve an increased number of host-derived, naïve T cells at the site of TP-DC vaccine injections. To accomplish this goal, we have embarked on a series of studies that utilize defined chemokines. One of these molecules, secondary lymphoid tissue chemokine (SLC), has been shown to be uniquely chemoattractant for naïve T cells and dendritic cells. We propose that gene modification of DC-based tumor vaccines to produce human SLC will enhance T-cell recruitment and immune priming to tumor-associated antigens, and thereby translate into improved antitumor vaccine efficacy in vivo. Utilizing an E1-, E3-deleted adenoviral vector containing the gene for human SLC, we have been able to transduce human DC to produce biologically active human SLC that chemoattracts human T cells in vitro. SLC production by transduced DC was markedly enhanced upon DC maturation. Additionally, these SLC-secreting DC were found to be viable to a large extent despite the cytopathic effect inherent in adenoviral gene transfer and, most importantly, functional as determined by their ability to prime autologous T cells to a known melanoma-associated antigen, MART-1. Based on these encouraging results, we plan to initiate Phase I clinical studies utilizing DC-SLC to treat patients with advanced solid tumors.

Adenoviridae↗
PubMed2004

Dendritic cell-based therapeutics for breast cancer.

Continual attempts to stimulate the immune system against malignancies have led to the development of various strategies based on active immunotherapy treatments. Dendritic cells are the most potent antigen presenting cells with the capacity to stimulate naive T cells and induce primary and secondary immune responses. Due to the pivotal role that DC play in eliciting and maintaining functional anti-tumor T cell responses, DC have been exploited as vaccines in an attempt to actively immunize patients. Initial solid tumor clinical trials involving DC-based immunization have shown progress in terms of eliciting T-cell reactivity and mediating tumor regression. These early promising data have led to multiple research endeavors to also employ DC immunotherapy for the treatment of poorly immunogenic malignancies such as breast cancer. Various strategies to load DC with tumor associated antigens in murine models of breast cancer as well as the state of human clinical trials are reviewed.

Breast Neoplasms↗
PubMed2003

Inducible expression of macrophage receptor Marco by dendritic cells following phagocytic uptake of dead cells uncovered by oligonucleotide arrays.

The efficient Ag presenting and immunostimulatory capacity of dendritic cells (DCs) has led to the use of tumor Ag-pulsed DCs in treatment regimens for cancer. Although vaccine studies involving tumor lysate-pulsed DCs have been performed, little, if any, information is available on the effects of phagocytic uptake of tumor lysate on DC biology and function. We have investigated gene expression pattern differences between unpulsed DCs and tumor lysate-pulsed-DCs, using Affymetrix MG-U74Av2 oligonucleotide arrays, which contain approximately 12,000 genes and expressed sequence tags. Upon 24 h tumor lysate pulsing, the levels of 87 transcripts increased at least 3-fold while the levels of 121 transcripts were reduced by one-third or more, with accompanying p values <0.01. Most of these genes encoded proteins important for DC effector functions including cytokines, chemokines, and receptors, such as IL-12p40, macrophage inflammatory protein-2, and IL-6; Ag presentation, such as carboxypeptidase D and H2-DM; cell adhesion (e.g., EGF-like module containing, mucin-like, hormone receptor-like sequence 1, rhoB); and T cell activation. Interestingly, we observed a high level of expression of a novel member of the class A scavenger receptor family, macrophage receptor with collagenous structure (Marco). Marco is thought to play an important role in the immune response by mediating binding and phagocytosis, but also in the formation of lamellipodia-like structures and of dendritic processes. Therefore, we have identified a repertoire of genes that likely play a role in DC function.

Animals↗
PubMed2002

A phase I trial of tumor lysate-pulsed dendritic cells in the treatment of advanced cancer.

PURPOSE: The objectives of this study were to assess the toxicity and immunological response induced by the intradermal (i.d) administration of tumor lysate-pulsed dendritic cells (DCs). EXPERIMENTAL DESIGN: Patients with stage IV solid malignancies were treated in cohorts that received 10(6), 10(7), and 10(8) DCs i.d. every 2 weeks for three vaccines. Each vaccine was composed of a mixture of half DCs pulsed with autologous tumor lysate and the other half with keyhole limpet hemocyanin (KLH). Peripheral blood mononuclear cells (PBMCs) harvested 1 month after the last immunization was compared with pretreatment PBMCs for immunological response. Delayed-type hypersensitivity reactivity to tumor antigen and KLH was also assessed. RESULTS: Fourteen patients received all three vaccines and were evaluable for toxicity and/or immunological monitoring. There were no grade 3 or 4 toxicities associated with the vaccines or major evidence of autoimmunity. Local accumulation of CD4(+) and CD8(+) T cells were found at the vaccination sites. There was a significant proliferative response of PBMCs to KLH induced by the vaccine. In 5 of 6 patients, the vaccine resulted in increased IFN-gamma production by PBMCs to KLH in an ELISPOT assay. Using the same assay, 3 of 7 patients' PBMCs displayed increased IFN-gamma production in response to autologous tumor lysate. One patient with melanoma also was observed to have an increased frequency of MART-1- and gp100-reactive CD8(+) T cells after vaccination. By delayed-type hypersensitivity testing, 8 of 9 and 4 of 10 patients demonstrated reactivity to KLH and autologous tumor, respectively. Two patients with melanoma experienced a partial and a minor response, respectively. CONCLUSION: The administration of tumor lysate-pulsed DCs is nontoxic and capable of inducing immunological response to tumor antigen. Additional studies are necessary to improve tumor rejection responses.

Adult↗
PubMedDate not supplied

Immunostimulatory effects of CpG-ODN upon dendritic cell-based immunotherapy in a murine melanoma model.

In this study, we examined the protective and therapeutic efficacy of the immunoadjuvant CpG in combination with dendritic cell (DC) immunotherapy in a murine melanoma model. We found that murine bone-marrow derived DC stimulated in vitro with CpG displayed both enhanced expression of maturation markers and secretion of IL-12p70 and IL-10. In addition, these matured DC demonstrated enhanced ability to stimulate antigen specific CD4+ and CD8+ T cell responses in vitro. In a protection model, C57BL/6 mice vaccinated with either antigen-pulsed immature or CpG matured DC were unable to reject a lethal B16 melanoma challenge. In contrast, long-term protection was achieved in mice vaccinated with both CpG and antigen-pulsed DC, which correlated with an enhanced antigen specific T cell immune response. In a therapeutic model of established subcutaneous B16 melanoma, C57BL/6 mice treated intratumorally with CpG and B16 lysate-pulsed DC demonstrated a reduced tumor burden and prolonged survival. In a similar model of established subcutaneous tumor, mice treated with CpG-matured DC pulsed with a melanoma peptide, TRP-2, alone were unable to achieve tumor regression. Conversely, mice that received the combined vaccine of CpG and peptide-pulsed DC displayed a reduced tumor burden. These experiments provide evidence that combined immunization with both antigen-pulsed DC and the immunoadjuvant, CpG, can lead to tumor regression and long-term survival in a murine B16 melanoma model.

Adjuvants, Immunologic↗