Novel myeloma-associated antigens revealed in the context of syngeneic hematopoietic stem cell transplantation

Biernacki, Melinda A.; Tai, Yu Tzu; Zhang, Guanglan; Alonso, Anselmo; Zhang, Wandi; Prabhala, Rao; Zhang, Li; Munshi, Nikhil C.; Neuberg, Donna; Soiffer, Robert J.; Ritz, Jérôme; Alyea, Edwin P.; Brusic, Vladimir; Anderson, Kenneth C.; Wu, Catherine J.

doi:10.1182/blood-2011-11-388926

Cited by 12 publications

(7 citation statements)

References 46 publications

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“…We and others have demonstrated that GvL responses are initiated and sustained by the development of coordinated cellular and humoral immunity against tumor antigens and are not limited to a sole alloantigen response (12)(13)(14)(15). These studies have further suggested that individual patients have unique profiles of immunogenic tumor antigens, likely reflecting the heterogeneity of the genetic alterations found in tumor cells from different patients as well as the diversity of HLA (12)(13)(14)(15). Based on these principles, vaccination with autologous, irradiated leukemia cells is an attractive approach to expand leukemia-reactive T cells, since this cancer vaccine formulation reliably includes personal tumor antigens and can potentially elicit polyclonal CD4 + and CD8 + antitumor T cell responses (16).…”

Section: Introductionmentioning

confidence: 99%

Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells

Burkhardt

Hainz²,

Stevenson³

et al. 2013

J. Clin. Invest.

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Background. Patients with advanced hematologic malignancies remain at risk for relapse following reducedintensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT). We conducted a prospective clinical trial to test whether vaccination with whole leukemia cells early after transplantation facilitates the expansion of leukemia-reactive T cells and thereby enhances antitumor immunity. Methods. We enrolled 22 patients with advanced chronic lymphocytic leukemia (CLL), 18 of whom received up to 6 vaccines initiated between days 30 and 45 after transplantation. Each vaccine consisted of irradiated autologous tumor cells admixed with GM-CSF-secreting bystander cells. Serial patient PBMC samples following transplantation were collected, and the impact of vaccination on T cell activity was evaluated.Results. At a median follow-up of 2.9 (range, 1-4) years, the estimated 2-year progression-free and overall survival rates of vaccinated subjects were 82% (95% CI, 54%-94%) and 88% (95% CI, 59%-97%), respectively. Although vaccination only had a modest impact on recovering T cell numbers, CD8 + T cells from vaccinated patients consistently reacted against autologous tumor, but not alloantigen-bearing recipient cells with increased secretion of the effector cytokine IFN-γ, unlike T cells from nonvaccinated CLL patients undergoing allo-HSCT. Further analysis confirmed that 17% (range, 13%-33%) of CD8 + T cell clones isolated from 4 vaccinated patients by limiting dilution of bulk tumor-reactive T cells solely reacted against CLL-associated antigens. Conclusion.Our studies suggest that autologous tumor cell vaccination is an effective strategy to advance longterm leukemia control following allo-HSCT.Trial registration. Clinicaltrials.gov NCT00442130.

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Section: Introductionmentioning

confidence: 99%

Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells

Burkhardt

Hainz²,

Stevenson³

et al. 2013

J. Clin. Invest.

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“…Id protein is not the only myeloma-specific antigen that can be targeted by the immune system, a variety of tumorassociated antigens have been identified in myeloma cells. Among the most studied, there are NY-ESO-1 (cancer testis antigen) [66], RHAMM-R3 (receptor for hyaluronic acid-mediated motility) [36], WT1 and MUC1 (see Table 3) [69] and DKK1 (Dickkopf-1 a Wnt/Bcatenin signaling inhibitor protein) [68]. NY-ESO-1 specific CTLs generated from MM patients were shown to kill primary myeloma cells, and a clinical trial evaluating the efficacy of a vaccination strategy targeting NY-ESO-1 in association with GM-CSF is underway.…”

Section: Cpg7909mentioning

confidence: 99%

“…However, no clinical studies employing DKK1-derived peptides have been performed so far. Recently, in syngenic hematopoietic stem cell transplant setting in which donor immune responses should exclusively target unique tumor epitopes, 6 new myeloma-specific antigens were discovered, although their immunological and clinical value has not been assessed yet [69]. Kang et al have identified two novel HLA-A2 restricted antigens derived by HLA-DOB exclusively expressed in B lineage cells and in thymic medullary epithelium, which were naturally processed and presented on MM cells.…”

Section: Cpg7909mentioning

confidence: 99%

Peptide vaccines for hematological malignancies: a missed promise?

et al. 2014

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Despite the crucial aid that newly developed target therapies are providing to chemotherapy and stem cell transplant, the cure for many hematological malignancies is still an unmet need. Although available therapies are able to induce an effective debulking of the tumor, most of the time, an insidious minimal residual disease survives current treatments and it is responsible for an immediate or delayed relapse. Peptide-derived antitumor vaccines have been developed with the idea that an artificially ''educated'' immune system may exert an active specific antitumor response able to control and ultimately eradicate underlying post-treatment residual disease. This review will summarize current knowledge of peptide vaccines for hematological malignancies, trying to analyze promises and pitfalls of a safe and intelligent tool that after many years from its first appearance has not yet established its potential role as alternative immune mediated therapeutic approach for hematopoietic tumors.

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“…39 Another study has shown that T-cell and humoral immune responses to myeloma-specific Ags are more common after autologous and syngeneic transplant than in untreated myeloma patients. 40 No studies have associated the development of autologous/ syngeneic GVHD with protection from relapse. This may be due to the lack of subsequent chronic GVHD in patients who develop acute autologous GVHD, as acute GVHD alone after allo-HCT for plasma cell myeloma does not seem to be associated with protection from relapse.…”

Section: Autologous Transplantation As a Platform For Cellular Immunomentioning

confidence: 99%

Cellular immunotherapy for plasma cell myeloma

Garfall

Vogl

Weiss

et al. 2013

Bone Marrow Transplant

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Allogeneic hematopoietic cell transplantation for plasma cell myeloma can lead to graft-vs-myeloma immunity and long-term survivorship, but limited efficacy and associated toxicities have prevented its widespread use. Cellular immunotherapies seek to induce more specific, reliable and potent antimyeloma immune responses with less treatment-related risk than is possible with allogeneic transplantation. Strategies under development include infusion of vaccine-primed and ex vivo expanded/costimulated autologous T cells after high-dose melphalan, genetic engineering of autologous T cells with receptors for myeloma-specific epitopes, administration of DC/plasma cell fusions and administration expanded marrow-infiltrating lymphocytes. In addition, novel immunomodulatory drugs such as inhibitors of the programmed death-1 T cell regulatory pathway may synergize with cellular immunotherapies.

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Novel myeloma-associated antigens revealed in the context of syngeneic hematopoietic stem cell transplantation

Abstract: Targets of curative donor-derived graftversus-myeloma (GVM) responses after

Cited by 12 publications

References 46 publications

Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells

Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells

Peptide vaccines for hematological malignancies: a missed promise?

Cellular immunotherapy for plasma cell myeloma

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