M Bendandi

Universidad de Navarra, Pamplona, Navarre, Spain

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Publications (131)865.79 Total impact

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    ABSTRACT: Non-Hodgkin's lymphoma (NHL) is the most common hematological malignancy both in Europe and in the United States. Follicular lymphoma (FL), a tumor comprised of mature B cells, represents one fourth of all NHL and, despite good response rates to standard treatments, tends to frequently relapse to such an extent that it is still considered incurable. Among several alternative therapeutic options actively being pursued, immunotherapy by idiotypic vaccination is in the forefront of clinical experimental medicine. The idiotype vaccine consists of the tumor-specific immunoglobulin conjugated with keyhole limpet hemocyanin (KLH) and administered together with an adjuvant. Over the last 20 years, researchers have proven that this vaccine can induce specific immune responses. Too, those patients with such responses experience a disease-free survival longer than normally achievable, although these latter results require further confirmation in large clinical trials. Traditionally, idiotype vaccines have been produced through hybridoma technology. In this chapter this technology is described.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1139:367-87. · 1.29 Impact Factor
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    ABSTRACT: CD28 is one of the main costimulatory receptors responsible for the proper activation of T lymphocytes. We have isolated two aptamers that bind to the CD28 receptor. As a monomer, one of them interfered with the binding of CD28 to its ligand (B7), precluding the costimulatory signal, whereas the other one was inactive. However, dimerization of any of the anti-CD28 aptamers was sufficient to provide an artificial costimulatory signal. No antibody has featured a dual function (i.e., the ability to work as agonist and antagonist) to date. Two different agonistic structures were engineered for each anti-CD28 aptamer. One showed remarkably improved costimulatory properties, surpassing the agonistic effect of an anti-CD28 antibody. Moreover, we showed in vivo that the CD28 agonistic aptamer is capable of enhancing the cellular immune response against a lymphoma idiotype and of prolonging survival of mice which receive the aptamer together with an idiotype vaccine. The CD28 aptamers described in this work could be used to modulate the immune response either blocking the interaction with B7 or enhancing vaccine-induced immune responses in cancer immunotherapy.Molecular Therapy - Nucleic Acids (2013) 2, e98; doi:10.1038/mtna.2013.26; published online 11 June 2013.
    Molecular therapy. Nucleic acids. 01/2013; 2:e98.
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    ABSTRACT: Idiotypic vaccination for folicular lymphoma induces a tumor-specific immune response which may kill tumor cells in vivo and prevent tumor relapse in patients. However, being based on a personalized vaccine against a person's own tumor, large scale randomized studies have produced contradictory results. The objective of this review is to define what an idiotype is and to outline the major results of twenty years of clinical research on idiotypic vaccination. We first identified the major proofs of principle obtained by its use between 1992 and 2006, focusing on both our and others' contributions. Then, we analyzed the results of randomized clinical trials, which have become available ove the last five years, and provided some of our most recent and original data.
    Advances in cancer: Cancer Research and Treatment. 01/2013; 2013.
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    ABSTRACT: To assess whether the addition of a customized, active immunotherapy to standard of care including fluorescence-guided surgery, may provide hints of an improved survival for patients with poor-prognosis, incurable glioblastoma multiform. Preliminary to our ongoing, phase-II clinical trial, we conducted a small pilot study enrolling five consecutive patients with resectable glioblastoma. In terms of Recursive Partitioning Analysis, four patients were class V and one was class IV. In all five cases, fluorescence-guided surgery was employed, followed by rapid steroid discontinuation. Patients were then treated with a combination of standard radio-chemotherapy with temozolomide and tumor lysate-pulsed, mature dendritic cell-based vaccinations. Though all five patients ultimately progressed, with any further treatment left to the sole decision of the treating oncologist, active immunotherapy was very well tolerated and induced specific immune responses in all three patients for whom enough material was available for such an assessment. Median progression-free survival was 16.1 mo. Even more important, median and mean overall survival were 27 mo and 26 mo, respectively. Three patients have died with an overall survival of 9 mo, 27 mo and 27.4 mo, while the other two are still alive at 32 mo and 36 mo, the former receiving treatment with bevacizumab, while the latter has now been off therapy for 12 mo. Four of five patients were alive at two years. Active immunotherapy with tumor lysate-pulsed, autologous dendritic cells is feasible, safe, well tolerated and biologically efficacious. A phase-II study is ongoing to possibly improve further on our very encouraging clinical results.
    World journal of clinical oncology. 11/2012; 3(11):142-9.
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    Leukemia & lymphoma 08/2012; · 2.61 Impact Factor
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    ABSTRACT: Colorectal cancer is a serious health problem affecting de novo more than one million people every year in the developed world. Despite recent advances in the development of novel therapeutic agents, metastatic colorectal cancer remains mostly incurable and its survival rates ominous even when patients respond to the most advanced treatments. Here, we describe a case in which a patient with metastatic colorectal cancer and high risk of relapse remains disease-free while being treated solely with twelve doses of autologous dendritic cells vaccines pulsed with autologous tumor lysate. A sustained, specific immune response elicited by vaccination has also been documented. Prior to receiving this experimental treatment, the patient had undergone both tumor resections and chemotherapy treatments six times, invariably relapsing/progressing within a year from each resection. We believe that the use of autologous vaccines consisting in dendritic cells pulsed with tumor lysate should be further investigate in human clinical trials, particularly in patients with minimal tumor burden and high risk of relapse. We also believe that this type of immunotherapy is more likely to be successful when used as an early rather than merely compassionate treatment option, given the fact that the more toxicity the immune system has received from previous approaches, the less it will be able to respond to tumor vaccination.
    The Journal of cancer research updates. 01/2012; 1(1):1-7.
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    ABSTRACT: Most patients with B-cell lymphoma face an often incurable disease, particularly those diagnosed with an indolent subtype. The addition of passive immunotherapy to old and new chemotherapy regimens has improved both response rates and disease-free survival, leading in many cases to an extended overall survival. However, a cure remains elusive in most cases. For this reason, the patient- and tumor-specific idiotype, that is the collection of epitopes exclusively presented by the tumor clone's surface immunoglobulin, has been extensively studied as a privileged target for vaccine therapy, aiming at preventing disease re-occurrence after standard treatment. BiovaxID(®) (Biovest International, FL, USA), the most clinically advanced among such therapeutic vaccines, finds itself at a crucial turning point when it comes to further development. Both clinical trials in which it has been formally employed have shown intriguing results. Independent studies using slightly different versions of a conceptually identical vaccine provided all proofs of principle required to ascertain the vaccine's value - biological and clinical efficacy as well as clinical benefit. However, all these data have failed to bring an idiotype vaccine to the market owing to reasons that often have very little to do with the product itself. In fact, some successful studies were not conceived with this goal in mind, while others simply did not enroll enough patients to convincingly make their case for regulatory approval. It is likely that one or more new clinical trials will have to be successfully completed to reach the ultimate goal - that is, to make BiovaxID available to most patients and to adequately position it in the very crowded therapeutic algorithm of B-cell lymphoma.
    Expert Review of Vaccines 12/2011; 10(12):1661-9. · 4.22 Impact Factor
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    ABSTRACT: Several types of B-cell malignancy, including but not limited to multiple myeloma and follicular lymphoma, are still considered incurable. In a substantial number of cases, patients must undergo either autologous or allogeneic stem cell transplantation as a standard of care procedure for their disease. Among experimental treatments for multiple myeloma and follicular lymphoma, idiotypic vaccination has been attempted over the last two decades with variable degrees of success. Few clinical trials have combined stem cell transplant procedures with idiotypic vaccination, and they are the subject of this review, which will also include some of our original data, as well as our overall evaluation of this field of clinical investigation. Although apparently at the opposite extremes of the therapeutic option array, toxicity-burdened stem cell transplantation and virtually innocuous idiotypic vaccination might well offer a sound curative opportunity to some patients with otherwise incurable B-cell malignancies, provided that the latter treatment first succeeds at obtaining regulatory approval.
    Current Topics in Medicinal Chemistry 06/2011; 11(13):1653-1660. · 3.70 Impact Factor
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    ABSTRACT: Over the last two decades, lymphoma idiotype vaccines have been the first human cancer vaccines to show striking evidence of biological and clinical efficacy on the one hand, as well as clinical benefit on the other. More recently, however, three large-scale, independent, randomized clinical trials on idiotypic vaccination have failed to achieve their main clinical endpoints for reasons likely to depend more on flaws in each clinical trial's study design than on each vaccination strategy per se. Independently of these considerations, a major hurdle for the development of this substantially innocuous and yet potentially very effective type of treatment has been the fact that, even to date, no factors ascertainable before vaccination have been prospectively singled out as predictors of subsequently vaccine-induced, idiotype-specific immune as well as clinical responses. The aim of this review article is precisely to analyze what has been and what could be done in this respect in order to give a greater chance of success to future trials aimed at regulatory approval of idiotype vaccines.
    World journal of clinical oncology. 06/2011; 2(6):237-44.
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    ABSTRACT: Despite having been the first cancer vaccine to provide clear-cut evidence of biological and clinical efficacy as well as of clinical benefit in humans, idiotype vaccines have failed to become the first therapeutic cancer vaccine to be granted regulatory approval. Indeed, idiotypic vaccination is still an experimental therapeutic option for some types of B-cell malignancy over 20 years after its first use in patients with lymphoma. The ultimate reason for this situation lies in the recent failure of three large-scale, independent, randomized trials to achieve their respective main clinical end points. Interestingly, each trial had been designed with intrinsic pitfalls that are likely to have influenced, and perhaps even entirely compromized, all chances each study had to succeed. Therefore, it is difficult to conclude whether any of the different idiotype vaccines employed so far may still represent an ideal candidate for further trials. Meanwhile, other idiotype vaccine formulations are under active investigation.
    Expert Review of Vaccines 06/2011; 10(6):801-9. · 4.22 Impact Factor
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    ABSTRACT: Several types of B-cell malignancy, including but not limited to multiple myeloma and follicular lymphoma, are still considered incurable. In a substantial number of cases, patients must undergo either autologous or allogeneic stem cell transplantation as a standard of care procedure for their disease. Among experimental treatments for multiple myeloma and follicular lymphoma, idiotypic vaccination has been attempted over the last two decades with variable degrees of success. Few clinical trials have combined stem cell transplant procedures with idiotypic vaccination, and they are the subject of this review, which will also include some of our original data, as well as our overall evaluation of this field of clinical investigation. Although apparently at the opposite extremes of the therapeutic option array, toxicity-burdened stem cell transplantation and virtually innocuous idiotypic vaccination might well offer a sound curative opportunity to some patients with otherwise incurable B-cell malignancies, provided that the latter treatment first succeeds at obtaining regulatory approval.
    Current topics in medicinal chemistry 03/2011; 11(13):1653-60. · 4.47 Impact Factor
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    ABSTRACT: Animal and clinical studies with plant-produced single-chain variable fragment lymphoma vaccines have demonstrated specific immunogenicity and safety. However, the expression levels of such fragments were highly variable and required complex engineering of the linkers. Moreover, the downstream processing could not be built around standard methods like protein A affinity capture. We report a novel vaccine manufacturing process, magnifection, devoid of the above-mentioned shortcomings and allowing consistent and efficient expression in plants of whole immunoglobulins (Igs). Full idiotype (Id)-containing IgG molecules of 20 lymphoma patients and 2 mouse lymphoma models were expressed at levels between 0.5 and 4.8 g/kg of leaf biomass. Protein A affinity capture purification yielded antigens of pharmaceutical purity. Several patient Igs produced in plants showed specific cross-reactivity with sera derived from the same patients immunized with hybridoma-produced Id vaccine. Mice vaccinated with plant- or hybridoma-produced Igs showed comparable protection levels in tumor challenge studies. This manufacturing process is reliable and robust, the manufacturing time from biopsy to vaccine is <12 weeks and the expression and purification of antigens require only 2 weeks. The process is also broadly applicable for manufacturing monoclonal antibodies in plants, providing 50- to 1000-fold higher yields than alternative plant expression methods.
    Annals of Oncology 12/2010; 21(12):2420-7. · 7.38 Impact Factor
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    ABSTRACT: After twenty years of use in humans, customized idiotypic vaccination yet remains a non-approved, experimental therapeutic option for patients with lymphoma and myeloma. Potentially applicable to all B-cell malignancies whose cells express a clonal immunoglobulin or its epitopes on their surface, this treatment is designed to prevent disease recurrence or progression. Mostly used in follicular lymphoma patients so far, idiotype vaccines have clearly shown biological efficacy, clinical efficacy and clinical benefit in this setting, although no study aiming at regulatory approval of the procedure has been able to meet its main clinical endpoints. In mantle cell lymphoma, only biological efficacy has been proven for idiotypic vaccination, while in multiple myeloma a limited number of studies support the notion of biological and perhaps even clinical efficacy, although no credible evidence of clinical benefit has still emerged. Idiotype vaccines have been produced and administered in a number of substantially different manners. Therefore, the results of most clinical trials cannot be easily compared, and even less pooled together in meaningful meta-analyses. A more creative and yet scientifically sound way to design clinical trials of customized active immunotherapies will be key to the future development of idiotype vaccines, particularly considering that we currently lack any clinical or biological indicator to possibly predict which patients are more likely to respond to idiotypic vaccination from an immunologic point of view. This review aims at summarizing the multifaceted success achieved by idiotype vaccines, as well as at outlining the challenges awaiting them in the near future: how to improve feasibility, immunogenicity and efficacy, as well as how to confirm benefit and gain regulatory approval.
    Current pharmaceutical design 01/2010; 16(3):300-7. · 4.41 Impact Factor
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    Maurizio Bendandi
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    ABSTRACT: The clonal immunoglobulin idiotype displayed on the surface of most malignant B cells is a patient- and tumour-specific antigen that can be used for therapeutic vaccination. Several studies have confirmed the biological efficacy of soluble protein idiotypic vaccination and two clinical trials have shown the clinical efficacy of this procedure. One study has demonstrated clinical benefit associated with idiotypic vaccination. However, three randomized clinical trials have recently failed to achieve their main end points for reasons that are probably unrelated to the vaccine. While scepticism towards this type of non-toxic medical intervention is mounting, such patient-specific treatments might yet see the light of day through better designed clinical trials.
    Nature Reviews Cancer 10/2009; 9(9):675-81. · 29.54 Impact Factor
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    ABSTRACT: A prospective randomized study on aggressive non-Hodgkin's lymphomas was conducted by investigators at several Italian institutions with the intent of comparing two third-generation conceptually different regimens: the regimen containing methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B), a short-term continuous twelve-week therapy, and F-MACHOP (5-fluorouracil, methotrexate with leucovorin rescue, cytarabine, cyclophosphamide, doxorubicin, vincristine, and prednisone), a monthly intensive cyclic treatment combining prednisone with six active non-cross-resistant cytotoxic drugs. The goals of this study were the response rate, relapse-free survival, and incidence of hematologic and nonhematologic toxicities. Two hundred-eighty-six patients included between 15 and 60 years fulfilled the criteria for entry to the study; 140 patients were treated with MACOP-B and 146 with F-MACHOP. The minimum follow-up was 24 months. Clinical characteristics of all patients were similar and known prognostic factors were equally distributed between the two groups. Complete remission (CR) was achieved by 61% and 67% of the patients treated with MACOP-B and F-MACHOP, respectively; 4% and 6% were primarily resistant, 2% and 5%, respectively, died of causes directly related to therapy. At 50 months, 74% of all CR patients were alive without disease and there were no significant differences in relapse-free survival between the two groups: 75% in the F-MACHOP group and 73% in the MACOP-B group at 50 months. There was a higher incidence of mucositis among patients treated with MACOP-B than among those given F-MACHOP (11% vs 3.5%). Higher incidences of severe cytopenia (51% vs 21%) and of fatal sepsis (5% vs 2%) were recorded among patients treated with F-MACHOP than with MACOP-B. The third-generation regimens, F-MACHOP and MACOP-B, are as effective as other regimens. A prognostic analysis taking into account the principal covariates (age, symptoms, stage, serum lactate dehydrogenase, mediastinum involvement, bulky disease, histology, therapy, and dose intensity) was assessed for their impact on complete response rate incidence and on relapse rate from complete response by multivariate analysis. The linear logistic model showed that symptoms, advanced stage, mediastinum involvement, and bulky disease are prognostic factors that increase the risk of a lower rate of complete response. These data confirm the important role of a pretreatment selection for the poor-risk patients and, on the basis of these parameters, it will probably be possible to consider these patients for high-dose therapy with autologous bone marrow transplantation or autologous hematopoietic stem-cell support.
    Leukemia & Lymphoma. 07/2009; 16(5-6).
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    ABSTRACT: Mantle cell lymphoma (MCL) is an aggressive B cell malignancy, which is believed to originate from naïve B cells in the mantle zone of lymph nodes. We speculate that a possible mechanistic hypothesis for the generation of MCL is one in which receptor editing and germinal centre exclusion could be involved in the molecular development and in the display of clinical characteristics of this rare, aggressive and scarcely understood lymphoma. The hypothesis is supported by a preferential autoimmune related IGVH gene utilization in MCL, where VH3-21, VH4-34 and VH5-51 genes are predominant, and by the fact that MCL expresses immunoglobulin light chain (IgL) lambda more frequently than other non-Hodgkin's lymphomas and that IgL lambda-producing B cells usually delete one or both their IgL kappa genes.
    Leukemia research 07/2009; 33(11):1437-9. · 2.36 Impact Factor
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    ABSTRACT: Myelodysplastic syndromes (MDS) are a group of hematopoietic disorders characterized by uni- or multilineage maturation defects of the bone marrow. Controversial therapeutic results have been obtained using growth factors or differentiating agents such as 134s retinoic acid. In this pilot study we evaluatedthe effects of all-trans retinoic acid (ATRA) in 10 MDS patients (5 male, 5 female). Six patients had refractory anemia (RA), I had refractory anemia with excess of blasts (RAEB), and 3 had refractory anemia with excess of blasts in transformation (RAEB-t). All patients received the same dose of ATRA (45 mg/sqm/day) orally for 6 weeks. A rise in hemoglobin concentration >Ig/dl was observed in 3/10 patients, while 5/10 patients showed an increase in granulocyte count >0.5 × 109/1 without concomitant increase in the percentage of blast cells in the bone marrow. A rise in the platelet count >50 × 109/1 was observed in 1/10 patients. All the effects were transient and maximal responses were obtained by the fourth week of treatment. Thereafter, the peripheral blood counts started todrop again, reaching pre-therapy values by the end of the treatment. This phcnomenon could be attributed either to the exhaustion of an ATRA-responding cell pool, the development of cellular resistance to ATRA or to a reduction of plasma ATRA levels after prolonged treatrncnt. According to our results, it seems that ATRA might have therapeutic efficacy in MDS, particularly if its effect Interleukin-I receptor type I (IL-IR), IL-2 receptor a subunit (IL-2R) and IL-6 receptor a subunit
    06/2009; 19(3-4):277-280.
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    ABSTRACT: During the last 2 decades, idiotypic vaccination has provided proof of principle of biological efficacy, clinical efficacy and clinical benefit in small follicular lymphoma trials. However, with the exception of anecdotal reports, most patients have received no more than 10 doses of their customised idiotype (Id) vaccine. Therefore, it is not known whether prolonged usage of idiotypic vaccination is safe. Since 2002, 18 previously treated patients with follicular lymphoma have received extended idiotypic vaccination at our institution outside clinical trials. Vaccination was provided as a compassionate alternative to no further treatment, and was meant to be stopped only upon complete consumption of the available patient- and tumor-specific vaccine [Id-keyhole limpet hemocyanin + granulocyte-macrophage colony-stimulating factor (Id-KLH + GM-CSF)], or in case of disease relapse or any serious non-local toxicity. So far, 18 patients have received an average of 18 doses of Id vaccine (median: 17; mean: 18; range: 10-31). Eleven patients are still actively receiving idiotypic vaccination: some of them are now over more than 6 years. Toxicity has been systematically negligible and mostly local. No patient has abandoned the vaccination program because of toxicity. Prolonged idiotypic vaccination with the soluble protein Id-KLH + GM-CSF formulation is safe and well tolerated.
    Leukemia & lymphoma 02/2009; 50(1):47-53. · 2.61 Impact Factor
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    ABSTRACT: El linfoma folicular (LF) está considerado como el segundo tipo de linfoma no-Hodgkin más común, representando más del 20% del total de los linfomas. Es una enfermedad de progresión lenta y curso indolente en la que, a pesar de la buena respuesta al tratamiento, las recaídas son muy frecuentes y cada vez es más difícil conseguir respuestas completas. Por ello, se puede considerar que hasta el momento, el LF es incurable. La búsqueda continua de nuevas estrategias terapéuticas en enfermedades neoplásicas, junto con un mejor conocimiento del sistema inmunitario, ha llevado a la aparición de una nueva disciplina, conocida con el nombre de inmunoterapia, que aprovecha la capacidad del sistema inmunitario de atacar lo extraño sin dañar lo propio. El LF es un tumor muy apropiado para este tipo de tratamiento por presentar un antígeno específico de tumor: el idiotipo de la inmunoglobulina monoclonal expresada en la membrana de todas las células tumorales. Se han realizado diversos estudios en los que se ha probado la inmunoterapia como tratamiento complementario al tratamiento convencional. Recientemente, nuestro grupo ha publicado un estudio en el que se observa claramente que los resultados que se obtienen tras la vacunación idiotípica, cuando se consigue la inmunización adecuada del paciente, son mejores que los obtenidos con quimioterapia sola. En este sentido, es necesario seguir investigando para aclarar si la vacunación idiotípica pudiera no sólo mantener remisiones completas duraderas en los pacientes vacunados, sino incluso conseguir la curación de los mismos. Por ello, resulta interesante abordar un mejor planteamiento de los ensayos clínicos, la mejora de la producción de la vacuna y el estudio de mecanismos de la célula tumoral capaces de modificar la inmunoglobulina específica del tumor.
    Anales del sistema sanitario de Navarra 01/2009; · 0.35 Impact Factor
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    ABSTRACT: : The activity of fludarabine monophosphate (FLU) and α-interferon (α-IFN) in low-grade non-Hodgkin's lymphoma (LG-NHL) and B-cell chronic lymphocytic leukemia (B-CLL) has been demonstrated in several clinical trials. In a study of 137 previously treated patients, of whom 77 had B-CLL and 60 with LG-NHL, we used FLU as salvage chemotherapy. Dosages of 25 mg/m2 were given in 30-min infusions for 5 consecutive d. Treatment was repeated every 28 d depending on the patient's clinical status for a maximum of 6 cycles. Entrance to the α-IFN maintenance portion of the study depended on patient response to initial FLU. All patients who had obtained a complete or partial response after the FLU therapy were randomized to receive α-IFN or no further therapy. The α-IFN dose was 3×106 units 3 times per wk until disease progression. At 4 yr with a median follow-up of 22 months the percentage of patients with persistent response ranged between 20% and 30% among all the responders. Thirty-five (45%) B-CLL patients achieved major responses (complete/partial response), as did 29 (48%) of those with LG-NHL. Among the 64 patients who achieved a good response to initial therapy and who have entered the second part of the trial, there has been a rate of prolongation of remission in favour of maintenance α-IFN (p = 0.02). FLU therapy is an effective drug inducing remission in pretreated B-CLL and LH-NHL patients. However, as with other therapeutic modalities, remission is rarely maintained beyond 2 yr. So far, maintenance α-IFN has not been shown to produce significantly longer remission after treatment with FLU in LG-NHL, and there is no trend towards prolonged remission in B-CLL patients. The role of FLU needs to be further evaluated in the management of lymphoproliferative disorders by introducing it in combination with other drugs (α-IFN) in the induction phase and in maintenance treatment.
    European Journal Of Haematology 01/2009; 59(2):82-88. · 2.55 Impact Factor

Publication Stats

3k Citations
865.79 Total Impact Points

Institutions

  • 2001–2013
    • Universidad de Navarra
      • • Department of Oncology
      • • Department of Neurology and Neurosurgery
      • • Department of Radiology
      • • School of Medicine
      • • Center for Applied Medical Research (CIMA)
      • • Department of Hematology
      Pamplona, Navarre, Spain
  • 2009
    • Hokkaido University Hospital
      Sapporo, Hokkaidō, Japan
  • 1995–2009
    • University of Bologna
      • Institute of Haematology
      Bolonia, Emilia-Romagna, Italy
  • 2005–2007
    • Clínica Universidad de Navarra
      Madrid, Madrid, Spain
  • 2006
    • Universidad de Pamplona
      Памплона, Norte de Santander, Colombia
  • 1999–2001
    • National Cancer Institute (USA)
      • Experimental Transplantation and Immunology Branch
      Maryland, United States