Immune and cell therapy of hematologic malignancies

Advances in molecular biology and immunology have identified means to activate the immune response against leukemia-associated antigens. Recent studies indicate that the stealth-like phenotype of leukemia cells can be reversed through transfer of genes encoding recombinant membrane-stabilized proteins of the tumor necrosis factor (TNF) imily, such as the one encoding CD154, the ligand for CD40. A phase I clinical trial using autologous CD154-transduced leukemia cells as a cellular vaccine has provided encouraging results. Treatment not only appears capable of inducing a cellular anti-leukemia immunity, but also may have a direct effect on leukemia cells by inducing latent sensitivity to Fas (CD95)-dependent leukemia-cell apoptosis. Phase II studies currently are underway using multiple injections of autologous leukemia cells made to express recombinant CD154 via gene transfer. Conceivably, we may be entering an era of effective gene therapy for hematologic malignancies.     

Angiogenesis and antiangiogenic therapy in hematologic malignancies

Angiogenesis, the generation of new blood capillaries from preexisting blood vessels, is tightly regulated in the adult organism. Although many of the initial studies were performed on solid tumors, increasing evidence indicates that angiogenesis also plays an important role in hematologic malignancies. Overexpression of angiogenic factors in particular VEGF and bFGF in most hematologic malignancies may explain the increased angiogenesis found in these malignancies and correlate with poor prognosis as well as decreased overall survival. In this review, we focus on the current literature of angiogenesis and antiangiogenic therapy in hematologic malignancies, and finally describe advances and potential challenges in antiangiogenic treatment in hematologic malignancies.     

Translational development of active immunotherapy for hematologic malignancies

The B-cell tumor-derived Ig receptor may be considered a model tumor antigen for cancer vaccine development. However, as a non-immunogenic, self-antigen, it also must be first rendered immunogenic by chemical or genetic fusion to carriers which enable the induction of protective antitumor immunity in experimental tumor models. Our group has demonstrated that active immunization of human patients with idiotypic protein vaccines containing soluble GM-CSF elicited antigen specific CD8+ T cell responses and antitumor effects. An alternative strategy to develop vaccines is the genetic fusion of tumor idiotype-derived single chain antigen with a chemokine moiety. Administration of these vaccines as fusion proteins or naked DNA vaccines may allow more efficient targeting of antigen presenting cells in vivo. Potent antitumor immunity was elicited in mice which was dependent on the generation of specific antibodies and both CD4+ and CD8+ effector T-cells. We propose that chemokine fusion may represent a novel, general strategy for formulating existing or newly identified tumor and HIV antigens into vaccines for cancer and AIDS, respectively, which elicit potent CD8+ T-cell immunity.     

The immune system as a foundation for immunologic therapy and hematologic malignancies: a historical perspective

In this review we aim to provide a historical overview of the immunotherapeutic approaches which have been developed for the treatment of hematological malignancies. After briefly summarizing the development of the theory of cancer immune surveillance, we describe how initial studies discovering the efficacy of the immune-mediated graft-versus-tumor effects after allogeneic hematopoietic cell transplantation led to new transplantation approaches (termed non-myeloablative transplantation) relying almost exclusively on graft-versus-tumor effects for tumor eradication. We then summarize important steps in the development of tumor vaccines and autologous adoptive immunotherapy in patients with hematological malignancies. Finally, we describe historical discoveries leading to the recent success with monoclonal antibodies as treatment for lymphomas, chronic lymphocytic leukemia, and acute myeloid leukemia.     

New targets for CAR T therapy in hematologic malignancies

As we expand our acumen of the intricacies of hematological malignancies at a genetic and cellular level, we have paved the way in advancing novel targeted therapeutic avenues such as chimeric antigen receptor T-cell therapies (CAR T). Engineering cells to target a specific antigen has led to dramatic remission rates in cases of relapsed/refractory non-Hodgkin lymphoma, acute lymphoblastic leukemia as well as multiple myeloma thus far with trials in place to further advance targeted therapies in other hematological malignancies. Most currently available CAR T therapies target CD19 antigen. Studies are underway exploring novel CAR T products aimed at other tumor-specific antigens with potential to improve the efficacy and reduce the toxicities. Early studies have confirmed safety and efficacy of CD22 and BCMA targeted CAR T therapies. Moreover, various other targets including CD20, CD30, CD123, kappa, and lambda light chains among others are under clinical investigation as potential avenues of targeted therapy. This review highlights the shift in the treatment paradigm in pursuing diverse antigen targets while addressing the challenges in terms of the efficacy and toxicity of current CAR T-cell therapies.     

Iron overload and hematologic malignancies

Although iron is essential for cell replication and survival, an increase of body iron stores has been implicated in the development of cancer. However, while the association between iron overload and hepatocellular carcinoma is well documented, the relationship with nonhepatocellular malignancies remains ill-defined. In this review, we briefly report the present knowledge regarding the association between iron overload and hematologic malignancies.     

Farnesyltransferase inhibitors in hematologic malignancies: new horizons in therapy

Farnesyltransferase inhibitors (FTIs) are small-molecule inhibitors that selectively inhibit farnesylation of a number of intracellular substrate proteins such as Ras. Preclinical work has revealed their ability to effectively inhibit tumor growth across a wide range of malignant phenotypes. Many hematologic malignancies appear to be reasonable disease targets, in that they express relevant biologic targets, such as Ras, mitogen-activated protein kinase (MAPK), AKT, and others that may depend on farnesyl protein transferase (FTase) activity to promote proliferation and survival. A host of phase 1 trials have been recently launched to assess the applicability of FTIs in hematologic malignancies, many of which demonstrate effective enzyme target inhibition, low toxicity, and some clinical responses. As a result, phase 2 trials have been initiated in a variety of hematologic malignancies and disease settings to further validate clinical activity and to identify downstream signal transduction targets that may be modified by these agents. It is anticipated that these studies will serve to define the optimal roles of FTIs in patients with hematologic malignancies and provide insight into effective methods by which to combine FTIs with other agents.     

Anti-cancer vaccine therapy for hematologic malignancies: An evolving era

The potential promise of therapeutic vaccination as effective therapy for hematologic malignancies is supported by the observation that allogeneic hematopoietic cell transplantation is curative for a subset of patients due to the graft-versus-tumor effect mediated by alloreactive lymphocytes. Tumor vaccines are being explored as a therapeutic strategy to re-educate host immunity to recognize and target malignant cells through the activation and expansion of effector cell populations. Via several mechanisms, tumor cells induce T cell dysfunction and senescence, amplifying and maintaining tumor cell immunosuppressive effects, resulting in failure of clinical trials of tumor vaccines and adoptive T cell therapies. The fundamental premise of successful vaccine design involves the introduction of tumor-associated antigens in the context of effective antigen presentation so that tolerance can be reversed and a productive response can be generated. With the increasing understanding of the role of both the tumor and tumor microenvironment in fostering immune tolerance, vaccine therapy is being explored in the context of immunomodulatory therapies. The most effective strategy may be to use combination therapies such as anti-cancer vaccines with checkpoint blockade to target critical aspects of this environment in an effort to prevent the re-establishment of tumor tolerance while limiting toxicity associated with autoimmunity.     

Angiogenesis in hematologic malignancies

Angiogenesis, defined as the blood vessel generation from preexisting blood vessels, was found to play an important role in the progression of solid tumors. In addition, bone marrow-derived endothelial precursor cells may contribute to tumor angiogenesis. Recently angiogenesis induction was described in several hematologic neoplasms as leukemia, lymphoma, myelodysplastic syndrome and multiple myeloma (MM). Clinical angiogenesis research also termed as angiodiagnosis has established the prognostic relevance of markers of angiogenesis e.g., microvessel density and circulating levels of angiogenic peptides. Development of antiangiogenic treatment for hematologic neoplasms has recently been sparked by the success of Thalidomide (Thal) which has antiangiogenic properties in MM. Antiangiogenic treatment strategies are now being tested in clinical trials on several types of hematologic neoplasms.     

Angiogenesis in hematologic malignancies

Angiogenesis is defined as the formation of new capillaries from preexisting blood vessels and plays an important role in the progression of solid tumors. Recently a similar relationship has been described in several hematologic malignancies. Expression of the angiogenic peptides vascular endothelial growth factor (VEGF) and basic fibroblast growth factor correlates with clinical characteristics in leukemia and non-Hodgkin's-lymphoma and the serum/plasma concentrations serve as predictors of poor prognosis. Increased bone marrow microvessels in multiple myeloma (MM) are correlated with decreased overall survival. Thalidomide which has antiangiogenic effects and direct cytotoxic effects was found to be effective in MM, myelodysplastic syndrome and acute myeloid leukemia (AML). Preliminary data indicate activity of VEGF-tyrosine kinase inhibitors in AML. Clinical research is now aimed at testing antiangiogenic treatment strategies in several hematologic neoplasms as well as identifying the best candidate patients for specific approaches.     

Advances in antifungal prophylaxis and empiric therapy in patients with hematologic malignancies

Abstract: Invasive fungal infection (IFI) is associated with significant morbidity and mortality in patients with hematologic malignancies. There have been significant changes in the epidemiology and outcomes of IFI in this patient population, due in part to advances in transplant procedures, supportive care, and use of newer antifungal agents. A thorough knowledge of risk factors, potential causative organisms, and the safety and efficacy of appropriate antifungal agents is required to optimize treatment. Proper diagnosis of IFI is challenging and the correlation of delays in diagnosis and treatment with poor outcome suggest that earlier intervention may result in more effective management of high‐risk patients. Because all risks may not be equal, stratifying high‐risk patients may further help target patients most likely to benefit from prophylaxis. This review focuses on various risk factors specific to patients with hematologic malignancies and discusses the use of preemptive, empiric, and prophylactic strategies in the management of IFI in this patient population.     

Monoclonal antibodies for the treatment of hematologic malignancies: schedule and maintenance therapy

In the last decade rituximab, alemtuzumab, and gemtuzumab ozogamicin (GO) have been used to treat patients with hematologic malignancies. Their efficacy and safety are now well established. Since their preclinical development, many studies have been performed to optimize dose and schedule. Rituximab is usually given at 375 mg/m(2), a dose that shows activity and little toxicity. It is normally administered as single agent or in combination with chemotherapy to induce remission in B-cell neoplasias. Moreover, given its low toxicity and long half-life, rituximab also can be used as maintenance therapy. Alemtuzumab is administered with a schedule of 30 mg, three times per week, after an initial dose escalation in the first week, showing activity against chronic lymphocytic leukemia (B-CLL) and some T-cell neoplasias. GO is administered at a dose of 9 mg/m(2) at 2-week intervals for two doses; it is the first monoclonal antibody approved for the treatment of relapsed or refractory CD33(+) acute myeloid leukemia (AML).     

The evolving role of monoclonal antibodies and dendritic cell therapy in hematologic malignancies

The approach for treatment of hematological cancers had changed in the last decade from non-specific eradication of tumor cells by chemotherapy to more specific strategies by activation of immune system. There are number of potential targets of immune responses in patients with hematological malignancies. Some have been developed like monoclonal antibody therapy and others that have yet to be define like dendritic cell infusion. In this review, we will discuss the evolving role of monoclonal antibody therapy and donor dendritic cell infusion in mounting on immune response in hematological malignancies.