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PubMed1999

Developing dendritic cell polynucleotide vaccination for prostate cancer immunotherapy.

Immunotherapy has been successfully used to treat some human malignancies, principally melanoma and renal cell carcinoma. Genetic-based cancer immunotherapies were proposed which prime T lymphocyte recognition of unique neo-antigens arising from specific mutations. Genetic immunization (polynucleotide vaccination, DNA vaccines) is a process whereby gene therapy methods are used to create vaccines and immunotherapies. Recent findings indicate that genetic immunization works indirectly via a bone marrow derived cell, probably a type of dendritic antigen presenting cell (APC). Direct targeting of genetic vaccines to these cells may provide an efficient method for stimulating cellular and humoral immune responses to infectious agents and tumor antigens. Initial studies have provided monocytic-derived dendritic cell (DC) isolation and culture techniques, simple methods for delivering genes into these cells, and have also uncovered potential obstacles to effective cancer immunotherapy which may restrict the utility of this paradigm to a subset of patients.

Antigens, Neoplasm↗
PubMed1999

Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function.

Inadequate function of dendritic cells (DCs) in tumor-bearing hosts is one mechanism of tumor escape from immune system control and may compromise the efficacy of cancer immunotherapy. Vascular endothelial growth factor (VEGF), produced by most tumors, not only plays an important role in tumor angiogenesis but also can inhibit the maturation of DCs from hematopoietic progenitors. Here, we investigate a novel combination of antiangiogenic and immunotherapy based on this dual role of VEGF. Two s.c. mouse tumor models were used: D459 cells, expressing mutant human p53; and MethA sarcoma with point mutations in the endogenous murine p53 gene. Therapy with anti-mouse VEGF antibody (10 microg i.p. twice a week over 4 weeks) was initiated when tumors became palpable. Treatment of established tumors with anti-VEGF antibody alone did not affect the rate of tumor growth. However, anti-VEGF antibody significantly improved the number and function of lymph node and spleen DCs in these tumor-bearing animals. To investigate the possible effects of this antibody on the immunotherapy of established tumors, tumor-bearing mice were immunized with DCs pulsed with the corresponding mutation-specific p53 peptides, together with injections of anti-VEGF antibody. Therapy with peptide-pulsed DCs alone resulted in considerable slowing of tumor growth but only during the period of treatment, and tumor growth resumed after the end of the therapy. Combined treatment with peptide-pulsed DCs and anti-VEGF antibody resulted in a prolonged and much more pronounced antitumor effect. This effect was associated with the induction of significant anti-p53 CTL responses only in this group of mice. These data suggest that inhibition of VEGF may be a valuable adjuvant in the immunotherapy of cancer.

Amino Acid Sequence↗
PubMed1998

The molecular basis of cancer immunotherapy by cytotoxic T lymphocytes.

The disappointing clinical results of cancer immunotherapy of the past few decades have not diminished the optimism about the potential of the new generation of immunotherapeutic strategies towards treatment of malignant disease. Tremendous progress has been made over recent years in unveiling the molecular basis of antigen presentation and recognition by cytotoxic T lymphocytes (CTL). The molecular concepts that have emerged from these studies have led to the design of novel anticancer vaccines and CTL-based immunotherapeutics. This review is to highlight the current molecular insights of antigen presentation and CTL recognition/activation, and their impact on the rational design of therapeutic interventions that may result in protective, CTL-based antitumor immunity.

Amino Acid Sequence↗
PubMed2003

Cancer immunotherapy: the past, the present and the future.

One of the most controversial issues in immunology for over a century has been whether an effective immune response can be elicited against malignant tumours. Whether the immunology community has believed cancer immunotherapy is feasible or impossible has been largely determined by the prevailing immunological paradigms at that time. In fact, during the last 110 years it is possible to trace at least five dramatic fluctuations in attitude towards cancer immunotherapy. It now appears, however, that overwhelming evidence is available to support the view that both the innate and adaptive immune responses can recognize and eliminate tumours. On the other hand, it remains to be seen if these immune responses can be harnessed to control cancer as, at the time of diagnosis, many tumours have already been immunoselected to be highly resistant to immune elimination. Based on these observations it is argued that immunotherapy approaches, other than the generation of tumour-specific cytotoxic T lymphocytes, must be explored. Alternative strategies include recruiting tumouricidal myeloid cells into tumours, generating antiangiogenic immune responses and directing innate immunity to hypoxia-induced ligands on tumour cells.

Animals↗
PubMedDate not supplied

Normalization of idiopathic arterial hypertension following cancer immunotherapy with interleukin-2.

It is known that IL-2 cancer immunotherapy is associated with hypotension. The present study was performed to evaluate the influence of low-dose IL-2 subcutaneous therapy on blood pressure in cancer patients with idiopathic hypertension requiring hypotensive therapy. The study included 12 patients, who received IL-2 at 6 million IU/day for at least 4 weeks. Mean values of both systolic and diastolic pressure significantly decreased under IL-2 therapy, and the hypotensive agents were interrupted within 2 weeks in 10/12 patients. Moreover, 6 of them still showed normal blood pressure values without hypotensive therapy after a median follow-up of 6 months. This preliminary study would suggest that low-dose IL-2 subcutaneous therapy may normalize blood pressure values in cancer patients with idiopathic hypertension.

Aged↗
PubMed2000

Alleviating oxidative stress in cancer immunotherapy: a role for histamine?

Interleukin-2 is a remarkable activator of lymphocytes with anti-neoplastic properties such as T-cells or natural killer cells, but tumor regression only rarely occurs in interleukin-2-treated cancer patients. In this review, we focus on interactions between monocytes/macrophages and T-cells/natural killer-cells, and in particular the role of such interactions for the outcome of cancer immunotherapy with interleukin-2. We propose that interleukin-2 therapy should be supplemented with compounds that alleviate toxicity inflicted by monocyte/macrophage-derived reactive oxygen metabolites within and around tumors. The hypothesis is founded on data demonstrating that (i) functions of intratumoral lymphocytes in many human malignant tumors are inhibited by reactive oxygen metabolites, generated by neighboring monocytes/macrophages, (ii) interleukin-2 only weakly activates T-cells or natural killer cells in an environment of oxidative stress, and (iii) inhibitors of the formation of reactive oxygen metabolites or scavengers of reactive oxygen metabolites synergize with interleukin-2 to activate these lymphocyte subsets. We also review the preclinical background to the use of histamine dihydrochloride, an inhibitor of reactive oxygen metabolite formation in monocytes/macrophages, as a supplement to cancer immunotherapy with interleukin-2.

Cell Communication↗
PubMed2004

Age-dependent differences in the efficacy of cancer immunotherapy in C57BL and AKR mouse strains.

While tumor incidence increases with age, tumor growth and metastasis often proceed at a slower rate in aged organisms. The mechanisms underlying this age-related reduced tumor development may suggest therapeutic modalities appropriate for the aged. Decreased tumor aggressiveness in the old was shown to be related to altered immune response. Consequently, the aim of the present study was to assess whether cancer immunotherapy has an age-dependent effect. Only a few studies have compared cancer immunotherapy efficiency as a function of age, most showing lower inhibition in older animals. In the present study, we tested the effect of two immunomodulators, levamisole and BCG, on two tumors, B16 melanoma and AKR lymphoma, in mice of different ages. We demonstrated a higher efficiency of immunotherapy in aged as compared to young mice, particularly at low immunomodulator doses. While decreased T cell function during aging is apparently established, nonspecific immunity is more preserved or even enhanced in later life. We found an increased number of macrophages in tumors of old compared to young mice and an increase in MAC-1+ cells in old levamisole-treated compared to non-treated mice. The stronger therapeutic effect of this immunomodulator in old mice might thus be due to an increased macrophage-mediated anti-tumoral effect.

Aging↗
PubMed2005

Heat labile enterotoxin of E. coli: a potential adjuvant for transcutaneous cancer immunotherapy.

Escherichia coli heat labile enterotoxin (LT) has been shown to penetrate intact skin and to activate adaptive immunity. A nontoxic mutant, nLT, and its B subunit (LTB), have been evaluated separately for their potential use as a tool for transcutaneous delivery of antigens for cancer immunotherapy. We have shown that FITC-labeled nLT is taken up by human dendritic cells (hDC) in vitro and in mouse skin, and induces maturation and activation of hDC in vitro. hDC matured with nLT enhanced nonspecific melanoma antigen uptake and presentation to autologous CD8+ T cells. In mouse in vivo studies, nLT or LTB were applied on the skin either mixed with recombinant gp100 or genetically fused with a multiepitope polypeptide (MEP). Fused LTB-MEP induced antibody production that was dependent on LTB cell binding. We conclude that LT derivatives may be useful for the transcutaneous delivery of tumor antigens for cancer immunotherapy.

Adjuvants, Immunologic↗
PubMed2006

Functional control of regulatory T cells and cancer immunotherapy.

Regulatory T (Treg) cells induce immune tolerance by suppressing host immune responses against self- or non-self-antigens. Hence, they not only play critical roles in preventing autoimmune diseases, but also may have detrimental effects on vaccines directed to cancer and infectious diseases. Understanding the antigen specificity and functional control of Treg cells will be crucial to the development of effective cancer immunotherapy. This review will discuss different subsets of Treg cells, the factors that contribute to Treg cell generation and suppressive function, and the ability of signaling through Toll-like receptor 8 to reverse the suppressive function of Treg cells. Importantly, this TLR pathway does not depend on interaction with dendritic cells, but operates independently in Treg cells, relying on TLR8 (with MyD88 as its sole receptor-proximal adaptor) to transduce signals generated by TLR8 ligands. Linking TLR signaling to the functional control of Treg cells opens intriguing opportunities to shift the balance between CD4(+) T-helper and Treg cells, in ways that may improve the outcome of cancer immunotherapy.

Humans↗
PubMed2003

Tenofovir, COX inhibitors and zileuton during cancer immunotherapies: up-regulated TNF-alpha increases antigen driven lymphocyte proliferation.

Current attempts at active immunization of patients to their adenocarcinomas have heretofore met with a curiously little success. The carrier antigens, viral vector proteins, and other co-administered antigens typically elicit strong cell-mediated or humoral responses while the relevant cancer antigen elicits undetectable or feeble responses and often minimal if any retardation of malignant tissue growth is seen. There are exceptions but clearly more effective cancer antigen immunization strategies are needed. Adenylate cyclase, AC, catalyses the conversion of ATP to cyclic adenosine monophosphate (cAMP). Increased cAMP down regulates tumor necrosis factor-alpha, TNF, and decreased cAMP reliably up-regulates synthesis and release of TNF. TNF enhances dendritic cell (DC) maturation processes started by other stimuli. TNF promotes antigen responding CD4+ and CD8+ lymphocytes' proliferation, and suppresses suppressor T cells during primary immunization. Tenofovir is an oral antiviral drug currently used in anti-HIV treatments. It is an acyclic nucleoside analogue of adenosine monophosphate that also happens to increase TNF. The mechanism has not been established but antagonism of cAMP's inhibition of TNF is the likely path. Prostaglandin E (PGE) is a stimulatory allosteric modifier of AC and thus suppresses TNF via the resultant increase of cAMP. Since cyclooxygenase, COX, is the rate-controlling enzyme in PGE production, COX inhibitors, otherwise known as non-steroidal anti-inflammatory drugs (NSAID), increase TNF synthesis and release by depriving AC of PGE. Indomethacin, diclofenac and ketorolac are COX inhibitors that have been on the market for many years that would be well suited for use to increase TNF levels. This paper reviews the data on TNF up-regulation by tenofovir and COX inhibitors and the consequent augmented antigen driven lymphocyte proliferation secondary to increased TNF and suggests exploration of tenofovir and COX inhibitors like indomethacin, diclofenac or ketorolac in augmentation of current cancer immunotherapy attempts. Profound COX inhibition can lead to a compensatory leukotriene increase and leukotrienes have been identified as growth and survival factors in various gastrointestinal cancers. Therefore, zileuton, an orally active 5-lipooxygenase inhibitor that prevents leukotriene synthesis, should be added whenever profound COX inhibition is undertaken in cancer immunotherapies.

Adenine↗
PubMed2004

Dendritic cells: immunobiology and cancer immunotherapy.

A recent workshop on "Dendritic Cells: Biology and Therapeutic Applications," sponsored by the Juan March Foundation, brought together basic and clinical research scientists to discuss the mechanisms underlying the control of immune responses and tolerance by dendritic cells (DCs), as well as recent research in cancer immunotherapy based on DC vaccination. Particular emphasis was placed on antigen processing and presentation by DCs, C-type lectin antigen receptors, DC maturation and polarization of T cell responses, the control of immunity versus tolerance by DCs, the developmental origin of DCs, and the use of DCs in cancer immunotherapy.

Antigen Presentation↗
PubMed1999

Dendritic cells: development, function and potential use for cancer immunotherapy.

Dendritic cells (DC) are potent antigen presenting cells that are essential for the initiation of primary immune responses. They richly express MHC, costimulatory and adhesion molecules necessary for the stimulation of naive T cell populations. Dendritic cells are located at sites of antigen capture where they demonstrate phagocytic capacity and subsequently migrate to lymphatic areas for antigen presentation. Their phenotypic and functional characteristics are intimately linked to their stage of maturation. The hematopoietic development of dendritic cells is distinct and may follow several precursor pathways some closely linked to monocytes. Generation of large numbers of cells for potential clinical use has recently been accomplished through the in vitro culturing of progenitors with cytokines. The use of dendritic cell vaccines for cancer immunotherapy has emerged as an exciting new focus of investigation. Various strategies have been adopted to introduce tumor antigens into dendritic cells so that they may be more effectively presented to T cells in the context of costimulation. Animal models demonstrate that dendritic cell tumor vaccines reverse T-cell anergy and result in subsequent tumor rejection. Incorporating the expanding knowledge of dendritic cell biology into vaccine design is essential for the generation of effective immunotherapy for cancer patients.

Animals↗
PubMed2004

Cancer immunotherapy: avoiding the road to perdition.

The hypothesis that human cancers express antigens that can be specifically targeted by cell mediated immunity has become a scientifically justifiable rationale for the design and clinical testing of novel tumor-associated antigens (TAA). Although a number of TAA have been recognized and it has been suggested that they could be useful in the immunological treatment of cancer, the complexity of human beings leads us to reflect on the need to establish new criteria for validating their real applicability. Herein, we show a system level-based approach that includes morphological and molecular techniques, which is specifically required to improve the capacity to produce desired results and to allow cancer immunotherapy to re-emerge from the mist in which it is currently shrouded.

Editorial↗
PubMed2005

Cancer immunotherapy targeting Wilms' tumor gene WT1 product.

The Wilms' tumor gene WT1 is expressed at high levels in leukemic blast cells in most acute myeloid and lymphoblastic leukemias. In myelodysplastic syndrome, WT1 mRNA expression levels increase along with disease progression; thus, WT1 mRNA is a tumor marker for leukemic blast cells. WT mRNA is also expressed at high levels in various types of solid cancers, including cancers of the lung, breast, colon and pancreas. Patients with WT1-expressing tumors produce antibodies and cytotoxic T-lymphocytes against WT1 protein, indicating that WT1 protein is highly immunogenic and a promising tumor antigen. Major histocompatibility complex class I-restricted cytotoxic T-lymphocyte and class II-restricted helper epitopes of WT1 protein were identified, and clinical studies of cancer immunotherapy using these cytotoxic T-lymphocyte epitope peptides were performed without significant adverse effect and with clinical results promising enough to encourage further clinical trials. The clinical efficacy of cancer immunotherapy targeting the WT1 protein should be clarified by a large-scale clinical study.

Animals↗
PubMed2006

Vaccines targeting tumour angiogenesis--a novel strategy for cancer immunotherapy.

AIMS: To review the concept of tumour angiogenesis and anti-angiogenic therapy, limitations of recently used anti-angiogenic therapeutics; provide an up-to-date overview of the growing number of reports on vaccines targeting tumour angiogenesis; and finally discuss potential complications and future directions in the development of more potent and specific vaccines. METHODS: A literature search was carried out from PubMed for indexed articles. The most important articles were analysed and discussed. FINDINGS: The search yielded a large number of important indexed published articles that were reviewed, screened and tracked for other relevant publications. The most relevant articles, including those previously published by authors, were analysed and discussed. CONCLUSIONS: Recently, different vaccine strategies have been reported to inhibit tumour growth and metastasis by induction of specific cellular and/or humoral immunity against angiogenesis-associated antigens in pre-clinical models, suggesting effective combination of anti-angiogenesis and cancer immunotherapy. Evaluation of tumour endothelial cells and clinical phase I study of the vaccines are recently ongoing, and should give us better insight into the possibilities of this novel strategy for cancer immunotherapy.

Cancer Vaccines↗
PubMed1978

Cancer immunotherapy.

This paper briefly reviews some mechanisms of tumor immunity and the principles of cancer immunotherapy. Cellular and humoral immunity can both influence tumor cells. Most of the cells belonging to the immune system can act on neoplastic cells. T cells can kill them, macrophages inhibit their growth, and K cells through their Fc receptor also destroy antibody-coated tumor cells. Cancer patients have usually depressed cellular immune functions. The goal of immunotherapy is to amplify the immune reactions in order to destroy the tumor cells. The modalities of immunotherapy are described. They may become important as adjuvant therapy. Immunotherapy has already been successfully in skin cancers, lung cancer and acute myeloblastic leukemia.

Humans↗
PubMed2002

Monitoring and isolation of blood dendritic cells from apheresis products in healthy individuals: a platform for cancer immunotherapy.

The fundamental role of dendritic cells (DC) in initiating and directing the primary immune response is well established. Furthermore, it is now accepted that DC may be useful in new vaccination strategies for preventing certain malignant and infectious diseases. As blood DC (BDC) physiology differs from that of the DC homologues generated in vitro from monocyte precursors, it is becoming more relevant to consider BDC for therapeutic interventions. Until recently, protocols for the isolation of BDC were laborious and inefficient; therefore, their use for investigative cancer immunotherapy is not widespread. In this study, we carefully documented BDC counts, yields and subsets during apheresis (Cobe Spectra), the initial and essential procedure in creating a BDC isolation platform for cancer immunotherapy. We established that an automated software package (Version 6.0 AutoPBPC) provides an operator-independent reliable source of mononuclear cells (MNC) for BDC preparation. Further, we observed that BDC might be recovered in high yields, often greater than 100% relative to the number of circulating BDC predicted by blood volume. An average of 66 million (range, 17-179) BDC per 10-l procedure were obtained, largely satisfying the needs for immunization. Higher yields were possible on total processed blood volumes of 15 l. BDC were not activated by the isolation procedure and, more importantly, both BDC subsets (CD11c(+)CD123(low) and CD11c(-)CD123(high)) were equally represented. Finally, we established that the apheresis product could be used for antibody-based BDC immunoselection and demonstrated that fully functional BDC can be obtained by this procedure.

Adult↗