Immunotherapy Of Malignant Diseases Research Articles

Prospects for the use of small interfering RNAs as inhibitors of immune checkpoints for immunotherapy in oncology

Immune therapy is one of the most promising areas of cancer treatment. It is aimed at a cascade of processes responsible for the antitumor immune response. The involved regulatory mechanisms become targets for various therapeutic approaches aimed at restoring the impaired functions of immune cells that eliminate cancer cells. The ability of malignant cells to affect receptors of immune checkpoints is one of the most important mechanisms for suppressing antitumor immunity. The development of immune check-point inhibitors (ICIs) based on monoclonal antibodies, as well as the methods of adoptive cell therapy (ACT), are a breakthrough in the immunotherapy of malignant diseases, but it carries a number of limitations such as insufficient efficiency, safety and cost-effectiveness. The use of RNA interference technologies opens up prospects for the development of fundamentally new class of ICIs and, as a consequence, the development of more efficient ACT methods. This review presents the main problems and prospects of the use of small interfering RNA (siRNA) as the ICIs are highlighted in order to optimize modern AKT approaches

Basic principles of immunotherapy

Immunotherapy for malignant diseases is defined as asystematic therapeutic approach that aims to target the individual's immune system to prevent the development of malignancies or to combat existing tumors. Nowadays, this includes various therapeutic approaches, such as immune checkpoint inhibitors, BiTEs (bispecific T‑cell engagers), CAR T‑cells (CAR: chimeric antigen receptors) and oncolytic viruses, which have not only different mechanisms of action and points of attack, but also have very different efficiencies in the treatment of solid and hematological malignancies. These approaches undoubtedly enrich the therapeutic portfolio in oncology-in palliative systematic therapy and also in the interaction with operative and ablative local therapeutic approaches.

The Highs and Lows of Cannabis in Cancer Treatment and Bone Marrow Transplantation.

In the last decade, we have observed an increased public and scientific interest in the clinical applications of medical cannabis. Currently, the application of cannabinoids in cancer patients is mainly due to their analgesic and anti-emetic effects. The direct effects of phyto-cannabinoids on cancer cells are under intensive research, and the data remain somewhat inconsistent. Although anti-proliferative properties were observed in vitro, conclusive data from animal models and clinical trials are lacking. Since immunotherapy of malignant diseases and bone marrow transplantation are integral approaches in hemato-oncology, the immuno-modulatory characteristic of cannabinoids is a fundamental aspect for consideration. The effect of cannabinoids on the immune system is presently under investigation, and some evidence for its immuno-regulatory properties has been shown. In addition, the interaction of cannabinoids and classical cytotoxic agents is a subject for further investigation. Here we discuss the current knowledge of cannabinoid-based treatments in preclinical models and the limited data in oncological patients. Particularly, we address the possible contradiction between the direct anti-tumor and the immune-modulatory effects of cannabinoids. Better understanding of the mechanism of cannabinoids influence is essential to design therapies that will allow cannabinoids to be incorporated into the clinic.

Of Chimeric Antigen Receptors and Antibodies: OX40 and 41BB Costimulation Sharpen Up T Cell-Based Immunotherapy of Cancer

Recent success in immunotherapy of malignant diseases has generated a considerable level of interest in controlling cancer by the immune system in the long term. To activate T cells in the immune ‑ suppressive tumor environment and to maintain an antitumor response, adequate costimulation is required along with a strong T cell receptor-peptide MHC interaction. For this purpose, stimulation by TNF receptor family members, OX40 and 41BB, is currently evaluated in early ‑ phase trials, mediated by agonistic anti‑ bodies or, alternatively, delivered to engineered T cells by a recombinant chimeric antigen recep‑ tor. We here briefly discuss both strategies and their clinical perspectives in the immunotherapy of cancer.

Thermal Stability of siRNA Modulates Aptamer- conjugated siRNA Inhibition

Oligonucleotide aptamer-mediated in vivo cell targeting of small interfering RNAs (siRNAs) is emerging as a useful approach to enhance the efficacy and reduce the adverse effects resulting from siRNA-mediated genetic interference. A current main impediment in aptamer-mediated siRNA targeting is that the activity of the siRNA is often compromised when conjugated to an aptamer, often requiring labor intensive and time consuming design and testing of multiple configurations to identify a conjugate in which the siRNA activity has not been significantly reduced. Here, we show that the thermal stability of the siRNA is an important parameter of siRNA activity in its conjugated form, and that siRNAs with lower melting temperature (Tm) are not or are minimally affected when conjugated to the 3′ end of 2′F-pyrimidine-modified aptamers. In addition, the configuration of the aptamer-siRNA conjugate retains activity comparable with the free siRNA duplex when the passenger strand is co-transcribed with the aptamer and 3′ overhangs on the passenger strand are removed. The approach described in this paper significantly reduces the time and effort necessary to screening siRNA sequences that retain biological activity upon aptamer conjugation, facilitating the process of identifying candidate aptamer-siRNA conjugates suitable for in vivo testing.

Immunotherapy of malignant disease with tumor antigen-specific monoclonal antibodies.

A few tumor antigen (TA)-specific monoclonal antibodies (mAb) have been approved by the Food and Drug Administration for the treatment of several major malignant diseases and are commercially available. Once in the clinic, mAbs have an average success rate of approximately 30% and are well tolerated. These results have changed the face of cancer therapy, bringing us closer to more specific and more effective biological therapy of cancer. The challenge facing tumor immunologists at present is represented by the identification of the mechanism(s) underlying the patients' differential clinical response to mAb-based immunotherapy. This information is expected to lead to the development of criteria to select patients to be treated with mAb-based immunotherapy. In the past, in vitro and in vivo evidence has shown that TA-specific mAbs can mediate their therapeutic effect by inducing tumor cell apoptosis, inhibiting the targeted antigen function, blocking tumor cell signaling, and/or mediating complement- or cell-dependent lysis of tumor cells. More recent evidence suggests that TA-specific mAb can induce TA-specific cytotoxic T-cell responses by enhancing TA uptake by dendritic cells and cross-priming of T cells. In this review, we briefly summarize the TA-specific mAbs that have received Food and Drug Administration approval. Next, we review the potential mechanisms underlying the therapeutic efficacy of TA-specific mAbs with emphasis on the induction of TA-specific cellular immune responses and their potential to contribute to the clinical efficacy of TA-specific mAb-based immunotherapy. Lastly, we discuss the potential negative effect of immune escape mechanisms on the clinical efficacy of TA-specific mAb-based immunotherapy.

Induction of clinical and immunological responses in patients with metastatic renal cell carcinoma after vaccinations with peptide pulsed dendritic cells

2507 Background: Pulsing of dendritic cells (DC) with tumor antigens and their applications in immunotherapy of malignant diseases has been shown effective. We analyzed the clinical and immunological responses in patients with metastatic renal cell carcinoma (RCC) using autologous mature monocyte derived DC. Methods: DC were pulsed with two HLA-A2 binding peptides deduced from MUC1. For the recruiting and activation of CD4+ T cells DC were further incubated with the PAN-DR binding peptide PADRE. Vaccinations were performed sc every two weeks four times and repeated monthly until tumor progression. After the fifth DC injection patients additionally received 3 injections/week of low dose IL-2 (1Mio IE/m2) sc. The enhancement of T cell precursor was monitored using IFN-γ ELISPOT and 51Cr-release assays. Furthermore, we tested the ability of PBMC to produce cytokines in response to challenge with vaccine-related epitopes by quantitative real-time PCR. Results: 20 patients were included in this study. In 6 patients regression of metastases was induced with 4 objective responses (OR) (1 CR, 3 PR) and 2 mixed responses. 4 patients had a stabilization of the disease. MUC1 peptide specific T cell responses in vivo were detected in the PBMC of all patients with OR. These in vivo induced T cells were able to recognize target cells pulsed with the cognate peptide or matched allogeneic tumor cells (A498) constitutively expressing MUC1 in an antigen and HLA restricted manner after in vitro restimulation. Interestingly, in patients responding to the treatment, T cell responses to antigens not used for vaccinations like adipophilin, telomerase or OFA could be detected indicating that epitope spreading might occur. Proliferative responses to the PADRE peptide were detectable in 11 out of 16 analyzed patients, in some patients already after the first 2 vaccinations. The treatment was well tolerated with no severe side effects. Conclusions: This study demonstrates that peptide pulsed DC can be effective in the treatment of metastatic RCC. Furthermore, analysis of epitope spreading in vaccinated patients might be a usefull parameter to correlate clinical and immunological responses. No significant financial relationships to disclose.

Targeting of tumor cells by lymphocytes engineered to express chimeric receptor genes.

Adoptive cellular immunotherapy of cancer has been limited to date mostly due to the poor immunogenicity of tumor cells, the immunocompromised status of cancer patients in advanced stages of their disease, and difficulties in raising sufficient numbers of autologous tumor-specific T lymphocytes. On the other hand, the slow tumor penetration and short half-life of exogenously administered tumor-specific monoclonal antibodies have provided major obstacles for an effective destruction of tumor cells by the humoral effector arm of the immune system. Attempts to improve the efficacy of adoptive cellular cancer immunotherapy have led to the development of novel strategies that combine advantages of T cell-based (i.e., efficient tumor penetration, cytokine release and cytotoxicity) and antibody-based (high specificity for tumor-associated antigens) immunotherapy by grafting cytotoxic T lymphocytes (CTLs) with chimeric receptors composed of antibody fragments (which recognize tumor-cell antigens) and a cellular activation motif. Antigen recognition is therefore not restricted by major histocompatibility genes, as the physiological T-cell receptor, but rather is directed to native cell surface structures. Since the requirements of major histocompatibility complex (MHC) restriction in the interaction of effector cells with target cells are bypassed, the tumor cell-binding of CTLs grafted with chimeric receptors is not affected by down-regulation of HLA class I antigens and by defects in the antigen-processing machinery. Ligand binding by the chimeric receptor triggers phosphorylation of immunoglobulin tyrosine activation motifs (ITAMs) in the cytoplasmic region of the molecule and this activates a signaling cascade that is required for the induction of cytotoxicity, cytokine secretion and proliferation. Here, the authors discuss the potential of lymphocytes grafted with chimeric antigen receptors in the immunotherapy of malignant disease.

Immunotherapy of malignant diseases--developments and prospects

Conventional strategies in cancer management, such as surgery, chemotherapy or radiation therapy are effective treatments for most tumors, but often fail in achieving complete remission. The reason for this failure is, that single tumor cells have already spread to various organs by the time the tumor is diagnosed and lead, often years later, to the development of metastases. Therefore it is insufficient to treat the tumor solely at its point of origin; tumor dissemination should be prevented too. Tumor immunotherapy is one of the treatment options that target tumor propagation. In cancer immunotherapy, the immune system of the patient is influenced such, that the tumor is recognized and attacked by the body's defences. Since these therapies specifically aim at tumor cells, they cause fewer adverse events and improve the quality of life of patients. This review outlines previous developments in cancer immunotherapies with a focus on active immunotherapies and vaccination strategies.

Anti-p53-directed immunotherapy of malignant disease.

Mutation and aberrant expression of the p53 tumour suppressor protein are the most frequent molecular alterations in human malignancy. Peptides derived from the p53 protein and presented by major histocompatibility complex molecules for T-cell recognition could serve as universal tumour-associated antigens for cancer immunotherapy. Because p53 normally functions as a ubiquitously expressed self-protein, controlling cell-cycle progression and apoptosis, it also represents a paradigm target molecule for tumour-reactive yet self-antigen-specific T cells. Tailoring p53-based cancer immunotherapy thus requires both interference with p53-specific self-tolerance and induction of the entire repertoire of p53-reactive T cells. Transferring selected T-cell receptor genes into human T cells offers a novel and appealing strategy to meet these requirements.

Immunotherapy of malignant diseases with peptide pulsed dendritic cells

Immunotherapy of malignant diseases with peptide pulsed dendritic cells

Immunotherapy of malignant diseases with peptide pulsed dendritic cells

Immunotherapy of malignant diseases with peptide pulsed dendritic cells

Grafting T cells with tumor specificity: the chimeric receptor strategy for use in immunotherapy of malignant diseases.

Appreciation of the complementary nature of T-cell- and antibody-based immunotherapy stimulated interest in developing approaches that combine their advantages and minimize their limitations. A recent strategy is based on permanent grafting of cytotoxic T cells with a recombinant chimeric receptor designed for cellular targeting with antibody-like specificity and for cellular activation after binding to antigen. The extracellular moiety of the chimeric receptor consists of an antigen-binding domain derived from an antibody, the intracellular moiety consists of a signalling domain for cellular activation, thus combining the broad specificity of antibody-based and major histocompatibility complex (MHC)-independent recognition with the potent antitumor activity of T cells. By generation of specific T cells against any antigen for which a suitable monoclonal antibody (MAb) exists, the chimeric receptor strategy has the potential to extend the adoptive immunotherapy for a variety of malignant and infectious diseases. However, little is known about the optimized design of this type of receptor. We here discuss our results in grafting T cells with chimeric receptors of various design with regard to efficient cellular activation.

Purification by affinity chromatography with anti-idiotypic monoclonal antibodies of immunoreactive monoclonal antibodies following labeling with 188Re.

Because of its high energy beta emissions and imageable gamma emissions, 188Re represents an attractive isotope to radiolabel monoclonal antibodies (mAb) recognizing human tumor-associated antigens for radioimaging and radioimmunotherapy in patients with malignant diseases. The application of 188Re is, however, hindered by the denaturation of a sizable proportion of antibody molecules during the labeling process. To overcome this problem, we have combined radiolabeling of mAb with 188Re with purification of immunoreactive 188Re-labeled mAb by affinity chromatography over columns of anti-idiotypic (anti-id) mAb. Utilizing the anti-high-molecular-weight melanoma-associated antigen (HMW-MAA) mAb 763.74 as a model system, we found that the immunoreactivity of mAb 763.74 labeled with 188Re to a specific activity of 1 mCi/mg increased from about 50% to at least 80% following passage over columns of immobilized anti-id mAb. Moreover, between 90-100% of immunoreactive mAb contained in radiolabeled preparations could be recovered from anti-id mAb columns. These results indicate that the procedure we have described may facilitate the application of 188Re for immunoscintigraphy and immunotherapy of malignant diseases.

Thyroid Functions in Patients Treated with Interleukin-2 and Lymphokine-activated Killer Cells

Treatment of malignant disease with interleukin-2 and lymphokine-activated killer cells activates autoreactive T lymphocytes, stimulates release of cytokines and induces expression of HLA-class II antigens by tumour cells. We studied eight patients with hepatocellular carcinoma treated with a total of 16 courses of recombinant human interleukin-2 and lymphokine-activated killer cells and observed them for features of autoimmune thyroid disease. During the course of treatment there were significant decreases in total serum T4 and T3 and free thyroxine levels, but no change in TSH levels when all patients were analysed as a group. This was due to a number of factors including suppression of thyroid hormone release, haemodilution during interleukin-2 infusion and actual removal of thyroid hormones from the circulation during leukapheresis. Thyroid hormones returned to normal levels during resting period. One patient subsequently developed compensated hypothyroidism (normal total T4, total T3 and free T4 but elevated TSH) and four patients had features of 'sick euthyroid syndrome' (low total T4, total T3 or free T4 but normal TSH). None of the patients studied developed antibodies to thyroglobulin or microsomes. In contrast, no abnormality of thyroid function was seen in any of the nine subjects who received no active treatment. In conclusion, thyroid dysfunction was associated with immunotherapy of malignant disease with interleukin-2 and lymphokine-activated killer cells. This may arise from direct hormonal effects of the cytokines on thyroid hormone production.

The Diagnostic and Therapeutic Use of Monoclonal Antibodies in Colorectal Cancer

Preliminary trials have illustrated that monoclonal antibodies can be administered safely, tumor binding can be achieved, and sensitive radioimaging may be possible. Additionally, clinical responses in patients with colorectal carcinoma can occur. The limitations of murine monoclonal therapy are now being addressed and in time will be overcome. Monoclonal antibodies offer great promise in the diagnosis and therapy of malignant disease. Further investigation using innovative approaches and in combination with other therapies may help to reach this goal.

The immunotherapeutic effect of anti Lyt-1 antibodies on local and metastatic tumor growth.

Monoclonal antibodies against the T cell differentiation antigen Lyt-1 were effective in the therapy of the murine Lewis lung carcinoma (3LL). A possible mechanism whereby anti Lyt-1 antibodies directly effect the tumor cells was unlikely because 3LL cells lack the Lyt-1 antigen. In addition, the curative effect of anti Lyt-1 antibodies was abrogated in mice depleted of T cells, supporting a mechanism whereby host Lyt-1+ cells were involved in tumor therapy. Treatment with anti Lyt-1 antibodies was not accompanied by depletion of Lyt-1+ cells from lymphoid organs, indicating that the administered antibodies altered Lyt-1+ cell functions without effecting their frequency. In view of the in vitro enhancing effects of anti Lyt-1 antibodies on responses, it is suggested that the potentiation of Lyt-1+ cell activity by passively administered anti Lyt-1 antibodies results in tumor rejection.

Announcement

Abstract Meeting of the International Association for Chemo- and Immunotherapy and the International Association for the Promotion of Clinical and Experimental Research in Medicine. The Congress on Immunotherapy of Malignant Diseases will meet in Vienna, Austria on November 9 and 10, 1977. The International Symposium on Cell Separation and Cryobiology will meet in Vienna, Austria on November 10 to 12, 1977; For information please write to: Dr. H. Rainer, c/o Wiener Medizinische Akademie, Alser Strasse 4, A-1090 Wien, Austria, Telephone (0222) 42 13 83, Cable: Medacad, Wien. Preliminary Notice: Course on Clinical Immunology. A course on Clinical Immunology under the auspices of the British Society for Immunology is to be held in Edinburgh, March 21–25, 1977, in Room 8, William Robertson Building, George Square. The object of this 5-day course is to provide a synposis of modern basic immunology as applied to clinical medicine. The registration fee up to 31st January, 1977 is ℒ45 (excluding accommodation and meals) and ℒ50 thereafter.

Virology, immunology, and immunotherapy of malignant disease.

Virology, immunology, and immunotherapy of malignant disease.

Virology, immunology, and immunotherapy of malignant disease

Virology, immunology, and immunotherapy of malignant disease