19 research outputs found
Potentiation of therapeutic immune responses against malignancies with monoclonal antibodies
Immunotherapeutic monoclonal antibodies (mAbs) can be
defined as those that exert their functions by tampering with
immune system cell molecules, causing an enhancement of
antitumor immune responses. Some of these antibodies are
agonistic ligands for surface receptors involved in the activation
of lymphocytes and/or antigen-presenting cells, whereas
others are antagonists of mechanisms that normally limit the
intensity of immune reactions. Several mAbs of this category
have been described to display in vivo antitumor activity in
mouse models. Only anti–CTLA-4 (CD152) mAb has entered
clinical trials, but the preclinical effects described for anti-
CD40, anti-CD137 (4-1BB), anti-CD102 (intercellular adhesion
molecule-2), and regulatory T cell-depleting mAbs should lead
to their prompt clinical development. Their use in combination
with immunizations against tumor antigens has been reported
to be endowed with synergistic properties. This new group of
antitumor agents holds promise for at least additive effects with
conventional therapies of cancer and deserves intensive translational
research
The immunotherapy potential of agonistic anti-CD137 (4-1BB) monoclonal antibodies for malignancies and chronic viral diseases
Pharmacological intervention on the immune system to
achieve more intense lymphocyte responses has potential application
in tumour immunology and in the treatment of chronic
viral diseases. Immunostimulating monoclonal antibodies are
defined as a new family of drugs that augment cellular immune
responses. They interact as artificial ligands with functional proteins
of the immune system, either activating or inhibiting their
functions. There are humanized monoclonal antibodies directed
to the inhibitory receptor CD152 (CTLA-4) that are being tested
in clinical trials with evidence of antitumoural activity. As a
drawback, anti-CTLA-4 monoclonal antibodies induce severe
autoimmunity reactions in a fraction of the patients. Anti-CD137
monoclonal antibodies have the ability to induce potent
immune responses mainly mediated by cytotoxic lymphocytes
with the result of frequent complete tumour eradications in
mice. Comparative studies in experimental models indicate that
the antitumour activity of anti-CD137 monoclonal antibodies is
superior to that of anti-CD152. CD137 (4-1BB) is a leukocyte differentiation
antigen selectively expressed on the surface of activated
T and NK lymphocytes, as well as on dendritic cells. Monoclonal
antibodies acting as artificial stimulatory ligands of this
receptor (anti-CD137 agonist antibodies) enhance cellular antitumoural
and antiviral immunity in a variety of mouse models.
Paradoxically, anti-CD137 monoclonal antibodies are therapeutic
or preventive in the course of model autoimmune diseases in
mice. In light of these experimental results, a number of
research groups have humanized antibodies against human
CD137 and early clinical trials are about to start
Low surface expression of B7-1 (CD80) is an immunoescape mechanism of colon carcinoma
Artificially enforced expression of CD80 (B7-1) and CD86 (B7-2) on tumor cells renders them more immunogenic by triggering the CD28 receptor on T cells. The enigma is that such B7s interact with much higher affinity with CTLA-4 (CD152), an inhibitory receptor expressed by activated T cells. We show that unmutated CD80 is spontaneously expressed at low levels by mouse colon carcinoma cell lines and other transplantable tumor cell lines of various tissue origins. Silencing of CD80 by interfering RNA led to loss of tumorigenicity of CT26 colon carcinoma in immunocompetent mice, but not in immunodeficient Rag-/- mice. CT26 tumor cells bind CTLA-4Ig, but much more faintly with a similar CD28Ig chimeric protein, thus providing an explanation for the dominant inhibitory effects on tumor immunity displayed by CD80 at that expression level. Interestingly, CD80-negative tumor cell lines such as MC38 colon carcinoma and B16 melanoma express CD80 at dim levels during in vivo growth in syngeneic mice. Therefore, low CD80 surface expression seems to give an advantage to cancer cells against the immune system. Our findings are similar with the inhibitory role described for the dim CD80 expression on immature dendritic cells, providing an explanation for the low levels of CD80 expression described in various human malignancies
Dendritic cells delivered inside human carcinomas are sequestered by interleukin-8
In the course of a clinical trial consisting of intratumoral injections of dendritic cells (DCs) transfected to produce interleukin-12, the use of (111)In-labeled tracing doses of DCs showed that most DCs remained inside tumor tissue, instead of migrating out. In search for factors that could explain this retention, it was found that tumors from patients suffering hepatocellular carcinoma, colorectal or pancreatic cancer were producing IL-8 and that this chemokine attracted monocyte-derived dendritic cells that uniformly express both IL-8 receptors CXCR1 and CXCR2. Accordingly, neutralizing antihuman IL-8 monoclonal antibodies blocked the chemotactic attraction of DCs by recombinant IL-8, as well as by the serum of the patients or culture supernatants of human colorectal carcinomas. In addition, tissue culture supernatants of colon carcinoma cells inhibited DC migration induced by MIP-3beta in an IL-8-dependent fashion. IL-8 production in malignant tissue and the responsiveness of DCs to IL-8 are a likely explanation of the clinical images, which suggest retention of DCs inside human malignant lesions. Impairment of DC migration toward lymphoid tissue could be involved in cancer immune evasion
Recombinant adenoviral vectors turn on the type I interferon system without inhibition of transgene expression and viral replication
Recombinant adenovirus administration gives rise to transgene-independent effects caused by the ability of the vector to activate innate immunity mechanisms. We show that recombinant adenoviruses encoding reporter genes trigger IFN-alpha and IFN-beta transcription from both plasmacytoid and myeloid mouse dendritic cells. Interestingly, IFN-beta and IFN-alpha5 are the predominant transcribed type I IFN genes both in vitro and in vivo. In human peripheral blood leukocytes type I IFNs are induced by adenoviral vectors, with a preponderance of IFN-beta together with IFN-alpha1 and IFN-alpha5 subtypes. Accordingly, functional type I IFN is readily detected in serum samples from human cancer patients who have been treated intratumorally with a recombinant adenovirus encoding thymidine kinase. Despite inducing functional IFN-alpha release in both mice and humans, gene transfer by recombinant adenoviruses is not interfered with by type I IFNs either in vitro or in vivo. Moreover, IFN-alpha does not impair replication of wild-type adenovirus. As a consequence, cancer gene therapy strategies with defective or replicative-competent adenoviruses are not expected to be hampered by the effect of the type I IFNs induced by the vector itself. However, type I IFN might modulate antitumor and antiadenoviral immune responses and thus influence the outcome of gene immunotherapy
Multi-layered action mechanisms of CD137 (4-1BB)-targeted immunotherapies
CD137 (also known as 4-1BB) is a surface co-stimulatory glycoprotein originally described as present on activated T lymphocytes. Artificial stimulation of this molecule with monoclonal antibodies or other agonist moieties therapeutically augments the cellular immune response against tumors, regardless of the absence of CD137 on tumor cells. These pharmacological agents, when administered systemically, surpass the immune effects of the membrane-bound natural ligand (CD137 or 4-1BB ligand), the activity of which is confined to cell-to-cell interactions. Greater affinity and broader distribution of the CD137 pharmacological agonists cause much more intense receptor crosslinking and stronger intracellular signals than the natural ligand. Target engagement on a variety of immune cell types such as T, natural killer and dendritic cells and on tumor vessels could switch on multiple mechanisms of action. As an agonist, anti-CD137 monoclonal antibody has entered Phase II clinical trials; elucidation of the mechanisms behind the antitumor efficacy requires further research in mice and patients to understand and rationally combine these new treatments
Cellular liaisons of natural killer lymphocytes in immunology and immunotherapy of cancer.
There is compelling evidence for the role of natural killer (NK) cells in tumor immunosurveillance and their beneficial effects on many experimentally successful immunotherapy strategies. NK cells mediate cell contact-dependent cellular cytotoxicity and produce pro-inflammatory cytokines, but do not rearrange antigen receptors. Their activation depends on various germline-encoded receptors, including CD16, which mediates recognition of antibody-coated target cells. NK cytotoxicity is checked by a repertoire of inhibitory receptors that scan adequate expression of major histocompatibility complex class I molecules on the potential target cell. Functional cross-talk of NK and dendritic cells suggests a critical role for NK cells in the initiation and regulation of cellular immunity. Considerable knowledge on the molecular basis of NK recognition/activation contrasts with a lack of successful translational research on these matters. However, there is plenty of opportunity for targeted intervention of inhibitory/activatory surface receptors and for adoptive cell therapy with autologous or allogeneic NK cells