CD137 (4-1BB) and T-Lymphocyte Exhaustion.

CD137 (4-1BB) costimulation results in the potent activation of antitumor T lymphocytes and elicits antitumor efficacy that is synergistic with anti-PD(L)1 checkpoint inhibitors, especially when using bispecific constructs. Emerging experimental evidence indicates that 4-1BB ligation prevents and may revert T-cell exhaustion. See related article by Jeon et al.

Low-Dose Ionizing γ-Radiation Elicits the Extrusion of Neutrophil Extracellular Traps.

Purpose: Patients with cancer frequently undergo radiotherapy in their clinical management with unintended irradiation of blood vessels and copiously irrigated organs in which polymorphonuclear leukocytes circulate. Following the observation that such low doses of ionizing radiation are able to induce neutrophils to extrude neutrophil extracellular traps (NET), we have investigated the mechanisms, consequences, and occurrence of such phenomena in patients undergoing radiotherapy.

Experimental Design: NETosis was analyzed in cultures of neutrophils isolated from healthy donors, patients with cancer, and cancer-bearing mice under confocal microscopy.

Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-β antagonists.

Intratumoral immunotherapy strategies for cancer based on interleukin-12 (IL-12)-encoding cDNA and mRNA are under clinical development in combination with anti-PD-(L)1 monoclonal antibodies. To make the most of these approaches, we have constructed chimeric mRNAs encoding single-chain IL-12 fused to single-chain fragment variable (scFv) antibodies that bind to transforming growth factor β (TGF-β) and CD137 (4-1BB). Several neutralizing TGF-β agents and CD137 agonists are also undergoing early-phase clinical trials.

Intratumoral injection of IL-12-encoding mRNA targeted to CSFR1 and PD-L1 exerts potent anti-tumor effects without substantial systemic exposure.

IL-12 is a potent cytokine for cancer immunotherapy. However, its systemic delivery as a recombinant protein has shown unacceptable toxicity in the clinic. Currently, the intratumoral injection of IL-12-encoding mRNA or DNA to avoid such side effects is being evaluated in clinical trials.

Intracavitary adoptive transfer of IL-12 mRNA-engineered tumor-specific CD8 T cells eradicates peritoneal metastases in mouse models.

Previous studies have shown that local delivery of tumor antigen-specific CD8 T lymphocytes engineered to transiently express single-chain IL-12 mRNA is highly efficacious. Peritoneal dissemination of cancer is a frequent and often fatal patient condition usually diagnosed when the tumor burden is too large and hence uncontrollable with current treatment options. In this study, we have modeled intracavitary adoptive T cell therapy with OVA-specific OT-I T cells electroporated with IL-12 mRNA to treat B16-OVA and PANC02-OVA tumor spread in the peritoneal cavity.

Intratumoral Gene Transfer of mRNAs Encoding IL12 in Combination with Decoy-Resistant IL18 Improves Local and Systemic Antitumor Immunity.

IL12-based local gene therapy of cancer constitutes an active area of clinical research using plasmids, mRNAs, and viral vectors. To improve antitumor effects, we have experimentally tested the combination of mRNA constructs encoding IL12 and IL18. Moreover, we have used a form of IL18 [decoy-resistant IL18 (DR-18)] which has preserved bioactivity but does not bind to the IL18 binding protein decoy receptor.

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.

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.

Intratumoural administration of dendritic cells: hostile environment and help by gene therapy.

Like paratroopers in special operations, dendritic cells (DCs) can be deployed behind the enemy borders of malignant tissue to ignite an antitumour immune response. 'Cross-priming T cell responses' is the code name for their mission, which consists of taking up antigen from transformed cells or their debris, migrating to lymphoid tissue ferrying the antigenic cargo, and meeting specific T cells. This must be accomplished in such an immunogenic manner that specific T lymphocytes would mount a robust enough response as to fully reject the malignancy.

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.

Effective tumor immunotherapy: start the engine, release the brakes, step on the gas pedal,...and get ready to face autoimmunity.

Cellular immune responses can destroy cancer cells, achieving the cure of experimental malignancies. An expanding wealth of knowledge on the molecular basis of how to prime and amplify a T cell response has fueled a number of strategies successful at treating established tumors (rather than merely preventing tumor grafting). The most efficacious approaches operate at different stages, including: 1) priming the immune response using tumor antigen-expressing dendritic cells or tumor cells transfected with genes that render them immunogenic, 2) sustaining and amplifying immunity using agonistic monoclonal antibodies against costimulatory molecules or immune-potentiating cytokines, and 3) eliminating mechanisms that self-regulate the strength of the immune response, such as inhibitory receptors or regulatory T cells.