Immunology and Biotherapies

Abstract

Scientific insights into the human immune system have recently led to unprecedented breakthroughs in immunotherapy. In the twenty-first century, drugs and cell-based therapies developed to bolster humoral and T cell immunity represent an established and growing component of cancer therapeutics. Although natural killer (NK) cells have long been known to have advantages over T cells in terms of their capacity to induce antigen-independent host immune responses against malignancies, their therapeutic potential in the clinic has been largely unexplored. A growing number of scientific discoveries into pathways that both activate and suppress NK cell function, as well as methods to sensitize tumours to NK cell cytotoxicity, have led to the development of numerous pharmacological and genetic methods to enhance NK cell antitumour immunity. These findings, as well as advances in our ability to expand NK cells ex vivoand manipulate their capacity to home to the tumour, have now provided investigators with a variety of new methods and strategies to harness the full potential of NK cell-based cancer immunotherapy in the clinic.

Via Krishan Maggon

Highlights

 

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T cells undergo metabolic remodeling to support their function.

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Metabolic pathways impact on T cell differentiation decisions and function in the periphery.

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Manipulating metabolic microenvironments may enhance T cell function in cancer.

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Metabolic pathways could be targeted for the treatment of human disease.

 

In the past several years a wealth of evidence has emerged illustrating how metabolism supports many aspects of T cell biology, as well as how metabolic changes drive T cell differentiation and fate. We outline developing principles in the regulation of T cell metabolism, and discuss how these processes are affected in settings of inflammation and cancer. In this context we discuss how metabolic pathways might be manipulated for the treatment of human disease, including how metabolism may be targeted to prevent T cell dysfunction in inhospitable microenvironments, to generate more effective adoptive cellular immunotherapies in cancer, and to direct T cell differentiation and function towards non-pathogenic phenotypes in settings of autoimmunity.

Via Krishan Maggon

Abstract

The concept of immunotherapy as a modality to treat cancer was recognized more than a hundred years ago. High-dose interleukin-2 (IL-2) was one of the first agents to demonstrate that the host's immune system can be harnessed to treat even advanced malignancy, as was shown in a subset of patients with renal cancer and melanoma. Many tumours are immunogenic and provoke a host immune response, but this is normally not sufficient to overcome host tolerance. For decades now, researchers have tried various methods to enhance host immunological responses, such as the use of non-specific immunotherapeutic cytokines, tumour vaccines, adoptive immunotherapy and the use of monoclonal antibodies against a wide variety of molecules. This review discusses the principles of the various types of immune therapy and focuses on some of the recent developments and successes in treatment. The article concentrates on the applications of immunotherapy in solid tumours, though it has immense value in haematological cancers.

Via Krishan Maggon

The better understanding of the mechanism in which
the immune system responds to the developing cancer provided the outcome in a
new era in cancer immunotherapy.

Via Krishan Maggon

Atara Biotherapeutics, Inc. (Nasdaq:ATRA) today announced that its collaborative partner, Memorial Sloan Kettering Cancer Center (MSK) has received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) for Atara's optioned cytotoxic T lymphocytes activated against Epstein-Barr Virus (EBV-CTL) in the treatment of patients with rituximab-refractory, EBV-associated lymphoproliferative disease (EBV-LPD), a type of malignancy occurring after allogeneic hematopoietic cell transplantation (HCT). Allogeneic HCT is also commonly called a bone marrow transplant. - 

 

The T-cell collaboration with MSK consists of three types of CTLs, each focusing on targets involved in cancers and serious infections. Using these cells, the power of the immune system can be employed to attack cancer cells and cells infected with certain viruses. T-cells may be effective even after failure of multiple other agents, and may avoid the toxicities of current treatments in patients with cancers and serious viral infections. CMV-CTLs and EBV-CTLs are currently in Phase 2 clinical trials and WT1-CTLs are currently in Phase 1 clinical studies.

 

The EBV-, CMV- and WT1-targeted T-cell product candidates share a common technology in which third-party donor-derived white blood cells are collected via leukapheresis (white blood cell collection) and are then enriched for T-cells. The T-cells are exposed to certain antigens (proteins that are recognized and attacked by the immune system), and the resulting activated T-cells are characterized and stored for future therapeutic use in a partially human leukocyte antigen, or HLA, matched patient. MSK has developed banks of these off-the-shelf, target-specific T-cell product candidates suitable for investigational use in patients with a wide range of HLA types.

Via Krishan Maggon

Cancer immunotherapy utilizing Vγ9Vδ2 T cells has been developed over the past decade. A large number of clinical trials have been conducted on various types of solid tumors as well as hematological malignancies. Vγ9Vδ2 T cell-based immunotherapy can be classified into two categories based on the methods of activation and expansion of these cells. Although the in vivo expansion of Vγ9Vδ2 T cells by phosphoantigens or nitrogen-containing bisphosphonates (N-bis) has been translated to early-phase clinical trials, in which the safety of the treatment was confirmed, problems such as activation-induced Vγ9Vδ2 T cell anergy and a decrease in the number of peripheral blood Vγ9Vδ2 T cells after infusion of these stimulants have not yet been solved. In addition, it is difficult to ex vivo expand Vγ9Vδ2 T cells from advanced cancer patients with decreased initial numbers of peripheral blood Vγ9Vδ2 T cells. In this article, we review the clinical studies and reports targeting Vγ9Vδ2 T cells and discuss the development and improvement of Vγ9Vδ2 T cell-based cancer immunotherapy.

Via Krishan Maggon

Ektomun® is a member of the highly innovative, validated family of Triomab® antibodies. It combines the halves of two distinct full-size antibodies, a GD2-specific mouse antibody and a T -cell specific rat antibody, in one molecule.

 

GD2 is a clinically validated tumor target opening many potential applications for ektomun®. It is broadly present in tumors of neuroectodermal origin, including small cell lung cancer (SCLC), melanoma, neuroblastoma and glioblastoma. In healthy tissues, however, GD2 expression is strictly limited to very few, distinct cell types.

 

Due to its trifunctional design, ektomun® can simultaneously bind to GD2, expressed by  tumor cells, to a T-cell and, via its Fc-region, to an accessory cell of the innate immune system, as e.g. macrophages, dendritic or NK cells.

 

The resulting tri-cell-complex triggers multiple immune mechanisms at the same time.  Not only are tumor cells specifically and potently destroyed, but a long-lasting anti-tumor immunity is also induced – an effect that can otherwise only be achieved through vaccination.

Via Krishan Maggon