Immunology and Biotherapies

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

Bispecific T-cell engagers for cancer immunotherapy Nature.com 

 

Abstract

Bispecific T-cell engagers (BiTEs) are a new class of immunotherapeutic molecules intended for the treatment of cancer. These molecules enhance the patient’s immune response to tumors by retargeting T cells to tumor cells. BiTEs are constructed of two single-chain variable fragments (scFv) connected in tandem by a flexible linker. One scFv binds to a T-cell-specific molecule, usually CD3, whereas the second scFv binds to a tumor-associated antigen. This structure and specificity allows a BiTE to physically link a T cell to a tumor cell, ultimately stimulating T-cell activation, tumor killing and cytokine production. BiTEs have been developed, which target several tumor-associated antigens, for a variety of both hematological and solid tumors. Several BiTEs are currently in clinical trials for their therapeutic efficacy and safety. This review examines the salient structural and functional features of BiTEs, as well as the current state of their clinical and preclinical development.

Via Krishan Maggon

Engineered T cell CAR therapy

 

A revolution is taking place in the field of adoptive immunotherapy, where T cells armed with a Chimeric Antigen Receptor (CAR) are being used to fight cancerous cells. Genome engineering is at the heart of this revolution. This groundbreaking technology relies mainly on the use of engineered nucleases and makes it possible to modify the genome of the T cell to give it new properties. Specifically, the engineered T cell can be transformed into an allogeneic product, or it can resist existing cancer treatments or even overcome checkpoint inhibition. Genome engineering is regarded as one of the most important breakthroughs of recent years, and is about to revolutionize immunotherapy. 

Decades of research have shown that it is possible to improve the ability of T cells to fight diseases by genome engineering. For example, T cells can be engineered by adding a new gene (called a chimeric antigen receptor or CAR) that will boost their ability to recognize and destroy cancer cells. Another possibility for T cells is to inactivate an existing gene that damages the immune response.

The possibilities provided by T cell genome engineering are endless. Very sophisticated strategies can be designed at will to open the door for a new era of treatments in indications such as infectious diseases, autoimmune diseases, and cancer.

 

Chimeric Antigen Receptors (CARs) are artificial molecules that, when present at the surface of immune effector cells, will enable them to recognize a desired protein (antigen) and trigger the killing of cells harboring this antigen at their surface (target cells).

These receptors are becoming one of the most promising approaches to fight cancer, through the development of adoptive cell transfer therapies. Indeed, immune cells (most usually T-lymphocytes) can be engineered to express a CAR able to recognize proteins present at the surface of cancer cells. Upon cell-to-cell contact between effector and targeted cells, antigen recognition will activate the effectors, giving them the signal to attack their targets, and leading ultimately to the killing of cancer cells.

CARs are constructed by assembling domains from different proteins, each of which enables the chimeric molecule to carry out specific functions. The most common CAR architecture comprises an extracellular domain containing a region that recognizes the targeted antigen and a spacer region that links it to the transmembrane domain (the part of the protein that spans the cellular membrane). This is then followed by an intracellular domain, responsible for transmitting an activation signal to the cell upon antigen recognition, causing the CAR-engineered cell to attack the tumor cell.

The target-binding moiety is usually derived from an antibody, while the intracellular portion can include, besides the domain leading to cell activation and cytotoxic response, one or more domains from co-stimulatory receptor proteins that could enhance the proliferative capacity and survival of the “therapeutic” cells.

Cellectis is currently developing a collection of CARs targeting antigens present on cells from various types of cancer, as well as a proprietary multi-chain architecture of these artificial receptors, aiming to further increase the efficacy of adoptive cell therapies in the future.

CELLECTIS’ UCART19 RECEIVES ADVANCED-THERAPY MEDICINAL PRODUCT CLASSIFICATION FROM EMAJune 23, 2014

 

READ MORE READ THE PRESS RELEASEPFIZER AND CELLECTIS ENTER INTO GLOBAL STRATEGIC CANCER IMMUNOTHERAPY COLLABORATIONJune 18, 2014 

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

Highlights

 

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The presence of immune infiltrate in tumors has been correlated with a good prognosis following treatment.

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Tumor-infiltrating lymphocytes have been utilized for the treatment of melanoma.

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To broaden this therapy for other cancers, T cells have been genetically modified with either a T cell receptor or a chimeric antigen receptor.

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Potential hurdles and novel strategies will be discussed for realizing the full potential of adoptive immunotherapy becoming a standard of care treatment for cancer.

Via Krishan Maggon

Via Krishan Maggon